Standard cell electrical and physical variability analysis based on automatic physical measurement for design-for-manufacturing purposes

NASA Astrophysics Data System (ADS)

Shauly, Eitan; Parag, Allon; Khmaisy, Hafez; Krispil, Uri; Adan, Ofer; Levi, Shimon; Latinski, Sergey; Schwarzband, Ishai; Rotstein, Israel

2011-04-01

A fully automated system for process variability analysis of high density standard cell was developed. The system consists of layout analysis with device mapping: device type, location, configuration and more. The mapping step was created by a simple DRC run-set. This database was then used as an input for choosing locations for SEM images and for specific layout parameter extraction, used by SPICE simulation. This method was used to analyze large arrays of standard cell blocks, manufactured using Tower TS013LV (Low Voltage for high-speed applications) Platforms. Variability of different physical parameters like and like Lgate, Line-width-roughness and more as well as of electrical parameters like drive current (Ion), off current (Ioff) were calculated and statistically analyzed, in order to understand the variability root cause. Comparison between transistors having the same W/L but with different layout configurations and different layout environments (around the transistor) was made in terms of performances as well as process variability. We successfully defined "robust" and "less-robust" transistors configurations, and updated guidelines for Design-for-Manufacturing (DfM).

Robust, low-noise, polarization-maintaining mode-locked Er-fiber laser with a planar lightwave circuit (PLC) device as a multi-functional element.

PubMed

Kim, Chur; Kwon, Dohyeon; Kim, Dohyun; Choi, Sun Young; Cha, Sang Jun; Choi, Ki Sun; Yeom, Dong-Il; Rotermund, Fabian; Kim, Jungwon

2017-04-15

We demonstrate a new planar lightwave circuit (PLC)-based device, integrated with a 980/1550 wavelength division multiplexer, an evanescent-field-interaction-based saturable absorber, and an output tap coupler, which can be employed as a multi-functional element in mode-locked fiber lasers. Using this multi-functional PLC device, we demonstrate a simple, robust, low-noise, and polarization-maintaining mode-locked Er-fiber laser. The measured full-width at half-maximum bandwidth is 6 nm centered at 1555 nm, corresponding to 217 fs transform-limited pulse duration. The measured RIN and timing jitter are 0.22% [10 Hz-10 MHz] and 6.6 fs [10 kHz-1 MHz], respectively. Our results show that the non-gain section of mode-locked fiber lasers can be easily implemented as a single PLC chip that can be manufactured by a wafer-scale fabrication process. The use of PLC processes in mode-locked lasers has the potential for higher manufacturability of low-cost and robust fiber and waveguide lasers.

Mechanical strength of welding zones produced by material extrusion additive manufacturing.

PubMed

Davis, Chelsea S; Hillgartner, Kaitlyn E; Han, Seung Hoon; Seppala, Jonathan E

2017-08-01

As more manufacturing processes and research institutions adopt customized manufacturing as a key element in their design strategies and finished products, the resulting mechanical properties of parts produced through additive manufacturing (AM) must be characterized and understood. In material extrusion (MatEx), the most recently extruded polymer filament must bond to the previously extruded filament via polymer diffusion to form a "weld". The strength of the weld limits the performance of the manufactured part and is controlled through processing conditions. Under-standing the role of processing conditions, specifically extruder velocity and extruder temperature, on the overall strength of the weld will allow optimization of MatEx-AM parts. Here, the fracture toughness of a single weld is determined through a facile "trouser tear" Mode III fracture experiment. The actual weld thickness is observed directly by optical microscopy characterization of cross sections of MatEx-AM samples. Representative data of weld strength as a function of printing parameters on a commercial 3D printer demonstrates the robustness of the method.

Additively Manufactured IN718 Components with Wirelessly Powered and Interrogated Embedded Sensing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Attridge, Paul; Bajekal, Sanjay; Klecka, Michael

A methodology is described for embedding commercial-off-the-shelf sensors together with wireless communication and power circuit elements using direct laser metal sintered additively manufactured components. Physics based models of the additive manufacturing processes and sensor/wireless level performance models guided the design and embedment processes. A combination of cold spray deposition and laser engineered net shaping was used to fashion the transmitter/receiving elements and embed the sensors, thereby providing environmental protection and component robustness/survivability for harsh conditions. By design, this complement of analog and digital sensors were wirelessly powered and interrogated using a health and utilization monitoring system; enabling real-time, in situmore » prognostics and diagnostics.« less

Evolving trends in mAb production processes

PubMed Central

Wolfe, Leslie S.; Mostafa, Sigma S.; Norman, Carnley

2017-01-01

Abstract Monoclonal antibodies (mAbs) have established themselves as the leading biopharmaceutical therapeutic modality. The establishment of robust manufacturing platforms are key for antibody drug discovery efforts to seamlessly translate into clinical and commercial successes. Several drivers are influencing the design of mAb manufacturing processes. The advent of biosimilars is driving a desire to achieve lower cost of goods and globalize biologics manufacturing. High titers are now routinely achieved for mAbs in mammalian cell culture. These drivers have resulted in significant evolution in process platform approaches. Additionally, several new trends in bioprocessing have arisen in keeping with these needs. These include the consideration of alternative expression systems, continuous biomanufacturing and non‐chromatographic separation formats. This paper discusses these drivers in the context of the kinds of changes they are driving in mAb production processes. PMID:29313024

Stochastic simulation and robust design optimization of integrated photonic filters

NASA Astrophysics Data System (ADS)

Weng, Tsui-Wei; Melati, Daniele; Melloni, Andrea; Daniel, Luca

2017-01-01

Manufacturing variations are becoming an unavoidable issue in modern fabrication processes; therefore, it is crucial to be able to include stochastic uncertainties in the design phase. In this paper, integrated photonic coupled ring resonator filters are considered as an example of significant interest. The sparsity structure in photonic circuits is exploited to construct a sparse combined generalized polynomial chaos model, which is then used to analyze related statistics and perform robust design optimization. Simulation results show that the optimized circuits are more robust to fabrication process variations and achieve a reduction of 11%-35% in the mean square errors of the 3 dB bandwidth compared to unoptimized nominal designs.

Robust, optimal subsonic airfoil shapes

NASA Technical Reports Server (NTRS)

Rai, Man Mohan (Inventor)

2008-01-01

Method system, and product from application of the method, for design of a subsonic airfoil shape, beginning with an arbitrary initial airfoil shape and incorporating one or more constraints on the airfoil geometric parameters and flow characteristics. The resulting design is robust against variations in airfoil dimensions and local airfoil shape introduced in the airfoil manufacturing process. A perturbation procedure provides a class of airfoil shapes, beginning with an initial airfoil shape.

Optimum Design of Forging Process Parameters and Preform Shape under Uncertainties

NASA Astrophysics Data System (ADS)

Repalle, Jalaja; Grandhi, Ramana V.

2004-06-01

Forging is a highly complex non-linear process that is vulnerable to various uncertainties, such as variations in billet geometry, die temperature, material properties, workpiece and forging equipment positional errors and process parameters. A combination of these uncertainties could induce heavy manufacturing losses through premature die failure, final part geometric distortion and production risk. Identifying the sources of uncertainties, quantifying and controlling them will reduce risk in the manufacturing environment, which will minimize the overall cost of production. In this paper, various uncertainties that affect forging tool life and preform design are identified, and their cumulative effect on the forging process is evaluated. Since the forging process simulation is computationally intensive, the response surface approach is used to reduce time by establishing a relationship between the system performance and the critical process design parameters. Variability in system performance due to randomness in the parameters is computed by applying Monte Carlo Simulations (MCS) on generated Response Surface Models (RSM). Finally, a Robust Methodology is developed to optimize forging process parameters and preform shape. The developed method is demonstrated by applying it to an axisymmetric H-cross section disk forging to improve the product quality and robustness.

Scaleable processes for the manufacture of therapeutic quantities of plasmid DNA.

PubMed

Shamlou, Parviz Ayazi

2003-06-01

The need for scaleable processes to manufacture therapeutic plasmid DNA (pDNA) is easy to overlook when attention is focused primarily on vector design and establishment of early clinical results. pDNA is a large molecule and has properties that are similar to those of the contaminating chromosomal DNA. These, combined with the low initial concentration of plasmids in the host cell, provide unique process challenges that require significant upfront design to establish robust manufacturing processes that can also comply with current Good Manufacturing Practice ('cGMP') and produce milligram-to-kilogram quantities of pDNA product. This review describes promising scaleable processes that are currently being assessed for production of therapeutic supercoiled pDNA. Fermentation strategies for improving supercoiled plasmid yield and reducing contaminant concentrations are reviewed, and downstream processes are assessed for their ability to efficiently remove cellular contaminants, separate the supercoiled form of the pDNA from its open circular and linear forms, and prepare the purified drug substance for formulation. Current strategies are presented for developing stable delivery systems, and approaches to quality assurance and quality control are discussed.

Six sigma: process of understanding the control and capability of ranitidine hydrochloride tablet.

PubMed

Chabukswar, Ar; Jagdale, Sc; Kuchekar, Bs; Joshi, Vd; Deshmukh, Gr; Kothawade, Hs; Kuckekar, Ab; Lokhande, Pd

2011-01-01

The process of understanding the control and capability (PUCC) is an iterative closed loop process for continuous improvement. It covers the DMAIC toolkit in its three phases. PUCC is an iterative approach that rotates between the three pillars of the process of understanding, process control, and process capability, with each iteration resulting in a more capable and robust process. It is rightly said that being at the top is a marathon and not a sprint. The objective of the six sigma study of Ranitidine hydrochloride tablets is to achieve perfection in tablet manufacturing by reviewing the present robust manufacturing process, to find out ways to improve and modify the process, which will yield tablets that are defect-free and will give more customer satisfaction. The application of six sigma led to an improved process capability, due to the improved sigma level of the process from 1.5 to 4, a higher yield, due to reduced variation and reduction of thick tablets, reduction in packing line stoppages, reduction in re-work by 50%, a more standardized process, with smooth flow and change in coating suspension reconstitution level (8%w/w), a huge cost reduction of approximately Rs.90 to 95 lakhs per annum, an improved overall efficiency by 30% approximately, and improved overall quality of the product.

Six Sigma: Process of Understanding the Control and Capability of Ranitidine Hydrochloride Tablet

PubMed Central

Chabukswar, AR; Jagdale, SC; Kuchekar, BS; Joshi, VD; Deshmukh, GR; Kothawade, HS; Kuckekar, AB; Lokhande, PD

2011-01-01

The process of understanding the control and capability (PUCC) is an iterative closed loop process for continuous improvement. It covers the DMAIC toolkit in its three phases. PUCC is an iterative approach that rotates between the three pillars of the process of understanding, process control, and process capability, with each iteration resulting in a more capable and robust process. It is rightly said that being at the top is a marathon and not a sprint. The objective of the six sigma study of Ranitidine hydrochloride tablets is to achieve perfection in tablet manufacturing by reviewing the present robust manufacturing process, to find out ways to improve and modify the process, which will yield tablets that are defect-free and will give more customer satisfaction. The application of six sigma led to an improved process capability, due to the improved sigma level of the process from 1.5 to 4, a higher yield, due to reduced variation and reduction of thick tablets, reduction in packing line stoppages, reduction in re-work by 50%, a more standardized process, with smooth flow and change in coating suspension reconstitution level (8%w/w), a huge cost reduction of approximately Rs.90 to 95 lakhs per annum, an improved overall efficiency by 30% approximately, and improved overall quality of the product. PMID:21607050

Prepreg effects on honeycomb composite manufacturing

NASA Astrophysics Data System (ADS)

Martin, Cary Joseph

Fiber reinforced composites offer many advantages over traditional materials and are widely utilized in aerospace applications. Advantages include a high stiffness to weight ratio and excellent fatigue resistance. However, the pace of new implementation is slow. The manufacturing processes used to transform composite intermediates into final products are poorly understood and are a source of much variability. This limits new implementation and increases the manufacturing costs of existing designs. One such problem is honeycomb core crush, in which a core-stiffened structure collapses during autoclave manufacture, making the structure unusable and increasing the overall manufacturing cost through increased scrap rates. Consequently, the major goal of this research was to investigate the scaling of core crush from prepreg process-structure-property relations to commercial composite manufacture. The material dependent nature of this defect was of particular interest. A methodology and apparatus were developed to measure the frictional resistance of prepreg materials under typical processing conditions. Through a characterization of commercial and experimental prepregs, it was found that core crush behavior was the result of differences in prepreg frictional resistance. This frictional resistance was related to prepreg morphology and matrix rheology and elasticity. Resin composition and prepreg manufacturing conditions were also found to affect manufacturing behavior. Mechanical and dimensional models were developed and demonstrated utility for predicting this crushing behavior. Collectively, this work explored and identified the process-structure-property relations as they relate to the manufacture of composite materials and suggested several avenues by which manufacturing-robust materials may be developed.

Design of forging process variables under uncertainties

NASA Astrophysics Data System (ADS)

Repalle, Jalaja; Grandhi, Ramana V.

2005-02-01

Forging is a complex nonlinear process that is vulnerable to various manufacturing anomalies, such as variations in billet geometry, billet/die temperatures, material properties, and workpiece and forging equipment positional errors. A combination of these uncertainties could induce heavy manufacturing losses through premature die failure, final part geometric distortion, and reduced productivity. Identifying, quantifying, and controlling the uncertainties will reduce variability risk in a manufacturing environment, which will minimize the overall production cost. In this article, various uncertainties that affect the forging process are identified, and their cumulative effect on the forging tool life is evaluated. Because the forging process simulation is time-consuming, a response surface model is used to reduce computation time by establishing a relationship between the process performance and the critical process variables. A robust design methodology is developed by incorporating reliability-based optimization techniques to obtain sound forging components. A case study of an automotive-component forging-process design is presented to demonstrate the applicability of the method.

In-line ATR-UV and Raman Spectroscopy for Monitoring API Dissolution Process During Liquid-Filled Soft-Gelatin Capsule Manufacturing.

PubMed

Wan, Boyong; Zordan, Christopher A; Lu, Xujin; McGeorge, Gary

2016-10-01

Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturing of liquid-filled soft-gelatin capsules (SGC). Attenuated total reflectance UV spectroscopy (ATR-UV) and Raman spectroscopy have been investigated for in-line monitoring of API dissolution during manufacturing of an SGC product. Calibration models have been developed with both techniques for in-line determination of API potency. Performance of both techniques was evaluated and compared. The ATR-UV methodology was found to be able to monitor the dissolution process and determine the endpoint, but was sensitive to temperature variations. The Raman technique was also capable of effectively monitoring the process and was more robust to the temperature variation and process perturbations by using an excipient peak for internal correction. Different data preprocessing methodologies were explored in an attempt to improve method performance.

Process and product development in the manufacturing of molecular therapeutics.

PubMed

Atkinson, E M; Christensen, J R

1999-08-01

In the development of molecular therapies, a great deal of attention has focused on tissue targets, gene delivery vectors, and expression cassettes. In order to become an approved therapy, however, a molecular therapeutic has to pass down the same product registration pathway as any other biological product. Moving from research into industrial production requires careful attention to regulatory, manufacturing and quality concerns. Early work on developing and characterizing robust and scaleable manufacturing processes will ultimately be rewarded by ease of implementation as the product is successful in clinical trials. Regulatory agencies require solid process and product characterization studies to demonstrate control and understanding of the molecular therapeutic. As the gene therapy industry matures, standards will continue to rise, creating an industry that is capable of producing safe, high-quality and effective therapies for many of the world's most difficult disease targets.

Application of Fourier transform near-infrared spectroscopy to optimization of green tea steaming process conditions.

PubMed

Ono, Daiki; Bamba, Takeshi; Oku, Yuichi; Yonetani, Tsutomu; Fukusaki, Eiichiro

2011-09-01

In this study, we constructed prediction models by metabolic fingerprinting of fresh green tea leaves using Fourier transform near-infrared (FT-NIR) spectroscopy and partial least squares (PLS) regression analysis to objectively optimize of the steaming process conditions in green tea manufacture. The steaming process is the most important step for manufacturing high quality green tea products. However, the parameter setting of the steamer is currently determined subjectively by the manufacturer. Therefore, a simple and robust system that can be used to objectively set the steaming process parameters is necessary. We focused on FT-NIR spectroscopy because of its simple operation, quick measurement, and low running costs. After removal of noise in the spectral data by principal component analysis (PCA), PLS regression analysis was performed using spectral information as independent variables, and the steaming parameters set by experienced manufacturers as dependent variables. The prediction models were successfully constructed with satisfactory accuracy. Moreover, the results of the demonstrated experiment suggested that the green tea steaming process parameters could be predicted on a larger manufacturing scale. This technique will contribute to improvement of the quality and productivity of green tea because it can objectively optimize the complicated green tea steaming process and will be suitable for practical use in green tea manufacture. Copyright © 2011 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Towards a manufacturing ecosystem for integrated photonic sensors (Conference Presentation)

NASA Astrophysics Data System (ADS)

Miller, Benjamin L.

2017-03-01

Laboratory-scale demonstrations of optical biosensing employing structures compatible with CMOS fabrication, including waveguides, Mach-Zehnder interferometers, ring resonators, and photonic crystals, have provided ample validation of the promise of these technologies. However, to date there are relatively few examples of integrated photonic biosensors in the commercial sphere. The lack of successful translation from the laboratory to the marketplace is due in part to a lack of robust manufacturing processes for integrated photonics overall. This talk will describe efforts within the American Institute for Manufacturing Photonics (AIM Photonics), a public-private consortium funded by the Department of Defense, State governments, Universities, and Corporate partners to accelerate manufacturing of integrated photonic sensors.

[INVITED] Computational intelligence for smart laser materials processing

NASA Astrophysics Data System (ADS)

Casalino, Giuseppe

2018-03-01

Computational intelligence (CI) involves using a computer algorithm to capture hidden knowledge from data and to use them for training ;intelligent machine; to make complex decisions without human intervention. As simulation is becoming more prevalent from design and planning to manufacturing and operations, laser material processing can also benefit from computer generating knowledge through soft computing. This work is a review of the state-of-the-art on the methodology and applications of CI in laser materials processing (LMP), which is nowadays receiving increasing interest from world class manufacturers and 4.0 industry. The focus is on the methods that have been proven effective and robust in solving several problems in welding, cutting, drilling, surface treating and additive manufacturing using the laser beam. After a basic description of the most common computational intelligences employed in manufacturing, four sections, namely, laser joining, machining, surface, and additive covered the most recent applications in the already extensive literature regarding the CI in LMP. Eventually, emerging trends and future challenges were identified and discussed.

Validation of the manufacturing process used to produce long-acting recombinant factor IX Fc fusion protein

PubMed Central

McCue, J; Osborne, D; Dumont, J; Peters, R; Mei, B; Pierce, G F; Kobayashi, K; Euwart, D

2014-01-01

Recombinant factor IX Fc (rFIXFc) fusion protein is the first of a new class of bioengineered long-acting factors approved for the treatment and prevention of bleeding episodes in haemophilia B. The aim of this work was to describe the manufacturing process for rFIXFc, to assess product quality and to evaluate the capacity of the process to remove impurities and viruses. This manufacturing process utilized a transferable and scalable platform approach established for therapeutic antibody manufacturing and adapted for production of the rFIXFc molecule. rFIXFc was produced using a process free of human- and animal-derived raw materials and a host cell line derived from human embryonic kidney (HEK) 293H cells. The process employed multi-step purification and viral clearance processing, including use of a protein A affinity capture chromatography step, which binds to the Fc portion of the rFIXFc molecule with high affinity and specificity, and a 15 nm pore size virus removal nanofilter. Process validation studies were performed to evaluate identity, purity, activity and safety. The manufacturing process produced rFIXFc with consistent product quality and high purity. Impurity clearance validation studies demonstrated robust and reproducible removal of process-related impurities and adventitious viruses. The rFIXFc manufacturing process produces a highly pure product, free of non-human glycan structures. Validation studies demonstrate that this product is produced with consistent quality and purity. In addition, the scalability and transferability of this process are key attributes to ensure consistent and continuous supply of rFIXFc. PMID:24811361

Process Analytical Technology (PAT): batch-to-batch reproducibility of fermentation processes by robust process operational design and control.

PubMed

Gnoth, S; Jenzsch, M; Simutis, R; Lübbert, A

2007-10-31

The Process Analytical Technology (PAT) initiative of the FDA is a reaction on the increasing discrepancy between current possibilities in process supervision and control of pharmaceutical production processes and its current application in industrial manufacturing processes. With rigid approval practices based on standard operational procedures, adaptations of production reactors towards the state of the art were more or less inhibited for long years. Now PAT paves the way for continuous process and product improvements through improved process supervision based on knowledge-based data analysis, "Quality-by-Design"-concepts, and, finally, through feedback control. Examples of up-to-date implementations of this concept are presented. They are taken from one key group of processes in recombinant pharmaceutical protein manufacturing, the cultivations of genetically modified Escherichia coli bacteria.

Gaussian process-based surrogate modeling framework for process planning in laser powder-bed fusion additive manufacturing of 316L stainless steel

DOE PAGES

Tapia, Gustavo; Khairallah, Saad A.; Matthews, Manyalibo J.; ...

2017-09-22

Here, Laser Powder-Bed Fusion (L-PBF) metal-based additive manufacturing (AM) is complex and not fully understood. Successful processing for one material, might not necessarily apply to a different material. This paper describes a workflow process that aims at creating a material data sheet standard that describes regimes where the process can be expected to be robust. The procedure consists of building a Gaussian process-based surrogate model of the L-PBF process that predicts melt pool depth in single-track experiments given a laser power, scan speed, and laser beam size combination. The predictions are then mapped onto a power versus scan speed diagrammore » delimiting the conduction from the keyhole melting controlled regimes. This statistical framework is shown to be robust even for cases where experimental training data might be suboptimal in quality, if appropriate physics-based filters are applied. Additionally, it is demonstrated that a high-fidelity simulation model of L-PBF can equally be successfully used for building a surrogate model, which is beneficial since simulations are getting more efficient and are more practical to study the response of different materials, than to re-tool an AM machine for new material powder.« less

Gaussian process-based surrogate modeling framework for process planning in laser powder-bed fusion additive manufacturing of 316L stainless steel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tapia, Gustavo; Khairallah, Saad A.; Matthews, Manyalibo J.

Here, Laser Powder-Bed Fusion (L-PBF) metal-based additive manufacturing (AM) is complex and not fully understood. Successful processing for one material, might not necessarily apply to a different material. This paper describes a workflow process that aims at creating a material data sheet standard that describes regimes where the process can be expected to be robust. The procedure consists of building a Gaussian process-based surrogate model of the L-PBF process that predicts melt pool depth in single-track experiments given a laser power, scan speed, and laser beam size combination. The predictions are then mapped onto a power versus scan speed diagrammore » delimiting the conduction from the keyhole melting controlled regimes. This statistical framework is shown to be robust even for cases where experimental training data might be suboptimal in quality, if appropriate physics-based filters are applied. Additionally, it is demonstrated that a high-fidelity simulation model of L-PBF can equally be successfully used for building a surrogate model, which is beneficial since simulations are getting more efficient and are more practical to study the response of different materials, than to re-tool an AM machine for new material powder.« less

A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms.

PubMed

Leane, Michael; Pitt, Kendal; Reynolds, Gavin

2015-01-01

This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the "right particles" are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience. This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.

Nanoband array electrode as a platform for high sensitivity enzyme-based glucose biosensing.

PubMed

Falk, Magnus; Sultana, Reshma; Swann, Marcus J; Mount, Andrew R; Freeman, Neville J

2016-12-01

We describe a novel glucose biosensor based on a nanoband array electrode design, manufactured using standard semiconductor processing techniques, and bio-modified with glucose oxidase immobilized at the nanoband electrode surface. The nanoband array architecture allows for efficient diffusion of glucose and oxygen to the electrode, resulting in a thousand-fold improvement in sensitivity and wide linear range compared to a conventional electrode. The electrode constitutes a robust and manufacturable sensing platform. Copyright © 2016 Elsevier B.V. All rights reserved.

Advanced metrology by offline SEM data processing

NASA Astrophysics Data System (ADS)

Lakcher, Amine; Schneider, Loïc.; Le-Gratiet, Bertrand; Ducoté, Julien; Farys, Vincent; Besacier, Maxime

2017-06-01

Today's technology nodes contain more and more complex designs bringing increasing challenges to chip manufacturing process steps. It is necessary to have an efficient metrology to assess process variability of these complex patterns and thus extract relevant data to generate process aware design rules and to improve OPC models. Today process variability is mostly addressed through the analysis of in-line monitoring features which are often designed to support robust measurements and as a consequence are not always very representative of critical design rules. CD-SEM is the main CD metrology technique used in chip manufacturing process but it is challenged when it comes to measure metrics like tip to tip, tip to line, areas or necking in high quantity and with robustness. CD-SEM images contain a lot of information that is not always used in metrology. Suppliers have provided tools that allow engineers to extract the SEM contours of their features and to convert them into a GDS. Contours can be seen as the signature of the shape as it contains all the dimensional data. Thus the methodology is to use the CD-SEM to take high quality images then generate SEM contours and create a data base out of them. Contours are used to feed an offline metrology tool that will process them to extract different metrics. It was shown in two previous papers that it is possible to perform complex measurements on hotspots at different process steps (lithography, etch, copper CMP) by using SEM contours with an in-house offline metrology tool. In the current paper, the methodology presented previously will be expanded to improve its robustness and combined with the use of phylogeny to classify the SEM images according to their geometrical proximities.

Bivalent rLP2086 (Trumenba®): Development of a well-characterized vaccine through commercialization.

PubMed

Sunasara, Khurram; Cundy, John; Srinivasan, Sriram; Evans, Brad; Sun, Weiqiang; Cook, Scott; Bortell, Eric; Farley, John; Griffin, Daniel; Bailey Piatchek, Michele; Arch-Douglas, Katherine

2018-05-24

The phrase "Process is the Product" is often applied to biologics, including multicomponent vaccines composed of complex components that evade complete characterization. Vaccine production processes must be defined and locked early in the development cycle to ensure consistent quality of the vaccine throughout scale-up, clinical studies, and commercialization. This approach of front-loading the development work helped facilitate the accelerated approval of the Biologic License Application for the well-characterized vaccine bivalent rLP2086 (Trumenba®, Pfizer Inc) in 2014 under Breakthrough Therapy Designation. Bivalent rLP2086 contains two rLP2086 antigens and is licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B in individuals 10-25years of age in the United States. This paper discusses the development of the manufacturing process of the two antigens for the purpose of making it amenable to any manufacturing facility. For the journey to commercialization, the operating model used to manage this highly accelerated program led to a framework that ensured "right the first time" execution, robust process characterization, and proactive process monitoring. This framework enabled quick problem identification and proactive resolutions, resulting in a robust control strategy for the commercial process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemistry, manufacturing and controls in passive transdermal drug delivery systems.

PubMed

Goswami, Tarun; Audett, Jay

2015-01-01

Transdermal drug delivery systems (TDDS) are used for the delivery of the drugs through the skin into the systemic circulation by applying them to the intact skin. The development of TDDS is a complex and multidisciplinary affair which involves identification of suitable drug, excipients and various other components. There have been numerous problems reported with respect to TDDS quality and performance. These problems can be reduced by appropriately addressing chemistry, manufacturing and controls requirements, which would thereby result in development of robust TDDS product and processes. This article provides recommendations on the chemistry, manufacturing and controls focusing on the unique technical aspects of TDDS.

Manufacturing plastic injection optical molds

NASA Astrophysics Data System (ADS)

Bourque, David

2008-08-01

ABCO Tool & Die, Inc. is a mold manufacturer specializing in the manufacturing of plastic injection molds for molded optical parts. The purpose of this presentation is to explain the concepts and procedures required to build a mold that produces precision optical parts. Optical molds can produce a variety of molded parts ranging from safety eyewear to sophisticated military lens parts, which must meet precise optical specifications. The manufacturing of these molds begins with the design engineering of precision optical components. The mold design and the related optical inserts are determined based upon the specific optical criteria and optical surface geometry. The mold manufacturing techniques will be based upon the optical surface geometry requirements and specific details. Manufacturing processes used will be specific to prescribed geometrical surface requirements of the molded part. The combined efforts result in a robust optical mold which can produce molded parts that meet the most precise optical specifications.

Application of quality by design principles to the development and technology transfer of a major process improvement for the manufacture of a recombinant protein.

PubMed

Looby, Mairead; Ibarra, Neysi; Pierce, James J; Buckley, Kevin; O'Donovan, Eimear; Heenan, Mary; Moran, Enda; Farid, Suzanne S; Baganz, Frank

2011-01-01

This study describes the application of quality by design (QbD) principles to the development and implementation of a major manufacturing process improvement for a commercially distributed therapeutic protein produced in Chinese hamster ovary cell culture. The intent of this article is to focus on QbD concepts, and provide guidance and understanding on how the various components combine together to deliver a robust process in keeping with the principles of QbD. A fed-batch production culture and a virus inactivation step are described as representative examples of upstream and downstream unit operations that were characterized. A systematic approach incorporating QbD principles was applied to both unit operations, involving risk assessment of potential process failure points, small-scale model qualification, design and execution of experiments, definition of operating parameter ranges and process validation acceptance criteria followed by manufacturing-scale implementation and process validation. Statistical experimental designs were applied to the execution of process characterization studies evaluating the impact of operating parameters on product quality attributes and process performance parameters. Data from process characterization experiments were used to define the proven acceptable range and classification of operating parameters for each unit operation. Analysis of variance and Monte Carlo simulation methods were used to assess the appropriateness of process design spaces. Successful implementation and validation of the process in the manufacturing facility and the subsequent manufacture of hundreds of batches of this therapeutic protein verifies the approaches taken as a suitable model for the development, scale-up and operation of any biopharmaceutical manufacturing process. Copyright © 2011 American Institute of Chemical Engineers (AIChE).

Validation of the manufacturing process used to produce long-acting recombinant factor IX Fc fusion protein.

PubMed

McCue, J; Osborne, D; Dumont, J; Peters, R; Mei, B; Pierce, G F; Kobayashi, K; Euwart, D

2014-07-01

Recombinant factor IX Fc (rFIXFc) fusion protein is the first of a new class of bioengineered long-acting factors approved for the treatment and prevention of bleeding episodes in haemophilia B. The aim of this work was to describe the manufacturing process for rFIXFc, to assess product quality and to evaluate the capacity of the process to remove impurities and viruses. This manufacturing process utilized a transferable and scalable platform approach established for therapeutic antibody manufacturing and adapted for production of the rFIXFc molecule. rFIXFc was produced using a process free of human- and animal-derived raw materials and a host cell line derived from human embryonic kidney (HEK) 293H cells. The process employed multi-step purification and viral clearance processing, including use of a protein A affinity capture chromatography step, which binds to the Fc portion of the rFIXFc molecule with high affinity and specificity, and a 15 nm pore size virus removal nanofilter. Process validation studies were performed to evaluate identity, purity, activity and safety. The manufacturing process produced rFIXFc with consistent product quality and high purity. Impurity clearance validation studies demonstrated robust and reproducible removal of process-related impurities and adventitious viruses. The rFIXFc manufacturing process produces a highly pure product, free of non-human glycan structures. Validation studies demonstrate that this product is produced with consistent quality and purity. In addition, the scalability and transferability of this process are key attributes to ensure consistent and continuous supply of rFIXFc. © 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Robustness analysis of non-ordinary Petri nets for flexible assembly/disassembly processes based on structural decomposition

NASA Astrophysics Data System (ADS)

Hsieh, Fu-Shiung

2011-03-01

Design of robust supervisory controllers for manufacturing systems with unreliable resources has received significant attention recently. Robustness analysis provides an alternative way to analyse a perturbed system to quickly respond to resource failures. Although we have analysed the robustness properties of several subclasses of ordinary Petri nets (PNs), analysis for non-ordinary PNs has not been done. Non-ordinary PNs have weighted arcs and have the advantage to compactly model operations requiring multiple parts or resources. In this article, we consider a class of flexible assembly/disassembly manufacturing systems and propose a non-ordinary flexible assembly/disassembly Petri net (NFADPN) model for this class of systems. As the class of flexible assembly/disassembly manufacturing systems can be regarded as the integration and interactions of a set of assembly/disassembly subprocesses, a bottom-up approach is adopted in this article to construct the NFADPN models. Due to the routing flexibility in NFADPN, there may exist different ways to accomplish the tasks. To characterise different ways to accomplish the tasks, we propose the concept of completely connected subprocesses. As long as there exists a set of completely connected subprocesses for certain type of products, the production of that type of products can still be maintained without requiring the whole NFADPN to be live. To take advantage of the alternative routes without enforcing liveness for the whole system, we generalise the concept of persistent production proposed to NFADPN. We propose a condition for persistent production based on the concept of completely connected subprocesses. We extend robustness analysis to NFADPN by exploiting its structure. We identify several patterns of resource failures and characterise the conditions to maintain operation in the presence of resource failures.

A thematic analysis of the strengths and weaknesses of manufacturers' submissions to the NICE Single Technology Assessment (STA) process.

PubMed

Carroll, Christopher; Kaltenthaler, Eva; FitzGerald, Patrick; Boland, Angela; Dickson, Rumona

2011-10-01

The NICE Single Technology Appraisal (STA) process in the UK has been underway for five years. Evidence Review Groups (ERGs) critically appraise submissions from manufacturers on the clinical and cost effectiveness of new technologies. This study analysed the ERGs' assessment of the strengths and weaknesses of 30 manufacturers' submissions to the STA process. Thematic analysis was performed on the textual descriptions of the strengths and weakness of manufacturer submissions, as outlined by the ERGs in their reports. Various themes emerged from the data. These themes related to the processes applied in the submissions; the content of the submission (e.g. the amount and quality of evidence); the reporting of the submissions' review and analysis processes; the reliability and validity of the submissions' findings; and how far the submission had satisfied the STA process objectives. STA submissions could be improved if attention were paid to transparency in the reporting, conduct and justification of review and modelling processes and analyses, as well as greater robustness in the choice of data and closer adherence to the scope or decision problem. Where this adherence is not possible, more detailed justification of the choice of evidence or data is required. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Robustness

NASA Astrophysics Data System (ADS)

Ryan, R.

1993-03-01

Robustness is a buzz word common to all newly proposed space systems design as well as many new commercial products. The image that one conjures up when the word appears is a 'Paul Bunyon' (lumberjack design), strong and hearty; healthy with margins in all aspects of the design. In actuality, robustness is much broader in scope than margins, including such factors as simplicity, redundancy, desensitization to parameter variations, control of parameter variations (environments flucation), and operational approaches. These must be traded with concepts, materials, and fabrication approaches against the criteria of performance, cost, and reliability. This includes manufacturing, assembly, processing, checkout, and operations. The design engineer or project chief is faced with finding ways and means to inculcate robustness into an operational design. First, however, be sure he understands the definition and goals of robustness. This paper will deal with these issues as well as the need for the requirement for robustness.

Robustness

NASA Technical Reports Server (NTRS)

Ryan, R.

1993-01-01

Robustness is a buzz word common to all newly proposed space systems design as well as many new commercial products. The image that one conjures up when the word appears is a 'Paul Bunyon' (lumberjack design), strong and hearty; healthy with margins in all aspects of the design. In actuality, robustness is much broader in scope than margins, including such factors as simplicity, redundancy, desensitization to parameter variations, control of parameter variations (environments flucation), and operational approaches. These must be traded with concepts, materials, and fabrication approaches against the criteria of performance, cost, and reliability. This includes manufacturing, assembly, processing, checkout, and operations. The design engineer or project chief is faced with finding ways and means to inculcate robustness into an operational design. First, however, be sure he understands the definition and goals of robustness. This paper will deal with these issues as well as the need for the requirement for robustness.

The fallacy of the overhead quick fix.

PubMed

Blaxill, M F; Hout, T M

1991-01-01

Facing pressure from a few large, low-cost competitors, Thornton, an old-guard specialty-equipment manufacturer, fought back by eliminating overhead. Over two-years, it outsourced components and consolidated operations. But instead of cutting overhead, it added more and became still more uncompetitive. Thornton is not alone in either its predicament or its failed reaction. Many large manufacturing companies are finding themselves at a cost disadvantage in markets they have dominated for years. One reason is excessive overhead structures, the result of an unchecked buildup of indirect employees needed to control rising organizational complexity. Another reason is the emergence of the "robust" competitor, comparable in size and product scope but able to produce at a lower unit overhead cost. Data collected from more than 100 manufacturing plants worldwide illustrate the differences between overhead cost structures of bureaucratic, niche, and robust companies. The gulf between these groups highlights the need for action by bureaucratic companies, and, in some cases, by niche companies. But high-overhead companies are doomed if they cut overhead out of the system either by outsourcing or downsizing. If they expect to retain their size and also become more cost competitive, they must rethink their manufacturing systems. Well-designed and well-controlled processes mean higher product quality, faster cycle time, improved flexibility, and lower overhead costs. Sustainable overhead reduction means a commitment to continuous improvement. This includes segmenting, mapping, and measuring existing processes and then working to improve them.(ABSTRACT TRUNCATED AT 250 WORDS)

Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression.

PubMed

Chattoraj, Sayantan; Sun, Changquan Calvin

2018-04-01

Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Development and validation of an affinity chromatography step using a peptide ligand for cGMP production of factor VIII.

PubMed

Kelley, Brian D; Tannatt, Molly; Magnusson, Robert; Hagelberg, Sigrid; Booth, James

2004-08-05

An affinity chromatography step was developed for purification of recombinant B-Domain Deleted Factor VIII (BDDrFVIII) using a peptide ligand selected from a phage display library. The peptide library had variegated residues, contained both within a disulfide bond-constrained ring and flanking the ring. The peptide ligand binds to BDDrFVIII with a dissociation constant of approximately 1 microM both in free solution and when immobilized on a chromatographic resin. The peptide is chemically synthesized and the affinity resin is produced by coupling the peptide to an agarose matrix preactivated with N-hydroxysuccinimide. Coupling conditions were optimized to give consistent and complete ligand incorporation and validated with a robustness study that tested various combinations of processing limits. The peptide affinity chromatographic operation employs conditions very similar to an immunoaffinity chromatography step currently in use for BDDrFVIII manufacture. The process step provides excellent recovery of BDDrFVIII from a complex feed stream and reduces host cell protein and DNA by 3-4 logs. Process validation studies established resin reuse over 26 cycles without changes in product recovery or purity. A robustness study using a factorial design was performed and showed that the step was insensitive to small changes in process conditions that represent normal variation in commercial manufacturing. A scaled-down model of the process step was qualified and used for virus removal studies. A validation package addressing the safety of the leached peptide included leaching rate measurements under process conditions, testing of peptide levels in product pools, demonstration of robust removal downstream by spiking studies, end product testing, and toxicological profiling of the ligand. The peptide ligand affinity step was scaled up for cGMP production of BDDrFVIII for clinical trials.

Virtual aluminum castings: An industrial application of ICME

NASA Astrophysics Data System (ADS)

Allison, John; Li, Mei; Wolverton, C.; Su, Xuming

2006-11-01

The automotive product design and manufacturing community is continually besieged by Hercule an engineering, timing, and cost challenges. Nowhere is this more evident than in the development of designs and manufacturing processes for cast aluminum engine blocks and cylinder heads. Increasing engine performance requirements coupled with stringent weight and packaging constraints are pushing aluminum alloys to the limits of their capabilities. To provide high-quality blocks and heads at the lowest possible cost, manufacturing process engineers are required to find increasingly innovative ways to cast and heat treat components. Additionally, to remain competitive, products and manufacturing methods must be developed and implemented in record time. To bridge the gaps between program needs and engineering reality, the use of robust computational models in up-front analysis will take on an increasingly important role. This article describes just such a computational approach, the Virtual Aluminum Castings methodology, which was developed and implemented at Ford Motor Company and demonstrates the feasibility and benefits of integrated computational materials engineering.

An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies.

PubMed

Morar-Mitrica, Sorina; Adams, Monica L; Crotts, George; Wurth, Christine; Ihnat, Peter M; Tabish, Tanvir; Antochshuk, Valentyn; DiLuzio, Willow; Dix, Daniel B; Fernandez, Jason E; Gupta, Kapil; Fleming, Michael S; He, Bing; Kranz, James K; Liu, Dingjiang; Narasimhan, Chakravarthy; Routhier, Eric; Taylor, Katherine D; Truong, Nobel; Stokes, Elaine S E

2018-02-01

The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product and process knowledge. The BPDG-Formulation Point Share discusses identified industry challenges with regard to biopharmaceutical DP robustness and presents some recommendations for best practices. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Critical Needs for Robust and Reliable Database for Design and Manufacturing of Ceramic Matrix Composites

NASA Technical Reports Server (NTRS)

Singh, M.

1999-01-01

Ceramic matrix composite (CMC) components are being designed, fabricated, and tested for a number of high temperature, high performance applications in aerospace and ground based systems. The critical need for and the role of reliable and robust databases for the design and manufacturing of ceramic matrix composites are presented. A number of issues related to engineering design, manufacturing technologies, joining, and attachment technologies, are also discussed. Examples of various ongoing activities in the area of composite databases. designing to codes and standards, and design for manufacturing are given.

Bioelectrochemical Integration of Waste Heat Recovery, Waste-to- Energy Conversion, and Waste-to-Chemical Conversion with Industrial Gas and Chemical Manufacturing Processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mac Dougall, James

2016-02-05

Many U.S. manufacturing facilities generate unrecovered, low-grade waste heat, and also generate or are located near organic-content waste effluents. Bioelectrochemical systems, such as microbial fuel cells and microbial electrolysis cells, provide a means to convert organic-content effluents into electric power and useful chemical products. A novel biochemical electrical system for industrial manufacturing processes uniquely integrates both waste heat recovery and waste effluent conversion, thereby significantly reducing manufacturing energy requirements. This project will enable the further development of this technology so that it can be applied across a wide variety of US manufacturing segments, including the chemical, food, pharmaceutical, refinery, andmore » pulp and paper industries. It is conservatively estimated that adoption of this technology could provide nearly 40 TBtu/yr of energy, or more than 1% of the U.S. total industrial electricity use, while reducing CO 2 emissions by more than 6 million tons per year. Commercialization of this technology will make a significant contribution to DOE’s Industrial Technology Program goals for doubling energy efficiency and providing a more robust and competitive domestic manufacturing base.« less

High-throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization.

PubMed

Kastner, Elisabeth; Kaur, Randip; Lowry, Deborah; Moghaddam, Behfar; Wilkinson, Alexander; Perrie, Yvonne

2014-12-30

Microfluidics has recently emerged as a new method of manufacturing liposomes, which allows for reproducible mixing in miliseconds on the nanoliter scale. Here we investigate microfluidics-based manufacturing of liposomes. The aim of these studies was to assess the parameters in a microfluidic process by varying the total flow rate (TFR) and the flow rate ratio (FRR) of the solvent and aqueous phases. Design of experiment and multivariate data analysis were used for increased process understanding and development of predictive and correlative models. High FRR lead to the bottom-up synthesis of liposomes, with a strong correlation with vesicle size, demonstrating the ability to in-process control liposomes size; the resulting liposome size correlated with the FRR in the microfluidics process, with liposomes of 50 nm being reproducibly manufactured. Furthermore, we demonstrate the potential of a high throughput manufacturing of liposomes using microfluidics with a four-fold increase in the volumetric flow rate, maintaining liposome characteristics. The efficacy of these liposomes was demonstrated in transfection studies and was modelled using predictive modeling. Mathematical modelling identified FRR as the key variable in the microfluidic process, with the highest impact on liposome size, polydispersity and transfection efficiency. This study demonstrates microfluidics as a robust and high-throughput method for the scalable and highly reproducible manufacture of size-controlled liposomes. Furthermore, the application of statistically based process control increases understanding and allows for the generation of a design-space for controlled particle characteristics. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Quality control of inkjet technology for DNA microarray fabrication.

PubMed

Pierik, Anke; Dijksman, Frits; Raaijmakers, Adrie; Wismans, Ton; Stapert, Henk

2008-12-01

A robust manufacturing process is essential to make high-quality DNA microarrays, especially for use in diagnostic tests. We investigated different failure modes of the inkjet printing process used to manufacture low-density microarrays. A single nozzle inkjet spotter was provided with two optical imaging systems, monitoring in real time the flight path of every droplet. If a droplet emission failure is detected, the printing process is automatically stopped. We analyzed over 1.3 million droplets. This information was used to investigate the performance of the inkjet system and to obtain detailed insight into the frequency and causes of jetting failures. Of all the substrates investigated, 96.2% were produced without any system or jetting failures. In 1.6% of the substrates, droplet emission failed and was correctly identified. Appropriate measures could then be taken to get the process back on track. In 2.2%, the imaging systems failed while droplet emission occurred correctly. In 0.1% of the substrates, droplet emission failure that was not timely detected occurred. Thus, the overall yield of the microarray manufacturing process was 99.9%, which is highly acceptable for prototyping.

Materials, Structures and Manufacturing: An Integrated Approach to Develop Expandable Structures

NASA Technical Reports Server (NTRS)

Belvin, W. Keith; Zander, Martin E.; Sleight, Daid W.; Connell, John; Holloway, Nancy; Palmieri, Frank

2012-01-01

Membrane dominated space structures are lightweight and package efficiently for launch; however, they must be expanded (deployed) in-orbit to achieve the desired geometry. These expandable structural systems include solar sails, solar power arrays, antennas, and numerous other large aperture devices that are used to collect, reflect and/or transmit electromagnetic radiation. In this work, an integrated approach to development of thin-film damage tolerant membranes is explored using advanced manufacturing. Bio-inspired hierarchical structures were printed on films using additive manufacturing to achieve improved tear resistance and to facilitate membrane deployment. High precision, robust expandable structures can be realized using materials that are both space durable and processable using additive manufacturing. Test results show this initial work produced higher tear resistance than neat film of equivalent mass. Future research and development opportunities for expandable structural systems designed using an integrated approach to structural design, manufacturing, and materials selection are discussed.

Comprehensive Lipidome-Wide Profiling Reveals Dynamic Changes of Tea Lipids during Manufacturing Process of Black Tea.

PubMed

Li, Jia; Hua, Jinjie; Zhou, Qinghua; Dong, Chunwang; Wang, Jinjin; Deng, Yuliang; Yuan, Haibo; Jiang, Yongwen

2017-11-22

As important biomolecules in Camellia sinensis L., lipids undergo substantial changes during black tea manufacture, which is considered to contribute to tea sensory quality. However, limited by analytical capacity, detailed lipid composition and its dynamic changes during black tea manufacture remain unclear. Herein, we performed tea lipidome profiling using high resolution liquid chromatography coupled to mass spectrometry (LC-MS), which allows simultaneous and robust analysis of 192 individual lipid species in black tea, covering 17 (sub)classes. Furthermore, dynamic changes of tea lipids during black tea manufacture were investigated. Significant alterations of lipid pattern were revealed, involved with chlorophyll degradation, metabolic pathways of glycoglycerolipids, and other extraplastidial membrane lipids. To our knowledge, this report presented most comprehensive coverage of lipid species in black tea. This study provides a global and in-depth metabolic map of tea lipidome during black tea manufacture.

Application of the quality by design approach to the drug substance manufacturing process of an Fc fusion protein: towards a global multi-step design space.

PubMed

Eon-duval, Alex; Valax, Pascal; Solacroup, Thomas; Broly, Hervé; Gleixner, Ralf; Strat, Claire L E; Sutter, James

2012-10-01

The article describes how Quality by Design principles can be applied to the drug substance manufacturing process of an Fc fusion protein. First, the quality attributes of the product were evaluated for their potential impact on safety and efficacy using risk management tools. Similarly, process parameters that have a potential impact on critical quality attributes (CQAs) were also identified through a risk assessment. Critical process parameters were then evaluated for their impact on CQAs, individually and in interaction with each other, using multivariate design of experiment techniques during the process characterisation phase. The global multi-step Design Space, defining operational limits for the entire drug substance manufacturing process so as to ensure that the drug substance quality targets are met, was devised using predictive statistical models developed during the characterisation study. The validity of the global multi-step Design Space was then confirmed by performing the entire process, from cell bank thawing to final drug substance, at its limits during the robustness study: the quality of the final drug substance produced under different conditions was verified against predefined targets. An adaptive strategy was devised whereby the Design Space can be adjusted to the quality of the input material to ensure reliable drug substance quality. Finally, all the data obtained during the process described above, together with data generated during additional validation studies as well as manufacturing data, were used to define the control strategy for the drug substance manufacturing process using a risk assessment methodology. Copyright © 2012 Wiley-Liss, Inc.

Manufacturing Research: Self-Directed Control

DTIC Science & Technology

1991-01-01

reduce this sensitivity. SDO is performing Taguchi’s parameter design . 1-13 Statistical Process Control SPC techniques will be used to monitor the process...Florida,R.E. Krieger Pub. Co., 1988. Dehnad, Khowrow, Quality Control . Robust Design . and the Taguchi Method, Pacific Grove, California, Wadsworth... control system. This turns out to be a non -trivial exercise. A human operator can see an event occur (such as the vessel pressurizing above its setpoint

Mitigating the risk of Zika virus contamination of raw materials and cell lines in the manufacture of biologicals.

PubMed

Zmurko, Joanna; Vasey, Douglas B; Donald, Claire L; Armstrong, Alison A; McKee, Marian L; Kohl, Alain; Clayton, Reginald F

2018-02-01

Ensuring the virological safety of biologicals is challenging due to the risk of viral contamination of raw materials and cell banks, and exposure during in-process handling to known and/or emerging viral pathogens. Viruses may contaminate raw materials and biologicals intended for human or veterinary use and remain undetected until appropriate testing measures are employed. The outbreak and expansive spread of the mosquito-borne flavivirus Zika virus (ZIKV) poses challenges to screening human- and animal -derived products used in the manufacture of biologicals. Here, we report the results of an in vitro study where detector cell lines were challenged with African and Asian lineages of ZIKV. We demonstrate that this pathogen is robustly detectable by in vitro assay, thereby providing assurance of detection of ZIKV, and in turn underpinning the robustness of in vitro virology assays in safety testing of biologicals.

Integrated Process Modeling-A Process Validation Life Cycle Companion.

PubMed

Zahel, Thomas; Hauer, Stefan; Mueller, Eric M; Murphy, Patrick; Abad, Sandra; Vasilieva, Elena; Maurer, Daniel; Brocard, Cécile; Reinisch, Daniela; Sagmeister, Patrick; Herwig, Christoph

2017-10-17

During the regulatory requested process validation of pharmaceutical manufacturing processes, companies aim to identify, control, and continuously monitor process variation and its impact on critical quality attributes (CQAs) of the final product. It is difficult to directly connect the impact of single process parameters (PPs) to final product CQAs, especially in biopharmaceutical process development and production, where multiple unit operations are stacked together and interact with each other. Therefore, we want to present the application of Monte Carlo (MC) simulation using an integrated process model (IPM) that enables estimation of process capability even in early stages of process validation. Once the IPM is established, its capability in risk and criticality assessment is furthermore demonstrated. IPMs can be used to enable holistic production control strategies that take interactions of process parameters of multiple unit operations into account. Moreover, IPMs can be trained with development data, refined with qualification runs, and maintained with routine manufacturing data which underlines the lifecycle concept. These applications will be shown by means of a process characterization study recently conducted at a world-leading contract manufacturing organization (CMO). The new IPM methodology therefore allows anticipation of out of specification (OOS) events, identify critical process parameters, and take risk-based decisions on counteractions that increase process robustness and decrease the likelihood of OOS events.

The fuzzy algorithm in the die casting mould for the application of multi-channel temperature control

NASA Astrophysics Data System (ADS)

Sun, Jin-gen; Chen, Yi; Zhang, Jia-nan

2017-01-01

Mould manufacturing is one of the most basic elements in the production chain of China. The mould manufacturing technology has become an important symbol to measure the level of a country's manufacturing industry. The die-casting mould multichannel intelligent temperature control method is studied by cooling water circulation, which uses fuzzy control to realize, aiming at solving the shortcomings of slow speed and big energy consumption during the cooling process of current die-casting mould. At present, the traditional PID control method is used to control the temperature, but it is difficult to ensure the control precision. While , the fuzzy algorithm is used to realize precise control of mould temperature in cooling process. The design is simple, fast response, strong anti-interference ability and good robustness. Simulation results show that the control method is completely feasible, which has higher control precision.

Manufacturing process used to produce long-acting recombinant factor VIII Fc fusion protein.

PubMed

McCue, Justin; Kshirsagar, Rashmi; Selvitelli, Keith; Lu, Qi; Zhang, Mingxuan; Mei, Baisong; Peters, Robert; Pierce, Glenn F; Dumont, Jennifer; Raso, Stephen; Reichert, Heidi

2015-07-01

Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a long-acting coagulation factor approved for the treatment of hemophilia A. Here, the rFVIIIFc manufacturing process and results of studies evaluating product quality and the capacity of the process to remove potential impurities and viruses are described. This manufacturing process utilized readily transferable and scalable unit operations and employed multi-step purification and viral clearance processing, including a novel affinity chromatography adsorbent and a 15 nm pore size virus removal nanofilter. A cell line derived from human embryonic kidney (HEK) 293H cells was used to produce rFVIIIFc. Validation studies evaluated identity, purity, activity, and safety. Process-related impurity clearance and viral clearance spiking studies demonstrate robust and reproducible removal of impurities and viruses, with total viral clearance >8-15 log10 for four model viruses (xenotropic murine leukemia virus, mice minute virus, reovirus type 3, and suid herpes virus 1). Terminal galactose-α-1,3-galactose and N-glycolylneuraminic acid, two non-human glycans, were undetectable in rFVIIIFc. Biochemical and in vitro biological analyses confirmed the purity, activity, and consistency of rFVIIIFc. In conclusion, this manufacturing process produces a highly pure product free of viruses, impurities, and non-human glycan structures, with scale capabilities to ensure a consistent and adequate supply of rFVIIIFc. Copyright © 2015 Biogen. Published by Elsevier Ltd.. All rights reserved.

Development and validation of a single robust HPLC method for the characterization of a pharmaceutical starting material and impurities from three suppliers using three separate synthetic routes.

PubMed

Sheldon, E M; Downar, J B

2000-08-15

Novel approaches to the development of analytical procedures for monitoring incoming starting material in support of chemical/pharmaceutical processes are described. High technology solutions were utilized for timely process development and preparation of high quality clinical supplies. A single robust HPLC method was developed and characterized for the analysis of the key starting material from three suppliers. Each supplier used a different process for the preparation of this material and, therefore, each suppliers' material exhibited a unique impurity profile. The HPLC method utilized standard techniques acceptable for release testing in a QC/manufacturing environment. An automated experimental design protocol was used to characterize the robustness of the HPLC method. The method was evaluated for linearity, limit of quantitation, solution stability, and precision of replicate injections. An LC-MS method that emulated the release HPLC method was developed and the identities of impurities were mapped between the two methods.

Robust Design of Sheet Metal Forming Process Based on Kriging Metamodel

NASA Astrophysics Data System (ADS)

Xie, Yanmin

2011-08-01

Nowadays, sheet metal forming processes design is not a trivial task due to the complex issues to be taken into account (conflicting design goals, complex shapes forming and so on). Optimization methods have also been widely applied in sheet metal forming. Therefore, proper design methods to reduce time and costs have to be developed mostly based on computer aided procedures. At the same time, the existence of variations during manufacturing processes significantly may influence final product quality, rendering non-robust optimal solutions. In this paper, a small size of design of experiments is conducted to investigate how a stochastic behavior of noise factors affects drawing quality. The finite element software (LS_DYNA) is used to simulate the complex sheet metal stamping processes. The Kriging metamodel is adopted to map the relation between input process parameters and part quality. Robust design models for sheet metal forming process integrate adaptive importance sampling with Kriging model, in order to minimize impact of the variations and achieve reliable process parameters. In the adaptive sample, an improved criterion is used to provide direction in which additional training samples can be added to better the Kriging model. Nonlinear functions as test functions and a square stamping example (NUMISHEET'93) are employed to verify the proposed method. Final results indicate application feasibility of the aforesaid method proposed for multi-response robust design.

Fatigue Strength Prediction for Titanium Alloy TiAl6V4 Manufactured by Selective Laser Melting

NASA Astrophysics Data System (ADS)

Leuders, Stefan; Vollmer, Malte; Brenne, Florian; Tröster, Thomas; Niendorf, Thomas

2015-09-01

Selective laser melting (SLM), as a metalworking additive manufacturing technique, received considerable attention from industry and academia due to unprecedented design freedom and overall balanced material properties. However, the fatigue behavior of SLM-processed materials often suffers from local imperfections such as micron-sized pores. In order to enable robust designs of SLM components used in an industrial environment, further research regarding process-induced porosity and its impact on the fatigue behavior is required. Hence, this study aims at a transfer of fatigue prediction models, established for conventional process-routes, to the field of SLM materials. By using high-resolution computed tomography, load increase tests, and electron microscopy, it is shown that pore-based fatigue strength predictions for a titanium alloy TiAl6V4 have become feasible. However, the obtained accuracies are subjected to scatter, which is probably caused by the high defect density even present in SLM materials manufactured following optimized processing routes. Based on thorough examination of crack surfaces and crack initiation sites, respectively, implications for optimization of prediction accuracy of the models in focus are deduced.

Multivariate data analysis on historical IPV production data for better process understanding and future improvements.

PubMed

Thomassen, Yvonne E; van Sprang, Eric N M; van der Pol, Leo A; Bakker, Wilfried A M

2010-09-01

Historical manufacturing data can potentially harbor a wealth of information for process optimization and enhancement of efficiency and robustness. To extract useful data multivariate data analysis (MVDA) using projection methods is often applied. In this contribution, the results obtained from applying MVDA on data from inactivated polio vaccine (IPV) production runs are described. Data from over 50 batches at two different production scales (700-L and 1,500-L) were available. The explorative analysis performed on single unit operations indicated consistent manufacturing. Known outliers (e.g., rejected batches) were identified using principal component analysis (PCA). The source of operational variation was pinpointed to variation of input such as media. Other relevant process parameters were in control and, using this manufacturing data, could not be correlated to product quality attributes. The gained knowledge of the IPV production process, not only from the MVDA, but also from digitalizing the available historical data, has proven to be useful for troubleshooting, understanding limitations of available data and seeing the opportunity for improvements. 2010 Wiley Periodicals, Inc.

A new large-scale manufacturing platform for complex biopharmaceuticals.

PubMed

Vogel, Jens H; Nguyen, Huong; Giovannini, Roberto; Ignowski, Jolene; Garger, Steve; Salgotra, Anil; Tom, Jennifer

2012-12-01

Complex biopharmaceuticals, such as recombinant blood coagulation factors, are addressing critical medical needs and represent a growing multibillion-dollar market. For commercial manufacturing of such, sometimes inherently unstable, molecules it is important to minimize product residence time in non-ideal milieu in order to obtain acceptable yields and consistently high product quality. Continuous perfusion cell culture allows minimization of residence time in the bioreactor, but also brings unique challenges in product recovery, which requires innovative solutions. In order to maximize yield, process efficiency, facility and equipment utilization, we have developed, scaled-up and successfully implemented a new integrated manufacturing platform in commercial scale. This platform consists of a (semi-)continuous cell separation process based on a disposable flow path and integrated with the upstream perfusion operation, followed by membrane chromatography on large-scale adsorber capsules in rapid cycling mode. Implementation of the platform at commercial scale for a new product candidate led to a yield improvement of 40% compared to the conventional process technology, while product quality has been shown to be more consistently high. Over 1,000,000 L of cell culture harvest have been processed with 100% success rate to date, demonstrating the robustness of the new platform process in GMP manufacturing. While membrane chromatography is well established for polishing in flow-through mode, this is its first commercial-scale application for bind/elute chromatography in the biopharmaceutical industry and demonstrates its potential in particular for manufacturing of potent, low-dose biopharmaceuticals. Copyright © 2012 Wiley Periodicals, Inc.

Prepreg and Melt Infiltration Technology Developed for Affordable, Robust Manufacturing of Ceramic Matrix Composites

NASA Technical Reports Server (NTRS)

Singh, Mrityunjay; Petko, Jeannie F.

2004-01-01

Affordable fiber-reinforced ceramic matrix composites with multifunctional properties are critically needed for high-temperature aerospace and space transportation applications. These materials have various applications in advanced high-efficiency and high-performance engines, airframe and propulsion components for next-generation launch vehicles, and components for land-based systems. A number of these applications require materials with specific functional characteristics: for example, thick component, hybrid layups for environmental durability and stress management, and self-healing and smart composite matrices. At present, with limited success and very high cost, traditional composite fabrication technologies have been utilized to manufacture some large, complex-shape components of these materials. However, many challenges still remain in developing affordable, robust, and flexible manufacturing technologies for large, complex-shape components with multifunctional properties. The prepreg and melt infiltration (PREMI) technology provides an affordable and robust manufacturing route for low-cost, large-scale production of multifunctional ceramic composite components.

Pharmaceutical 3D printing: Design and qualification of a single step print and fill capsule.

PubMed

Smith, Derrick M; Kapoor, Yash; Klinzing, Gerard R; Procopio, Adam T

2018-06-10

Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug-containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin-walled drug-free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule 'shell' and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension '.gcode') were modified by creating discrete zones, so-called 'zoning process', with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X-ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work. Copyright © 2018 Elsevier B.V. All rights reserved.

Toward precision manufacturing of immunogene T-cell therapies.

PubMed

Xu, Jun; Melenhorst, J Joseph; Fraietta, Joseph A

2018-05-01

Cancer can be effectively targeted using a patient's own T cells equipped with synthetic receptors, including chimeric antigen receptors (CARs) that redirect and reprogram these lymphocytes to mediate tumor rejection. Over the past two decades, several strategies to manufacture genetically engineered T cells have been proposed, with the goal of generating optimally functional cellular products for adoptive transfer. Based on this work, protocols for manufacturing clinical-grade CAR T cells have been established, but these complex methods have been used to treat only a few hundred individuals. As CAR T-cell therapy progresses into later-phase clinical trials and becomes an option for more patients, a major consideration for academic institutions and industry is developing robust manufacturing processes that will permit scaling-out production of immunogene T-cell therapies in a reproducible and efficient manner. In this review, we will discuss the steps involved in cell processing, the major obstacles surrounding T-cell manufacturing platforms and the approaches for improving cellular product potency. Finally, we will address the challenges of expanding CAR T-cell therapy to a global patient population. Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Conductor requirements for high-temperature superconducting utility power transformers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pleva, E. F.; Mehrotra, V.; Schwenterly, S W

High-temperature superconducting (HTS) coated conductors in utility power transformers must satisfy a set of operating requirements that are driven by two major considerations-HTS transformers must be economically competitive with conventional units, and the conductor must be robust enough to be used in a commercial manufacturing environment. The transformer design and manufacturing process will be described in order to highlight the various requirements that it imposes on the HTS conductor. Spreadsheet estimates of HTS transformer costs allow estimates of the conductor cost required for an HTS transformer to be competitive with a similarly performing conventional unit.

Robust design of microchannel cooler

NASA Astrophysics Data System (ADS)

He, Ye; Yang, Tao; Hu, Li; Li, Leimin

2005-12-01

Microchannel cooler has offered a new method for the cooling of high power diode lasers, with the advantages of small volume, high efficiency of thermal dissipation and low cost when mass-produced. In order to reduce the sensitivity of design to manufacture errors or other disturbances, Taguchi method that is one of robust design method was chosen to optimize three parameters important to the cooling performance of roof-like microchannel cooler. The hydromechanical and thermal mathematical model of varying section microchannel was calculated using finite volume method by FLUENT. A special program was written to realize the automation of the design process for improving efficiency. The optimal design is presented which compromises between optimal cooling performance and its robustness. This design method proves to be available.

Designing high-performance cost-efficient embedded SRAM in deep-submicron era

NASA Astrophysics Data System (ADS)

Kobozeva, Olga; Venkatraman, Ramnath; Castagnetti, Ruggero; Duan, Franklin; Kamath, Arvind; Ramesh, Shiva

2004-05-01

We have previously presented the smallest and fastest 6 Transistor (6T)-Static Random Access Memories (SRAM) bitcells for System-on-Chip (SoC) high-density (HD) memories in 0.18 μm and 0.13 μm technologies. Our 1.87 μm2 6TSRAM bitcell with cell current of 47 μA and industry lowest soft error rate (0.35 FIT/Kbit) is used to assemble memory blocks embedded into SoC designs in 0.13 μm process technology. Excellent performance is achieved at a low overall cost, as our bitcells are based on standard CMOS process and demonstrate high yields in manufacturing. This paper discusses our methodology of embedded SRAM bitcell design. The key aspects of our approach are: 1) judicious selection of tightest achievable yet manufacturable design rules to build the cell; 2) compatibility with standard Optical Proximity Correction (OPC) flow; 3) use of parametric testing and yield analysis to achieve excellent design robustness and manufacturability. A thorough understanding of process limitations, particularly those related to photolithography was critical to the successful design and manufacturing of our aggressive, yet robust SRAM bitcells. The patterning of critical layers, such as diffusion, poly gate, contact and metal 1 has profound implications on functionality, electrical performance and manufacturability of memories. We have conducted the development of SRAM bitcells using two approaches for OPC: a) "manual" OPC, wherein the bitcell layout of each of the critical layers is achieved using iterative improvement of layout & aerial image simulation and b) automated OPC-compatible design, wherein the drawn bitcell layout becomes a subject of a full chip OPC. While manual-OPC remains a popular option, automated OPC-compatible bitcell design is very attractive, as it does not require additional development costs to achieve fab-to-fab portability. In both cases we have obtained good results with respect to patterning of the critical layers, electrical performance of the bitcell and memory yields. A critical part of our memory technology development effort is the design of memory-specific test structures that are used for: a) verifying electrical characteristics of SRAM transistors and b) confirming the robustness of the design rules used within the SRAM cell. In addition to electrical test structures, we have a fully functional SRAM test chip called RAMPCM that is composed of sub-blocks each designated to evaluate the robustness of a specific critical design rule used within the bitcells. The results from the electrical testing and RAMPCM yield analysis are used to identify opportunities for improvements in the layout design. The paper will also suggest some techniques that can result in more design friendly OPC solutions. Our work indicates that future IC designs can benefit from an automated OPC tool that can intelligently handle layout modifications according to design priorities.

Bi-Objective Flexible Job-Shop Scheduling Problem Considering Energy Consumption under Stochastic Processing Times.

PubMed

Yang, Xin; Zeng, Zhenxiang; Wang, Ruidong; Sun, Xueshan

2016-01-01

This paper presents a novel method on the optimization of bi-objective Flexible Job-shop Scheduling Problem (FJSP) under stochastic processing times. The robust counterpart model and the Non-dominated Sorting Genetic Algorithm II (NSGA-II) are used to solve the bi-objective FJSP with consideration of the completion time and the total energy consumption under stochastic processing times. The case study on GM Corporation verifies that the NSGA-II used in this paper is effective and has advantages to solve the proposed model comparing with HPSO and PSO+SA. The idea and method of the paper can be generalized widely in the manufacturing industry, because it can reduce the energy consumption of the energy-intensive manufacturing enterprise with less investment when the new approach is applied in existing systems.

Bi-Objective Flexible Job-Shop Scheduling Problem Considering Energy Consumption under Stochastic Processing Times

PubMed Central

Zeng, Zhenxiang; Wang, Ruidong; Sun, Xueshan

2016-01-01

This paper presents a novel method on the optimization of bi-objective Flexible Job-shop Scheduling Problem (FJSP) under stochastic processing times. The robust counterpart model and the Non-dominated Sorting Genetic Algorithm II (NSGA-II) are used to solve the bi-objective FJSP with consideration of the completion time and the total energy consumption under stochastic processing times. The case study on GM Corporation verifies that the NSGA-II used in this paper is effective and has advantages to solve the proposed model comparing with HPSO and PSO+SA. The idea and method of the paper can be generalized widely in the manufacturing industry, because it can reduce the energy consumption of the energy-intensive manufacturing enterprise with less investment when the new approach is applied in existing systems. PMID:27907163

A hybrid life-cycle inventory for multi-crystalline silicon PV module manufacturing in China

NASA Astrophysics Data System (ADS)

Yao, Yuan; Chang, Yuan; Masanet, Eric

2014-11-01

China is the world’s largest manufacturer of multi-crystalline silicon photovoltaic (mc-Si PV) modules, which is a key enabling technology in the global transition to renewable electric power systems. This study presents a hybrid life-cycle inventory (LCI) of Chinese mc-Si PV modules, which fills a critical knowledge gap on the environmental implications of mc-Si PV module manufacturing in China. The hybrid LCI approach combines process-based LCI data for module and poly-silicon manufacturing plants with a 2007 China IO-LCI model for production of raw material and fuel inputs to estimate ‘cradle to gate’ primary energy use, water consumption, and major air pollutant emissions (carbon dioxide, methane, sulfur dioxide, nitrous oxide, and nitrogen oxides). Results suggest that mc-Si PV modules from China may come with higher environmental burdens that one might estimate if one were using LCI results for mc-Si PV modules manufactured elsewhere. These higher burdens can be reasonably explained by the efficiency differences in China’s poly-silicon manufacturing processes, the country’s dependence on highly polluting coal-fired electricity, and the expanded system boundaries associated with the hybrid LCI modeling framework. The results should be useful for establishing more conservative ranges on the potential ‘cradle to gate’ impacts of mc-Si PV module manufacturing for more robust LCAs of PV deployment scenarios.

The strategic relevance of manufacturing technology: An overall quality concept to promote innovation preventing drug shortage.

PubMed

Panzitta, Michele; Ponti, Mauro; Bruno, Giorgio; Cois, Giancarlo; D'Arpino, Alessandro; Minghetti, Paola; Mendicino, Francesca Romana; Perioli, Luana; Ricci, Maurizio

2017-01-10

Manufacturing is the bridge between research and patient: without product, there is no clinical outcome. Shortage has a variety of causes, in this paper we analyse only causes related to manufacturing technology and we use shortage as a paradigm highliting the relevance of Pharmaceutical Technology. Product and process complexity and capacity issues are the main challenge for the Pharmaceutical Industry Supply chain. Manufacturing Technology should be acknowledged as a R&D step and as a very important matter during University degree in Pharmacy and related disciplines, promoting collaboration between Academia and Industry, measured during HTA step and rewarded in terms of price and reimbursement. The above elements are not yet properly recognised, and manufacturing technology is taken in to consideration only when a shortage is in place. In a previous work, Panzitta et al. proposed to perform a full technology assessment at the Health Technological Assessment stage, evaluating three main technical aspects of a medicine: manufacturing process, physicochemical properties, and formulation characteristics. In this paper, we develop the concept of manufacturing appraisal, providing a technical overview of upcoming challenges, a risk based approach and an economic picture of shortage costs. We develop also an overall quality concept, not limited to GMP factors but broaden to all elements leading to a robust supply and promoting technical innovation. Copyright © 2016 Elsevier B.V. All rights reserved.

Study of Out-Time on the Processing and Properties of IM7/977-3 Composites

NASA Technical Reports Server (NTRS)

Miller, Sandi G.; Sutter, James K.; Scheiman, Daniel A.; Maryanski, Michael; Schlea, Michelle

2010-01-01

The capability to manufacture large structures leads to weight savings and reduced risk relative to joining smaller components. However, manufacture of increasingly large composite components is pushing the out-life limits of epoxy/ carbon fiber prepreg. IM7/977-3 is an autoclave processable prepreg material, commonly used in aerospace structures. The out-life limit is reported as 30 days by the manufacturer. The purpose of this work was to evaluate the material processability and composite properties of 977-3 resin and IM7/977-3 prepreg that had been aged at room temperature for up to 60 days. The neat resin was evaluated by differential scanning calorimetry, DSC, to characterize cure behavior of the aged material, as well as any change in activation energy. The rise in the modulus of the uncured prepreg was monitored throughout the 60 days by dynamic mechanical analysis, DMA. Composite panels made of the fresh and aged prepreg material were also characterized by DMA. The overall test results suggested that IM7/977-3 was a robust material that offered quality laminates throughout this aging process when processed by autoclave.

Out-Life Characteristics of IM7/977-3 Composites

NASA Technical Reports Server (NTRS)

Miller, Sandi G.; Sutter, James K.; Hou, Tan-Hung; Scheiman, Daniel A.; Martin, Richard E.; Maryanski, Michael; Schlea, Michelle; Gardner, John M.; Schiferl, Zack R.

2010-01-01

The capability to manufacture large structures leads to weight savings and reduced risk relative to joining smaller components. However, manufacture of increasingly large composite components is pushing the out-time limits of epoxy/ carbon fiber prepreg. IM7/977-3 is an autoclave processable prepreg material, commonly used in aerospace structures. The out-time limit is reported as 30 days by the manufacturer. The purpose of this work was to evaluate the material processability and composite properties of 977-3 resin and IM7/977-3 prepreg that had been aged at room temperature for up to 60 days. The effects of room temperature aging on the thermal and visco-elastic properties of the materials were investigated. Neat resin was evaluated by differential scanning calorimetry to characterize thermal properties and change in activation energy of cure. Neat resin was also evaluated by rheometry to characterize its processability in composite fabrication. IM7/977-3 prepreg was evaluated by dynamic mechanical analysis to characterize the curing behavior. Prepreg tack was also evaluated over 60 days. The overall test results suggested that IM7/977-3 was a robust material that offered quality laminates throughout this aging process when processed by autoclave.

Simulation Based Low-Cost Composite Process Development at the US Air Force Research Laboratory

NASA Technical Reports Server (NTRS)

Rice, Brian P.; Lee, C. William; Curliss, David B.

2003-01-01

Low-cost composite research in the US Air Force Research Laboratory, Materials and Manufacturing Directorate, Organic Matrix Composites Branch has focused on the theme of affordable performance. Practically, this means that we use a very broad view when considering the affordability of composites. Factors such as material costs, labor costs, recurring and nonrecurring manufacturing costs are balanced against performance to arrive at the relative affordability vs. performance measure of merit. The research efforts discussed here are two projects focused on affordable processing of composites. The first topic is the use of a neural network scheme to model cure reaction kinetics, then utilize the kinetics coupled with simple heat transport models to predict, in real-time, future exotherms and control them. The neural network scheme is demonstrated to be very robust and a much more efficient method that mechanistic cure modeling approach. This enables very practical low-cost processing of thick composite parts. The second project is liquid composite molding (LCM) process simulation. LCM processing of large 3D integrated composite parts has been demonstrated to be a very cost effective way to produce large integrated aerospace components specific examples of LCM processes are resin transfer molding (RTM), vacuum assisted resin transfer molding (VARTM), and other similar approaches. LCM process simulation is a critical part of developing an LCM process approach. Flow simulation enables the development of the most robust approach to introducing resin into complex preforms. Furthermore, LCM simulation can be used in conjunction with flow front sensors to control the LCM process in real-time to account for preform or resin variability.

Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies

PubMed Central

Wang, X; Rivière, I

2015-01-01

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) and genetically engineered T lymphocytes expressing chimeric antigen receptors (CARs) or conventional alpha/beta T-cell receptors (TCRs), collectively termed adoptive cell therapy (ACT), is an emerging novel strategy to treat cancer patients. Application of ACT has been constrained by the ability to isolate and expand functional tumor-reactive T cells. The transition of ACT from a promising experimental regimen to an established standard of care treatment relies largely on the establishment of safe, efficient, robust and cost-effective cell manufacturing protocols. The manufacture of cellular products under current good manufacturing practices (cGMPs) has a critical role in the process. Herein, we review current manufacturing methods for the large-scale production of clinical-grade TILs, virus-specific and genetically modified CAR or TCR transduced T cells in the context of phase I/II clinical trials as well as the regulatory pathway to get these complex personalized cellular products to the clinic. PMID:25721207

Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies.

PubMed

Wang, X; Rivière, I

2015-03-01

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) and genetically engineered T lymphocytes expressing chimeric antigen receptors (CARs) or conventional alpha/beta T-cell receptors (TCRs), collectively termed adoptive cell therapy (ACT), is an emerging novel strategy to treat cancer patients. Application of ACT has been constrained by the ability to isolate and expand functional tumor-reactive T cells. The transition of ACT from a promising experimental regimen to an established standard of care treatment relies largely on the establishment of safe, efficient, robust and cost-effective cell manufacturing protocols. The manufacture of cellular products under current good manufacturing practices (cGMPs) has a critical role in the process. Herein, we review current manufacturing methods for the large-scale production of clinical-grade TILs, virus-specific and genetically modified CAR or TCR transduced T cells in the context of phase I/II clinical trials as well as the regulatory pathway to get these complex personalized cellular products to the clinic.

Advanced metal lift-off process using electron-beam flood exposure of single-layer photoresist

NASA Astrophysics Data System (ADS)

Minter, Jason P.; Ross, Matthew F.; Livesay, William R.; Wong, Selmer S.; Narcy, Mark E.; Marlowe, Trey

1999-06-01

In the manufacture of many types of integrated circuit and thin film devices, it is desirable to use a lift-of process for the metallization step to avoid manufacturing problems encountered when creating metal interconnect structures using plasma etch. These problems include both metal adhesion and plasma etch difficulties. Key to the success of the lift-off process is the creation of a retrograde or undercut profile in the photoresists before the metal deposition step. Until now, lift-off processing has relied on costly multi-layer photoresists schemes, image reversal, and non-repeatable photoresist processes to obtain the desired lift-off profiles in patterned photoresist. This paper present a simple, repeatable process for creating robust, user-defined lift-off profiles in single layer photoresist using a non-thermal electron beam flood exposure. For this investigation, lift-off profiles created using electron beam flood exposure of many popular photoresists were evaluated. Results of lift-off profiles created in positive tone AZ7209 and ip3250 are presented here.

Comparability of automated human induced pluripotent stem cell culture: a pilot study.

PubMed

Archibald, Peter R T; Chandra, Amit; Thomas, Dave; Chose, Olivier; Massouridès, Emmanuelle; Laâbi, Yacine; Williams, David J

2016-12-01

Consistent and robust manufacturing is essential for the translation of cell therapies, and the utilisation automation throughout the manufacturing process may allow for improvements in quality control, scalability, reproducibility and economics of the process. The aim of this study was to measure and establish the comparability between alternative process steps for the culture of hiPSCs. Consequently, the effects of manual centrifugation and automated non-centrifugation process steps, performed using TAP Biosystems' CompacT SelecT automated cell culture platform, upon the culture of a human induced pluripotent stem cell (hiPSC) line (VAX001024c07) were compared. This study, has demonstrated that comparable morphologies and cell diameters were observed in hiPSCs cultured using either manual or automated process steps. However, non-centrifugation hiPSC populations exhibited greater cell yields, greater aggregate rates, increased pluripotency marker expression, and decreased differentiation marker expression compared to centrifugation hiPSCs. A trend for decreased variability in cell yield was also observed after the utilisation of the automated process step. This study also highlights the detrimental effect of the cryopreservation and thawing processes upon the growth and characteristics of hiPSC cultures, and demonstrates that automated hiPSC manufacturing protocols can be successfully transferred between independent laboratories.

Update On The Development, Testing, And Manufacture Of High Density LEU-Foil Targets For The Production Of Mo-99

DOE Office of Scientific and Technical Information (OSTI.GOV)

Creasy, John T

2015-05-12

This project has the objective to reduce and/or eliminate the use of HEU in commerce. Steps in the process include developing a target testing methodology that is bounding for all Mo-99 target irradiators, establishing a maximum target LEU-foil mass, developing a LEU-foil target qualification document, developing a bounding target failure analysis methodology (failure in reactor containment), optimizing safety vs. economics (goal is to manufacture a safe, but relatively inexpensive target to offset the inherent economic disadvantage of using LEU in place of HEU), and developing target material specifications and manufacturing QC test criteria. The slide presentation is organized under themore » following topics: Objective, Process Overview, Background, Team Structure, Key Achievements, Experiment and Activity Descriptions, and Conclusions. The High Density Target project has demonstrated: approx. 50 targets irradiated through domestic and international partners; proof of concept for two front end processing methods; fabrication of uranium foils for target manufacture; quality control procedures and steps for manufacture; multiple target assembly techniques; multiple target disassembly devices; welding of targets; thermal, hydraulic, and mechanical modeling; robust target assembly parametric studies; and target qualification analysis for insertion into very high flux environment. The High Density Target project has tested and proven several technologies that will benefit current and future Mo-99 producers.« less

Argon-oxygen atmospheric pressure plasma treatment on carbon fiber reinforced polymer for improved bonding

NASA Astrophysics Data System (ADS)

Chartosias, Marios

Acceptance of Carbon Fiber Reinforced Polymer (CFRP) structures requires a robust surface preparation method with improved process controls capable of ensuring high bond quality. Surface preparation in a production clean room environment prior to applying adhesive for bonding would minimize risk of contamination and reduce cost. Plasma treatment is a robust surface preparation process capable of being applied in a production clean room environment with process parameters that are easily controlled and documented. Repeatable and consistent processing is enabled through the development of a process parameter window utilizing techniques such as Design of Experiments (DOE) tailored to specific adhesive and substrate bonding applications. Insight from respective plasma treatment Original Equipment Manufacturers (OEMs) and screening tests determined critical process factors from non-factors and set the associated factor levels prior to execution of the DOE. Results from mode I Double Cantilever Beam (DCB) testing per ASTM D 5528 [1] standard and DOE statistical analysis software are used to produce a regression model and determine appropriate optimum settings for each factor.

Microencapsulation of Bacterial Cells by Emulsion Technique for Probiotic Application.

PubMed

Mandal, Surajit; Hati, Subrota

2017-01-01

Probiotics are dietary concepts to improve the dynamics of intestinal microbial balance favorably. Careful screening of probiotic strains for their technological suitability can also allow selection of strains with the best manufacturing and food technology characteristics. However, even the most robust probiotic bacteria are currently in the range of food applications to which they can be applied. Additionally, bacteria with exceptional functional heath properties are ruled out due to technological limitations. New process and formulation technologies will enable both expansion of the range of products in to which probiotics can be applied and the use of efficacious stains that currently cannot be manufactured or stored with existing technologies. Viability of probiotics has been both a marketing and technological concern for many industrial produces. Probiotics are difficult to work with, the bacteria often die during processing, and shelf life is unpredictable. Probiotics are extremely susceptible environmental conditions such as oxygen, processing and preservation treatments, acidity, and salt concentration, which collectively affect the overall viability of probiotics. Manufacturers have long been fortifying products with probiotics; they have faced significant processing challenges regarding the stability and survivability of probiotics during processing and preservation treatments, storage as well during their passage through GIT. Application of microencapsulation significantly improves the stability of probiotics during food processing and gastrointestinal transit.

Optical hiding with visual cryptography

NASA Astrophysics Data System (ADS)

Shi, Yishi; Yang, Xiubo

2017-11-01

We propose an optical hiding method based on visual cryptography. In the hiding process, we convert the secret information into a set of fabricated phase-keys, which are completely independent of each other, intensity-detected-proof and image-covered, leading to the high security. During the extraction process, the covered phase-keys are illuminated with laser beams and then incoherently superimposed to extract the hidden information directly by human vision, without complicated optical implementations and any additional computation, resulting in the convenience of extraction. Also, the phase-keys are manufactured as the diffractive optical elements that are robust to the attacks, such as the blocking and the phase-noise. Optical experiments verify that the high security, the easy extraction and the strong robustness are all obtainable in the visual-cryptography-based optical hiding.

Impact of Alternative Medical Device Approval Processes on Costs and Health

PubMed Central

George, Benjamin P.; Venkataraman, Vinayak; Dorsey, E. Ray

2014-01-01

Background Medical devices are often introduced prior to randomized‐trial evidence of efficacy and this slows completion of trials. Alternative regulatory approaches include restricting device use outside of trials prior to trial evidence of efficacy (like the drug approval process) or restricting out‐of‐trial use but permitting coverage within trials such as Medicare's Coverage with Study Participation (CSP). Methods We compared the financial impact to manufacturers and insurers of three regulatory alternatives: (1) limited regulation (current approach), (2) CSP, and (3) restrictive regulation (like the current drug approval process). Using data for patent foramen ovale closure devices, we modeled key parameters including recruitment time, probability of device efficacy, market adoption, and device cost/price to calculate profits to manufacturers, costs to insurers, and overall societal impact on health. Results For manufacturers, profits were greatest under CSP—driven by faster market adoption of effective devices—followed by restrictive regulation. Societal health benefit in total quality‐adjusted life years was greatest under CSP. Insurers’ expenditures for ineffective devices were greatest with limited regulation. Findings were robust over a reasonable range of probabilities of trial success. Conclusions Regulation restricting out‐of‐trial device use and extending limited insurance coverage to clinical trial participants may balance manufacturer and societal interests. PMID:25185975

Integrating Fiber Optic Strain Sensors into Metal Using Ultrasonic Additive Manufacturing

NASA Astrophysics Data System (ADS)

Hehr, Adam; Norfolk, Mark; Wenning, Justin; Sheridan, John; Leser, Paul; Leser, Patrick; Newman, John A.

2018-03-01

Ultrasonic additive manufacturing, a rather new three-dimensional (3D) printing technology, uses ultrasonic energy to produce metallurgical bonds between layers of metal foils near room temperature. This low temperature attribute of the process enables integration of temperature sensitive components, such as fiber optic strain sensors, directly into metal structures. This may be an enabling technology for Digital Twin applications, i.e., virtual model interaction and feedback with live load data. This study evaluates the consolidation quality, interface robustness, and load sensing limits of commercially available fiber optic strain sensors embedded into aluminum alloy 6061. Lastly, an outlook on the technology and its applications is described.

FDA, CE mark or something else?-Thinking fast and slow.

PubMed

Mishra, Sundeep

There is a robust debate going on among the Medical Device stake-holders whether FDA is better or CE mark or something else. Currently process of obtaining an FDA approval is bogged down by ever-increasing unpredictability, inconsistency, prolonged time, and huge expense but CE mark has its own problems. Historically, the Japanese review process has tended to be the slowest among the big three but recently with the introduction of accelerated review process there has been a significant progress. While the goal of an innovator/manufacturer is to develop, manufacture and market a medical device that addresses an unmet clinical need, the requisite regulatory approval process can be very confusing. Not only there is a whole lot of jargon tossed around by regulatory affair professionals: "substantial equivalence," "PMDA," "CE mark," "Notified body," "510K" and "PMA" but the actual approval process can also be very tardy, inconsistent and expensive. Copyright © 2016 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

Manufacture of Regularly Shaped Sol-Gel Pellets

NASA Technical Reports Server (NTRS)

Leventis, Nicholas; Johnston, James C.; Kinder, James D.

2006-01-01

An extrusion batch process for manufacturing regularly shaped sol-gel pellets has been devised as an improved alternative to a spray process that yields irregularly shaped pellets. The aspect ratio of regularly shaped pellets can be controlled more easily, while regularly shaped pellets pack more efficiently. In the extrusion process, a wet gel is pushed out of a mold and chopped repetitively into short, cylindrical pieces as it emerges from the mold. The pieces are collected and can be either (1) dried at ambient pressure to xerogel, (2) solvent exchanged and dried under ambient pressure to ambigels, or (3) supercritically dried to aerogel. Advantageously, the extruded pellets can be dropped directly in a cross-linking bath, where they develop a conformal polymer coating around the skeletal framework of the wet gel via reaction with the cross linker. These pellets can be dried to mechanically robust X-Aerogel.

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review.

PubMed

Buckley, Kevin; Ryder, Alan G

2017-06-01

The production of active pharmaceutical ingredients (APIs) is currently undergoing its biggest transformation in a century. The changes are based on the rapid and dramatic introduction of protein- and macromolecule-based drugs (collectively known as biopharmaceuticals) and can be traced back to the huge investment in biomedical science (in particular in genomics and proteomics) that has been ongoing since the 1970s. Biopharmaceuticals (or biologics) are manufactured using biological-expression systems (such as mammalian, bacterial, insect cells, etc.) and have spawned a large (>€35 billion sales annually in Europe) and growing biopharmaceutical industry (BioPharma). The structural and chemical complexity of biologics, combined with the intricacy of cell-based manufacturing, imposes a huge analytical burden to correctly characterize and quantify both processes (upstream) and products (downstream). In small molecule manufacturing, advances in analytical and computational methods have been extensively exploited to generate process analytical technologies (PAT) that are now used for routine process control, leading to more efficient processes and safer medicines. In the analytical domain, biologic manufacturing is considerably behind and there is both a huge scope and need to produce relevant PAT tools with which to better control processes, and better characterize product macromolecules. Raman spectroscopy, a vibrational spectroscopy with a number of useful properties (nondestructive, non-contact, robustness) has significant potential advantages in BioPharma. Key among them are intrinsically high molecular specificity, the ability to measure in water, the requirement for minimal (or no) sample pre-treatment, the flexibility of sampling configurations, and suitability for automation. Here, we review and discuss a representative selection of the more important Raman applications in BioPharma (with particular emphasis on mammalian cell culture). The review shows that the properties of Raman have been successfully exploited to deliver unique and useful analytical solutions, particularly for online process monitoring. However, it also shows that its inherent susceptibility to fluorescence interference and the weakness of the Raman effect mean that it can never be a panacea. In particular, Raman-based methods are intrinsically limited by the chemical complexity and wide analyte-concentration-profiles of cell culture media/bioprocessing broths which limit their use for quantitative analysis. Nevertheless, with appropriate foreknowledge of these limitations and good experimental design, robust analytical methods can be produced. In addition, new technological developments such as time-resolved detectors, advanced lasers, and plasmonics offer potential of new Raman-based methods to resolve existing limitations and/or provide new analytical insights.

Process quality engineering for bioreactor-driven manufacturing of tissue-engineered constructs for bone regeneration.

PubMed

Papantoniou Ir, Ioannis; Chai, Yoke Chin; Luyten, Frank P; Schrooten Ir, Jan

2013-08-01

The incorporation of Quality-by-Design (QbD) principles in tissue-engineering bioprocess development toward clinical use will ensure that manufactured constructs possess prerequisite quality characteristics addressing emerging regulatory requirements and ensuring the functional in vivo behavior. In this work, the QbD principles were applied on a manufacturing process step for the in vitro production of osteogenic three-dimensional (3D) hybrid scaffolds that involves cell matrix deposition on a 3D titanium (Ti) alloy scaffold. An osteogenic cell source (human periosteum-derived cells) cultured in a bioinstructive medium was used to functionalize regular Ti scaffolds in a perfusion bioreactor, resulting in an osteogenic hybrid carrier. A two-level three-factor fractional factorial design of experiments was employed to explore a range of production-relevant process conditions by simultaneously changing value levels of the following parameters: flow rate (0.5-2 mL/min), cell culture duration (7-21 days), and cell-seeding density (1.5×10(3)-3×10(3) cells/cm(2)). This approach allowed to evaluate the individual impact of the aforementioned process parameters upon key quality attributes of the produced hybrids, such as collagen production, mineralization level, and cell number. The use of a fractional factorial design approach helped create a design space in which hybrid scaffolds of predefined quality attributes may be robustly manufactured while minimizing the number of required experiments.

Life‐cycle and cost of goods assessment of fed‐batch and perfusion‐based manufacturing processes for mAbs

PubMed Central

Bunnak, Phumthep; Allmendinger, Richard; Ramasamy, Sri V.; Lettieri, Paola

2016-01-01

Life‐cycle assessment (LCA) is an environmental assessment tool that quantifies the environmental impact associated with a product or a process (e.g., water consumption, energy requirements, and solid waste generation). While LCA is a standard approach in many commercial industries, its application has not been exploited widely in the bioprocessing sector. To contribute toward the design of more cost‐efficient, robust and environmentally‐friendly manufacturing process for monoclonal antibodies (mAbs), a framework consisting of an LCA and economic analysis combined with a sensitivity analysis of manufacturing process parameters and a production scale‐up study is presented. The efficiency of the framework is demonstrated using a comparative study of the two most commonly used upstream configurations for mAb manufacture, namely fed‐batch (FB) and perfusion‐based processes. Results obtained by the framework are presented using a range of visualization tools, and indicate that a standard perfusion process (with a pooling duration of 4 days) has similar cost of goods than a FB process but a larger environmental footprint because it consumed 35% more water, demanded 17% more energy, and emitted 17% more CO2 than the FB process. Water consumption was the most important impact category, especially when scaling‐up the processes, as energy was required to produce process water and water‐for‐injection, while CO2 was emitted from energy generation. The sensitivity analysis revealed that the perfusion process can be made more environmentally‐friendly than the FB process if the pooling duration is extended to 8 days. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1324–1335, 2016 PMID:27390260

Life-cycle and cost of goods assessment of fed-batch and perfusion-based manufacturing processes for mAbs.

PubMed

Bunnak, Phumthep; Allmendinger, Richard; Ramasamy, Sri V; Lettieri, Paola; Titchener-Hooker, Nigel J

2016-09-01

Life-cycle assessment (LCA) is an environmental assessment tool that quantifies the environmental impact associated with a product or a process (e.g., water consumption, energy requirements, and solid waste generation). While LCA is a standard approach in many commercial industries, its application has not been exploited widely in the bioprocessing sector. To contribute toward the design of more cost-efficient, robust and environmentally-friendly manufacturing process for monoclonal antibodies (mAbs), a framework consisting of an LCA and economic analysis combined with a sensitivity analysis of manufacturing process parameters and a production scale-up study is presented. The efficiency of the framework is demonstrated using a comparative study of the two most commonly used upstream configurations for mAb manufacture, namely fed-batch (FB) and perfusion-based processes. Results obtained by the framework are presented using a range of visualization tools, and indicate that a standard perfusion process (with a pooling duration of 4 days) has similar cost of goods than a FB process but a larger environmental footprint because it consumed 35% more water, demanded 17% more energy, and emitted 17% more CO 2 than the FB process. Water consumption was the most important impact category, especially when scaling-up the processes, as energy was required to produce process water and water-for-injection, while CO 2 was emitted from energy generation. The sensitivity analysis revealed that the perfusion process can be made more environmentally-friendly than the FB process if the pooling duration is extended to 8 days. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1324-1335, 2016. © 2016 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers.

Enhancing cell and gene therapy manufacture through the application of advanced fluorescent optical sensors (Review).

PubMed

Harrison, Richard P; Chauhan, Veeren M

2017-12-15

Cell and gene therapies (CGTs) are examples of future therapeutics that can be used to cure or alleviate the symptoms of disease, by repairing damaged tissue or reprogramming defective genetic information. However, despite the recent advancements in clinical trial outcomes, the path to wide-scale adoption of CGTs remains challenging, such that the emergence of a "blockbuster" therapy has so far proved elusive. Manufacturing solutions for these therapies require the application of scalable and replicable cell manufacturing techniques, which differ markedly from the existing pharmaceutical incumbent. Attempts to adopt this pharmaceutical model for CGT manufacture have largely proved unsuccessful. The most significant challenges facing CGT manufacturing are process analytical testing and quality control. These procedures would greatly benefit from improved sensory technologies that allow direct measurement of critical quality attributes, such as pH, oxygen, lactate and glucose. In turn, this would make manufacturing more robust, replicable and standardized. In this review, the present-day state and prospects of CGT manufacturing are discussed. In particular, the authors highlight the role of fluorescent optical sensors, focusing on their strengths and weaknesses, for CGT manufacture. The review concludes by discussing how the integration of CGT manufacture and fluorescent optical sensors could augment future bioprocessing approaches.

Automated Enrichment, Transduction, and Expansion of Clinical-Scale CD62L+ T Cells for Manufacturing of Gene Therapy Medicinal Products

PubMed Central

Priesner, Christoph; Aleksandrova, Krasimira; Esser, Ruth; Mockel-Tenbrinck, Nadine; Leise, Jana; Drechsel, Katharina; Marburger, Michael; Quaiser, Andrea; Goudeva, Lilia; Arseniev, Lubomir; Kaiser, Andrew D.; Glienke, Wolfgang; Koehl, Ulrike

2016-01-01

Multiple clinical studies have demonstrated that adaptive immunotherapy using redirected T cells against advanced cancer has led to promising results with improved patient survival. The continuously increasing interest in those advanced gene therapy medicinal products (GTMPs) leads to a manufacturing challenge regarding automation, process robustness, and cell storage. Therefore, this study addresses the proof of principle in clinical-scale selection, stimulation, transduction, and expansion of T cells using the automated closed CliniMACS® Prodigy system. Naïve and central memory T cells from apheresis products were first immunomagnetically enriched using anti-CD62L magnetic beads and further processed freshly (n = 3) or split for cryopreservation and processed after thawing (n = 1). Starting with 0.5 × 108 purified CD3+ T cells, three mock runs and one run including transduction with green fluorescent protein (GFP)-containing vector resulted in a median final cell product of 16 × 108 T cells (32-fold expansion) up to harvesting after 2 weeks. Expression of CD62L was downregulated on T cells after thawing, which led to the decision to purify CD62L+CD3+ T cells freshly with cryopreservation thereafter. Most important in the split product, a very similar expansion curve was reached comparing the overall freshly CD62L selected cells with those after thawing, which could be demonstrated in the T cell subpopulations as well by showing a nearly identical conversion of the CD4/CD8 ratio. In the GFP run, the transduction efficacy was 83%. In-process control also demonstrated sufficient glucose levels during automated feeding and medium removal. The robustness of the process and the constant quality of the final product in a closed and automated system give rise to improve harmonized manufacturing protocols for engineered T cells in future gene therapy studies. PMID:27562135

An international technology platform for influenza vaccines.

PubMed

Hendriks, Jan; Holleman, Marit; de Boer, Otto; de Jong, Patrick; Luytjes, Willem

2011-07-01

Since 2008, the World Health Organization has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or improve their pandemic influenza vaccine production capacity. To facilitate this ambitious project, an influenza vaccine technology platform (or "hub") was established at the Netherlands Vaccine Institute for training and technology transfer to developing countries. During its first two years of operation, a robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production was established under international Good Manufacturing Practice standards, as well as in-process and release assays. A course curriculum was designed, including a two-volume practical handbook on production and quality control. Four generic hands-on training courses were successfully realized for over 40 employees from 15 developing country manufacturers. Planned extensions to the curriculum include cell-culture based technology for viral vaccine production, split virion influenza production, and generic adjuvant formulation. We conclude that technology transfer through the hub model works well, significantly builds vaccine manufacturing capacity in developing countries, and thereby increases global and equitable access to vaccines of high public health relevance. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Impact of Granule Density on Tabletting and Pharmaceutical Product Performance.

PubMed

van den Ban, Sander; Goodwin, Daniel J

2017-05-01

The impact of granule densification in high-shear wet granulation on tabletting and product performance was investigated, at pharmaceutical production scale. Product performance criteria need to be balanced with the need to deliver manufacturability criteria to assure robust industrial scale tablet manufacturing processes. A Quality by Design approach was used to determine in-process control specifications for tabletting, propose a design space for disintegration and dissolution, and to understand the permitted operating limits and required controls for an industrial tabletting process. Granules of varying density (filling density) were made by varying water amount added, spray rate, and wet massing time in a design of experiment (DoE) approach. Granules were compressed into tablets to a range of thicknesses to obtain tablets of varying breaking force. Disintegration and dissolution performance was evaluated for the tablets made. The impact of granule filling density on tabletting was rationalised with compressibility, tabletability and compactibility. Tabletting and product performance criteria provided competing requirements for porosity. An increase in granule filling density impacted tabletability and compactability and limited the ability to achieve tablets of adequate mechanical strength. An increase in tablet solid fraction (decreased porosity) impacted disintegration and dissolution. An attribute-based design space for disintegration and dissolution was specified to achieve both product performance and manufacturability. The method of granulation and resulting granule filling density is a key design consideration to achieve both product performance and manufacturability required for modern industrial scale pharmaceutical product manufacture and distribution.

Performance Optimization Control of ECH using Fuzzy Inference Application

NASA Astrophysics Data System (ADS)

Dubey, Abhay Kumar

Electro-chemical honing (ECH) is a hybrid electrolytic precision micro-finishing technology that, by combining physico-chemical actions of electro-chemical machining and conventional honing processes, provides the controlled functional surfaces-generation and fast material removal capabilities in a single operation. Process multi-performance optimization has become vital for utilizing full potential of manufacturing processes to meet the challenging requirements being placed on the surface quality, size, tolerances and production rate of engineering components in this globally competitive scenario. This paper presents an strategy that integrates the Taguchi matrix experimental design, analysis of variances and fuzzy inference system (FIS) to formulate a robust practical multi-performance optimization methodology for complex manufacturing processes like ECH, which involve several control variables. Two methodologies one using a genetic algorithm tuning of FIS (GA-tuned FIS) and another using an adaptive network based fuzzy inference system (ANFIS) have been evaluated for a multi-performance optimization case study of ECH. The actual experimental results confirm their potential for a wide range of machining conditions employed in ECH.

Towards Robust Designs Via Multiple-Objective Optimization Methods

NASA Technical Reports Server (NTRS)

Man Mohan, Rai

2006-01-01

Fabricating and operating complex systems involves dealing with uncertainty in the relevant variables. In the case of aircraft, flow conditions are subject to change during operation. Efficiency and engine noise may be different from the expected values because of manufacturing tolerances and normal wear and tear. Engine components may have a shorter life than expected because of manufacturing tolerances. In spite of the important effect of operating- and manufacturing-uncertainty on the performance and expected life of the component or system, traditional aerodynamic shape optimization has focused on obtaining the best design given a set of deterministic flow conditions. Clearly it is important to both maintain near-optimal performance levels at off-design operating conditions, and, ensure that performance does not degrade appreciably when the component shape differs from the optimal shape due to manufacturing tolerances and normal wear and tear. These requirements naturally lead to the idea of robust optimal design wherein the concept of robustness to various perturbations is built into the design optimization procedure. The basic ideas involved in robust optimal design will be included in this lecture. The imposition of the additional requirement of robustness results in a multiple-objective optimization problem requiring appropriate solution procedures. Typically the costs associated with multiple-objective optimization are substantial. Therefore efficient multiple-objective optimization procedures are crucial to the rapid deployment of the principles of robust design in industry. Hence the companion set of lecture notes (Single- and Multiple-Objective Optimization with Differential Evolution and Neural Networks ) deals with methodology for solving multiple-objective Optimization problems efficiently, reliably and with little user intervention. Applications of the methodologies presented in the companion lecture to robust design will be included here. The evolutionary method (DE) is first used to solve a relatively difficult problem in extended surface heat transfer wherein optimal fin geometries are obtained for different safe operating base temperatures. The objective of maximizing the safe operating base temperature range is in direct conflict with the objective of maximizing fin heat transfer. This problem is a good example of achieving robustness in the context of changing operating conditions. The evolutionary method is then used to design a turbine airfoil; the two objectives being reduced sensitivity of the pressure distribution to small changes in the airfoil shape and the maximization of the trailing edge wedge angle with the consequent increase in airfoil thickness and strength. This is a relevant example of achieving robustness to manufacturing tolerances and wear and tear in the presence of other objectives.

High-Performance Flexible Perovskite Solar Cells by Using a Combination of Ultrasonic Spray-Coating and Low Thermal Budget Photonic Curing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanjib, Das; Yang, Bin; Gu, Gong

Realizing the commercialization of high-performance and robust perovskite solar cells urgently requires the development of economically scalable processing techniques. Here we report a high-throughput ultrasonic spray-coating (USC) process capable of fabricating perovskite film-based solar cells on glass substrates with power conversion efficiency (PCE) as high as 13.04%. Perovskite films with high uniformity, crystallinity, and surface coverage are obtained in a single step. Moreover, we report USC processing on TiOx/ITO-coated polyethylene terephthalate (PET) substrates to realize flexible perovskite solar cells with PCE as high as 8.02% that are robust under mechanical stress. In this case, an optical curing technique was usedmore » to achieve a highly-conductive TiOx layer on flexible PET substrates for the first time. The high device performance and reliability obtained by this combination of USC processing with optical curing appears very promising for roll-to-roll manufacturing of high-efficiency, flexible perovskite solar cells.« less

Engineered particles demonstrate improved flow properties at elevated drug loadings for direct compression manufacturing.

PubMed

Trementozzi, Andrea N; Leung, Cheuk-Yui; Osei-Yeboah, Frederick; Irdam, Erwin; Lin, Yiqing; MacPhee, J Michael; Boulas, Pierre; Karki, Shyam B; Zawaneh, Peter N

2017-05-15

Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D 50 =24μm) and particle engineered wet milled API (D 50 =70μm and 90μm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ff c <4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ff c >10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized. Copyright © 2017 Elsevier B.V. All rights reserved.

Effective inactivation of a wide range of viruses by pasteurization.

PubMed

Gröner, Albrecht; Broumis, Connie; Fang, Randel; Nowak, Thomas; Popp, Birgit; Schäfer, Wolfram; Roth, Nathan J

2018-01-01

Careful selection and testing of plasma reduces the risk of blood-borne viruses in the starting material for plasma-derived products. Furthermore, effective measures such as pasteurization at 60°C for 10 hours have been implemented in the manufacturing process of therapeutic plasma proteins such as human albumin, coagulation factors, immunoglobulins, and enzyme inhibitors to inactivate blood-borne viruses of concern. A comprehensive compilation of the virus reduction capacity of pasteurization is presented including the effect of stabilizers used to protect the therapeutic protein from modifications during heat treatment. The virus inactivation kinetics of pasteurization for a broad range of viruses were evaluated in the relevant intermediates from more than 15 different plasma manufacturing processes. Studies were carried out under the routine manufacturing target variables, such as temperature and product-specific stabilizer composition. Additional studies were also performed under robustness conditions, that is, outside production specifications. The data demonstrate that pasteurization inactivates a wide range of enveloped and nonenveloped viruses of diverse physicochemical characteristics. After a maximum of 6 hours' incubation, no residual infectivity could be detected for the majority of enveloped viruses. Effective inactivation of a range of nonenveloped viruses, with the exception of nonhuman parvoviruses, was documented. Pasteurization is a very robust and reliable virus inactivation method with a broad effectiveness against known blood-borne pathogens and emerging or potentially emerging viruses. Pasteurization has proven itself to be a highly effective step, in combination with other complementary safety measures, toward assuring the virus safety of final product. © 2017 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

Wireless Sensors and Networks for Advanced Energy Management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hardy, J.E.

Numerous national studies and working groups have identified low-cost, very low-power wireless sensors and networks as a critical enabling technology for increasing energy efficiency, reducing waste, and optimizing processes. Research areas for developing such sensor and network platforms include microsensor arrays, ultra-low power electronics and signal conditioning, data/control transceivers, and robust wireless networks. A review of some of the research in the following areas will be discussed: (1) Low-cost, flexible multi-sensor array platforms (CO{sub 2}, NO{sub x}, CO, humidity, NH{sub 3}, O{sub 2}, occupancy, etc.) that enable energy and emission reductions in applications such as buildings and manufacturing; (2) Modelingmore » investments (energy usage and savings to drive capital investment decisions) and estimated uptime improvements through pervasive gathering of equipment and process health data and its effects on energy; (3) Robust, self-configuring wireless sensor networks for energy management; and (4) Quality-of-service for secure and reliable data transmission from widely distributed sensors. Wireless communications is poised to support technical innovations in the industrial community, with widespread use of wireless sensors forecasted to improve manufacturing production and energy efficiency and reduce emissions. Progress being made in wireless system components, as described in this paper, is helping bring these projected improvements to reality.« less

Optimising the design and operation of semi-continuous affinity chromatography for clinical and commercial manufacture.

PubMed

Pollock, James; Bolton, Glen; Coffman, Jon; Ho, Sa V; Bracewell, Daniel G; Farid, Suzanne S

2013-04-05

This paper presents an integrated experimental and modelling approach to evaluate the potential of semi-continuous chromatography for the capture of monoclonal antibodies (mAb) in clinical and commercial manufacture. Small-scale single-column experimental breakthrough studies were used to derive design equations for the semi-continuous affinity chromatography system. Verification runs with the semi-continuous 3-column and 4-column periodic counter current (PCC) chromatography system indicated the robustness of the design approach. The product quality profiles and step yields (after wash step optimisation) achieved were comparable to the standard batch process. The experimentally-derived design equations were incorporated into a decisional tool comprising dynamic simulation, process economics and sizing optimisation. The decisional tool was used to evaluate the economic and operational feasibility of whole mAb bioprocesses employing PCC affinity capture chromatography versus standard batch chromatography across a product's lifecycle from clinical to commercial manufacture. The tool predicted that PCC capture chromatography would offer more significant savings in direct costs for early-stage clinical manufacture (proof-of-concept) (∼30%) than for late-stage clinical (∼10-15%) or commercial (∼5%) manufacture. The evaluation also highlighted the potential facility fit issues that could arise with a capture resin (MabSelect) that experiences losses in binding capacity when operated in continuous mode over lengthy commercial campaigns. Consequently, the analysis explored the scenario of adopting the PCC system for clinical manufacture and switching to the standard batch process following product launch. The tool determined the PCC system design required to operate at commercial scale without facility fit issues and with similar costs to the standard batch process whilst pursuing a process change application. A retrofitting analysis established that the direct cost savings obtained by 8 proof-of-concept batches would be sufficient to pay back the investment cost of the pilot-scale semi-continuous chromatography system. Copyright © 2013 Elsevier B.V. All rights reserved.

PEM-INST-001: Instructions for Plastic Encapsulated Microcircuit (PEM) Selection, Screening, and Qualification

NASA Technical Reports Server (NTRS)

Teverovsky, Alexander; Sahu, Kusum

2003-01-01

Potential users of plastic encapsulated microcircuits (PEMs) need to be reminded that unlike the military system of producing robust high-reliability microcircuits that are designed to perform acceptably in a variety of harsh environments, PEMs are primarily designed for use in benign environments where equipment is easily accessed for repair or replacement. The methods of analysis applied to military products to demonstrate high reliability cannot always be applied to PEMs. This makes it difficult for users to characterize PEMs for two reasons: 1. Due to the major differences in design and construction, the standard test practices used to ensure that military devices are robust and have high reliability often cannot be applied to PEMs that have a smaller operating temperature range and are typically more frail and susceptible to moisture absorption. In contrast, high-reliability military microcircuits usually utilize large, robust, high-temperature packages that are hermetically sealed. 2. Unlike the military high-reliability system, users of PEMs have little visibility into commercial manufacturers proprietary design, materials, die traceability, and production processes and procedures. There is no central authority that monitors PEM commercial product for quality, and there are no controls in place that can be imposed across all commercial manufacturers to provide confidence to high-reliability users that a common acceptable level of quality exists for all PEMs manufacturers. Consequently, there is no guaranteed control over the type of reliability that is built into commercial product, and there is no guarantee that different lots from the same manufacturer are equally acceptable. And regarding application, there is no guarantee that commercial products intended for use in benign environments will provide acceptable performance and reliability in harsh space environments. The qualification and screening processes contained in this document are intended to detect poor-quality lots and screen out early random failures from use in space flight hardware. However, since it cannot be guaranteed that quality was designed and built into PEMs that are appropriate for space applications, users cannot screen in quality that may not exist. It must be understood that due to the variety of materials, processes, and technologies used to design and produce PEMs, this test process may not accelerate and detect all failure mechanisms. While the tests herein will increase user confidence that PEMs with otherwise unknown reliability can be used in space environments, such testing may not guarantee the same level of reliability offered by military microcircuits. PEMs should only be used where due to performance needs there are no alternatives in the military high-reliability market, and projects are willing to accept higher risk.

Methodology for balancing design and process tradeoffs for deep-subwavelength technologies

NASA Astrophysics Data System (ADS)

Graur, Ioana; Wagner, Tina; Ryan, Deborah; Chidambarrao, Dureseti; Kumaraswamy, Anand; Bickford, Jeanne; Styduhar, Mark; Wang, Lee

2011-04-01

For process development of deep-subwavelength technologies, it has become accepted practice to use model-based simulation to predict systematic and parametric failures. Increasingly, these techniques are being used by designers to ensure layout manufacturability, as an alternative to, or complement to, restrictive design rules. The benefit of model-based simulation tools in the design environment is that manufacturability problems are addressed in a design-aware way by making appropriate trade-offs, e.g., between overall chip density and manufacturing cost and yield. The paper shows how library elements and the full ASIC design flow benefit from eliminating hot spots and improving design robustness early in the design cycle. It demonstrates a path to yield optimization and first time right designs implemented in leading edge technologies. The approach described herein identifies those areas in the design that could benefit from being fixed early, leading to design updates and avoiding later design churn by careful selection of design sensitivities. This paper shows how to achieve this goal by using simulation tools incorporating various models from sparse to rigorously physical, pattern detection and pattern matching, checking and validating failure thresholds.

Robustness testing in pharmaceutical freeze-drying: inter-relation of process conditions and product quality attributes studied for a vaccine formulation.

PubMed

Schneid, Stefan C; Stärtzel, Peter M; Lettner, Patrick; Gieseler, Henning

2011-01-01

The recent US Food and Drug Administration (FDA) legislation has introduced the evaluation of the Design Space of critical process parameters in manufacturing processes. In freeze-drying, a "formulation" is expected to be robust when minor deviations of the product temperature do not negatively affect the final product quality attributes. To evaluate "formulation" robustness by investigating the effect of elevated product temperature on product quality using a bacterial vaccine solution. The vaccine solution was characterized by freeze-dry microscopy to determine the critical formulation temperature. A conservative cycle was developed using the SMART™ mode of a Lyostar II freeze dryer. Product temperature was elevated to imitate intermediate and aggressive cycle conditions. The final product was analyzed using X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), Karl Fischer, and modulated differential scanning calorimetry (MDSC), and the life cell count (LCC) during accelerated stability testing. The cakes processed at intermediate and aggressive conditions displayed larger pores with microcollapse of walls and stronger loss in LCC than the conservatively processed product, especially during stability testing. For all process conditions, a loss of the majority of cells was observed during storage. For freeze-drying of life bacterial vaccine solutions, the product temperature profile during primary drying appeared to be inter-related to product quality attributes.

Design Considerations for Human Rating of Liquid Rocket Engines

NASA Technical Reports Server (NTRS)

Parkinson, Douglas

2010-01-01

I.Human-rating is specific to each engine; a. Context of program/project must be understood. b. Engine cannot be discussed independently from vehicle and mission. II. Utilize a logical combination of design, manufacturing, and test approaches a. Design 1) It is crucial to know the potential ways a system can fail, and how a failure can propagate; 2) Fault avoidance, fault tolerance, DFMR, caution and warning all have roles to play. b. Manufacturing and Assembly; 1) As-built vs. as-designed; 2) Review procedures for assembly and maintenance periodically; and 3) Keep personnel trained and certified. c. There is no substitute for test: 1) Analytical tools are constantly advancing, but still need test data for anchoring assumptions; 2) Demonstrate robustness and explore sensitivities; 3) Ideally, flight will be encompassed by ground test experience. III. Consistency and repeatability is key in production a. Maintain robust processes and procedures for inspection and quality control based upon development and qualification experience; b. Establish methods to "spot check" quality and consistency in parts: 1) Dedicated ground test engines; 2) Random components pulled from the line/lot to go through "enhanced" testing.

Using manufacturing message specification for monitor and control at Venus

NASA Technical Reports Server (NTRS)

Heuser, W. Randy; Chen, Richard L.; Stockett, Michael H.

1993-01-01

The flexibility and robustness of a monitor and control (M&C) system are a direct result of the underlying interprocessor communications architecture. A new architecture for M&C at the Deep Space Communications Complexes (DSCC's) has been developed based on the Manufacturing Message Specification (MMS) process control standard of the Open System Interconnection (OSI) suite of protocols. This architecture has been tested both in a laboratory environment and under operational conditions at the Deep Space Network (DSN) experimental Venus station (DSS-13). The Venus experience in the application of OSI standards to support M&C has been extremely successful. MMS meets the functional needs of the station and provides a level of flexibility and responsiveness previously unknown in that environment. The architecture is robust enough to meet current operational needs and flexible enough to provide a migration path for new subsystems. This paper will describe the architecture of the Venus M&C system, discuss how MMS was used and the requirements this imposed on other parts of the system, and provide results from systems and operational testing at the Venus site.

Application of quality by design for 3D printed bone prostheses and scaffolds

PubMed Central

Martinez-Marquez, Daniel; Mirnajafizadeh, Ali; Carty, Christopher P.

2018-01-01

3D printing is an emergent manufacturing technology recently being applied in the medical field for the development of custom bone prostheses and scaffolds. However, successful industry transformation to this new design and manufacturing approach requires technology integration, concurrent multi-disciplinary collaboration, and a robust quality management framework. This latter change enabler is the focus of this study. While a number of comprehensive quality frameworks have been developed in recent decades to ensure that the manufacturing of medical devices produces reliable products, they are centred on the traditional context of standardised manufacturing techniques. The advent of 3D printing technologies and the prospects for mass customisation provides significant market opportunities, but also presents a serious challenge to regulatory bodies tasked with managing and assuring product quality and safety. Before 3D printing bone prostheses and scaffolds can gain traction, industry stakeholders, such as regulators, clients, medical practitioners, insurers, lawyers, and manufacturers, would all require a high degree of confidence that customised manufacturing can achieve the same quality outcomes as standardised manufacturing. A Quality by Design (QbD) approach to custom 3D printed prostheses can help to ensure that products are designed and manufactured correctly from the beginning without errors. This paper reports on the adaptation of the QbD approach for the development process of 3D printed custom bone prosthesis and scaffolds. This was achieved through the identification of the Critical Quality Attributes of such products, and an extensive review of different design and fabrication methods for 3D printed bone prostheses. Research outcomes include the development of a comprehensive design and fabrication process flow diagram, and categorised risks associated with the design and fabrication processes of such products. An extensive systematic literature review and post-hoc evaluation survey with experts was completed to evaluate the likely effectiveness of the herein suggested QbD framework. PMID:29649231

Application of quality by design for 3D printed bone prostheses and scaffolds.

PubMed

Martinez-Marquez, Daniel; Mirnajafizadeh, Ali; Carty, Christopher P; Stewart, Rodney A

2018-01-01

3D printing is an emergent manufacturing technology recently being applied in the medical field for the development of custom bone prostheses and scaffolds. However, successful industry transformation to this new design and manufacturing approach requires technology integration, concurrent multi-disciplinary collaboration, and a robust quality management framework. This latter change enabler is the focus of this study. While a number of comprehensive quality frameworks have been developed in recent decades to ensure that the manufacturing of medical devices produces reliable products, they are centred on the traditional context of standardised manufacturing techniques. The advent of 3D printing technologies and the prospects for mass customisation provides significant market opportunities, but also presents a serious challenge to regulatory bodies tasked with managing and assuring product quality and safety. Before 3D printing bone prostheses and scaffolds can gain traction, industry stakeholders, such as regulators, clients, medical practitioners, insurers, lawyers, and manufacturers, would all require a high degree of confidence that customised manufacturing can achieve the same quality outcomes as standardised manufacturing. A Quality by Design (QbD) approach to custom 3D printed prostheses can help to ensure that products are designed and manufactured correctly from the beginning without errors. This paper reports on the adaptation of the QbD approach for the development process of 3D printed custom bone prosthesis and scaffolds. This was achieved through the identification of the Critical Quality Attributes of such products, and an extensive review of different design and fabrication methods for 3D printed bone prostheses. Research outcomes include the development of a comprehensive design and fabrication process flow diagram, and categorised risks associated with the design and fabrication processes of such products. An extensive systematic literature review and post-hoc evaluation survey with experts was completed to evaluate the likely effectiveness of the herein suggested QbD framework.

NASA's Preparations for ESA's L3 Gravitational Wave Mission

NASA Technical Reports Server (NTRS)

Stebbins, Robin

2016-01-01

Telescope Subsystem - Jeff Livas (GSFC): Demonstrate pathlength stability, straylight and manufacturability. Phase Measurement System - Bill Klipstein (JPL): Key measurement functions demonstrated. Incorporate full flight functionality. Laser Subsystem - Jordan Camp (GSFC): ECL master oscillator, phase noise of fiber power amplifier, demonstrate end-to-end performance in integrated system, lifetime. Micronewton Thrusters - John Ziemer (JPL): Propellant storage and distribution, system robustness, manufacturing yield, lifetime. Arm-locking Demonstration - Kirk McKenzie (JPL): Studying a demonstration of laser frequency stabilization with GRACE Follow-On. Torsion Pendulum - John Conklin (UF): Develop U.S. capability with GRS and torsion pendulum test bed. Multi-Axis Heterodyne Interferometry - Ira Thorpe (GSFC): Investigate test mass/optical bench interface. UV LEDs - John Conklin+ (UF): Flight qualify UV LEDs to replace mercury lamps in discharging system. Optical Bench - Guido Mueller (UF): Investigate alternate designs and fabrication processes to ease manufacturability. LISA researchers at JPL are leading the Laser Ranging Interferometer instrument on the GRACE Follow-On mission.

Statistical analysis and yield management in LED design through TCAD device simulation

NASA Astrophysics Data System (ADS)

Létay, Gergö; Ng, Wei-Choon; Schneider, Lutz; Bregy, Adrian; Pfeiffer, Michael

2007-02-01

This paper illustrates how technology computer-aided design (TCAD), which nowadays is an essential part of CMOS technology, can be applied to LED development and manufacturing. In the first part, the essential electrical and optical models inherent to LED modeling are reviewed. The second part of the work describes a methodology to improve the efficiency of the simulation procedure by using the concept of process compact models (PCMs). The last part demonstrates the capabilities of PCMs using an example of a blue InGaN LED. In particular, a parameter screening is performed to find the most important parameters, an optimization task incorporating the robustness of the design is carried out, and finally the impact of manufacturing tolerances on yield is investigated. It is indicated how the concept of PCMs can contribute to an efficient design for manufacturing DFM-aware development.

Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules.

PubMed

Jin, Jianjian; Gkitsas, Nikolaos; Fellowes, Vicki S; Ren, Jiaqiang; Feldman, Steven A; Hinrichs, Christian S; Stroncek, David F; Highfill, Steven L

2018-01-24

Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64-92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems.

Multivariate statistical process control in product quality review assessment - A case study.

PubMed

Kharbach, M; Cherrah, Y; Vander Heyden, Y; Bouklouze, A

2017-11-01

According to the Food and Drug Administration and the European Good Manufacturing Practices (GMP) guidelines, Annual Product Review (APR) is a mandatory requirement in GMP. It consists of evaluating a large collection of qualitative or quantitative data in order to verify the consistency of an existing process. According to the Code of Federal Regulation Part 11 (21 CFR 211.180), all finished products should be reviewed annually for the quality standards to determine the need of any change in specification or manufacturing of drug products. Conventional Statistical Process Control (SPC) evaluates the pharmaceutical production process by examining only the effect of a single factor at the time using a Shewhart's chart. It neglects to take into account the interaction between the variables. In order to overcome this issue, Multivariate Statistical Process Control (MSPC) can be used. Our case study concerns an APR assessment, where 164 historical batches containing six active ingredients, manufactured in Morocco, were collected during one year. Each batch has been checked by assaying the six active ingredients by High Performance Liquid Chromatography according to European Pharmacopoeia monographs. The data matrix was evaluated both by SPC and MSPC. The SPC indicated that all batches are under control, while the MSPC, based on Principal Component Analysis (PCA), for the data being either autoscaled or robust scaled, showed four and seven batches, respectively, out of the Hotelling T 2 95% ellipse. Also, an improvement of the capability of the process is observed without the most extreme batches. The MSPC can be used for monitoring subtle changes in the manufacturing process during an APR assessment. Copyright © 2017 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Towards the implementation of quality by design to the production of therapeutic monoclonal antibodies with desired glycosylation patterns.

PubMed

del Val, Ioscani Jimenez; Kontoravdi, Cleo; Nagy, Judit M

2010-01-01

Quality by design (QbD) is a scheme for the development, manufacture, and approval of pharmaceutical products. The end goal of QbD is to ensure product quality by building it into the manufacturing process. The main regulatory bodies are encouraging its implementation to the manufacture of all new pharmaceuticals including biological products. Monoclonal antibodies (mAbs) are currently the leading products of the biopharmaceutical industry. It has been widely reported that glycosylation directly influences the therapeutic mechanisms by which mAbs function in vivo. In addition, glycosylation has been identified as one of the main sources of monoclonal antibody heterogeneity, and thus, a critical parameter to follow during mAb manufacture. This article reviews the research on glycosylation of mAbs over the past 2 decades under the QbD scope. The categories presented under this scope are: (a) definition of the desired clinical effects of mAbs, (b) definition of the glycosylation-associated critical quality attributes (glycCQAs) of mAbs, (c) assessment of process parameters that pose a risk for mAb glycCQAs, and (d) methods for accurately quantifying glycCQAs of mAbs. The information available in all four areas leads us to conclude that implementation of QbD to the manufacture of mAbs with specific glycosylation patterns will be a reality in the near future. We also foresee that the implementation of QbD will lead to the development of more robust and efficient manufacturing processes and to a new generation of mAbs with increased clinical efficacy. Copyright © 2010 American Institute of Chemical Engineers (AIChE).

Development and Testing of High Surface Area Iridium Anodes for Molten Oxide Electrolysis

NASA Technical Reports Server (NTRS)

Shchetkovskiy, Anatoliy; McKechnie, Timothy; Sadoway, Donald R.; Paramore, James; Melendez, Orlando; Curreri, Peter A.

2010-01-01

Processing of lunar regolith into oxygen for habitat and propulsion is needed to support future space missions. Direct electrochemical reduction of molten regolith is an attractive method of processing, because no additional chemical reagents are needed. The electrochemical processing of molten oxides requires high surface area, inert anodes. Such electrodes need to be structurally robust at elevated temperatures (1400-1600?C), be resistant to thermal shock, have good electrical conductivity, be resistant to attack by molten oxide (silicate), be electrochemically stable and support high current density. Iridium with its high melting point, good oxidation resistance, superior high temperature strength and ductility is the most promising candidate for anodes in high temperature electrochemical processes. Several innovative concepts for manufacturing such anodes by electrodeposition of iridium from molten salt electrolyte (EL-Form? process) were evaluated. Iridium electrodeposition to form of complex shape components and coating was investigated. Iridium coated graphite, porous iridium structure and solid iridium anodes were fabricated. Testing of electroformed iridium anodes shows no visible degradation. The result of development, manufacturing and testing of high surface, inert iridium anodes will be presented.

Development and Testing of High Surface Area Iridium Anodes for Molten Oxide Electrolysis

NASA Technical Reports Server (NTRS)

Shchetkovskiy, Anatoliy; McKechnie, Timothy; Sadoway, Donald R.; Paramore, James; Melendez, Orlando; Curreri, Peter A.

2010-01-01

Processing of lunar regolith into oxygen for habitat and propulsion is needed to support future space missions. Direct electrochemical reduction of molten regolith is an attractive method of processing, because no additional chemical reagents are needed. The electrochemical processing of molten oxides requires high surface area, inert anodes. Such electrodes need to be structurally robust at elevated temperatures (1400-1600 C), be resistant to thermal shock, have good electrical conductivity, be resistant to attack by molten oxide (silicate), be electrochemically stable and support high current density. Iridium with its high melting point, good oxidation resistance, superior high temperature strength and ductility is the most promising candidate for anodes in high temperature electrochemical processes. Several innovative concepts for manufacturing such anodes by electrodeposition of iridium from molten salt electrolyte (EL-Form process) were evaluated. Iridium electrodeposition to form of complex shape components and coating was investigated. Iridium coated graphite, porous iridium structure and solid iridium anodes were fabricated. Testing of electroformed iridium anodes shows no visible degradation. The result of development, manufacturing and testing of high surface, inert iridium anodes will be presented.

Application of advanced diffraction based optical metrology overlay capabilities for high-volume manufacturing

NASA Astrophysics Data System (ADS)

Chen, Kai-Hsiung; Huang, Guo-Tsai; Hsieh, Hung-Chih; Ni, Wei-Feng; Chuang, S. M.; Chuang, T. K.; Ke, Chih-Ming; Huang, Jacky; Rao, Shiuan-An; Cumurcu Gysen, Aysegul; d'Alfonso, Maxime; Yueh, Jenny; Izikson, Pavel; Soco, Aileen; Wu, Jon; Nooitgedagt, Tjitte; Ottens, Jeroen; Kim, Yong Ho; Ebert, Martin

2017-03-01

On-product overlay requirements are becoming more challenging with every next technology node due to the continued decrease of the device dimensions and process tolerances. Therefore, current and future technology nodes require demanding metrology capabilities such as target designs that are robust towards process variations and high overlay measurement density (e.g. for higher order process corrections) to enable advanced process control solutions. The impact of advanced control solutions based on YieldStar overlay data is being presented in this paper. Multi patterning techniques are applied for critical layers and leading to additional overlay measurement demands. The use of 1D process steps results in the need of overlay measurements relative to more than one layer. Dealing with the increased number of overlay measurements while keeping the high measurement density and metrology accuracy at the same time presents a challenge for high volume manufacturing (HVM). These challenges are addressed by the capability to measure multi-layer targets with the recently introduced YieldStar metrology tool, YS350. On-product overlay results of such multi-layers and standard targets are presented including measurement stability performance.

Survival and engraftment of dopaminergic neurons manufactured by a Good Manufacturing Practice-compatible process.

PubMed

Peng, Jun; Liu, Qiuyue; Rao, Mahendra S; Zeng, Xianmin

2014-09-01

We have previously reported a Good Manufacturing Practice (GMP)-compatible process for generating authentic dopaminergic neurons in defined media from human pluripotent stem cells and determined the time point at which dopaminergic precursors/neurons (day 14 after neuronal stem cell [NSC] stage) can be frozen, shipped and thawed without compromising their viability and ability to mature in vitro. One important issue we wished to address is whether dopaminergic precursors/neurons manufactured by our GMP-compatible process can be cryopreserved and engrafted in animal Parkinson disease (PD) models. In this study, we evaluated the efficacy of freshly prepared and cryopreserved dopaminergic neurons in the 6-hydroxydopamine-lesioned rat PD model. We showed functional recovery up to 6 months post-transplantation in rats transplanted with our cells, whether freshly prepared or cryopreserved. In contrast, no motor improvement was observed in two control groups receiving either medium or cells at a slightly earlier stage (day 10 after NSC stage). Histologic analysis at the end point of the study (6 months post-transplantation) showed robust long-term survival of donor-derived tyrosine hydroxylase (TH)(+) dopaminergic neurons in rats transplanted with day 14 dopaminergic neurons. Moreover, TH(+) fibers emanated from the graft core into the surrounding host striatum. Consistent with the behavioral analysis, no or few TH(+) neurons were detected in animals receiving day 10 cells, although human cells were present in the graft. Importantly, no tumors were detected in any grafted rats, but long-term tumorigenic studies will need to determine the safety of our products. Dopaminergic neurons manufactured by a GMP-compatible process from human ESC survived and engrafted efficiently in the 6-OHDA PD rat model. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Characterization of a pneumatic balloon actuator for use in refreshable Braille displays.

PubMed

Fan, Richard E; Feinman, Adam M; Wottawa, Christopher; King, Chih-Hung; Franco, Miguel L; Dutson, Erik P; Grundfest, Warren S; Culjat, Martin O

2009-01-01

Many existing refreshable Braille display technologies are costly or lack robust performance. A process has been developed to fabricate consistent and reliable pneumatic balloon actuators at low material cost, using a novel manufacturing process. This technique has been adapted for use in refreshable Braille displays that feature low power consumption, ease of manufacture and small form factor. A prototype refreshable cell, conforming to American Braille standards, was developed and tested. The cell was fabricated from molded PDMS to form balloon actuators with a spin-coated silicone film, and fast pneumatic driving elements and an electronic control system were developed to drive the Braille dots. Perceptual testing was performed to determine the feasibility of the approach using a single blind human subject. The subject was able to detect randomized Braille letters rapidly generated by the actuator with 100% character detection accuracy.

Synchrotron X-ray CT characterization of titanium parts fabricated by additive manufacturing. Part II. Defects.

PubMed

Scarlett, Nicola Vivienne Yorke; Tyson, Peter; Fraser, Darren; Mayo, Sheridan; Maksimenko, Anton

2016-07-01

Synchrotron X-ray tomography (SXRT) has been applied to the study of defects within three-dimensional printed titanium parts. These parts were made using the Arcam EBM(®) (electron beam melting) process which uses powdered titanium alloy, Ti64 (Ti alloy with approximately 6%Al and 4%V) as the feed and an electron beam for the sintering/welding. The experiment was conducted on the Imaging and Medical Beamline of the Australian Synchrotron. The samples represent a selection of complex shapes with a variety of internal morphologies. Inspection via SXRT has revealed a number of defects which may not otherwise have been seen. The location and nature of such defects combined with detailed knowledge of the process conditions can contribute to understanding the interplay between design and manufacturing strategy. This fundamental understanding may subsequently be incorporated into process modelling, prediction of properties and the development of robust methodologies for the production of defect-free parts.

Assessment of a virtual functional prototyping process for the rapid manufacture of passive-dynamic ankle-foot orthoses.

PubMed

Schrank, Elisa S; Hitch, Lester; Wallace, Kevin; Moore, Richard; Stanhope, Steven J

2013-10-01

Passive-dynamic ankle-foot orthosis (PD-AFO) bending stiffness is a key functional characteristic for achieving enhanced gait function. However, current orthosis customization methods inhibit objective premanufacture tuning of the PD-AFO bending stiffness, making optimization of orthosis function challenging. We have developed a novel virtual functional prototyping (VFP) process, which harnesses the strengths of computer aided design (CAD) model parameterization and finite element analysis, to quantitatively tune and predict the functional characteristics of a PD-AFO, which is rapidly manufactured via fused deposition modeling (FDM). The purpose of this study was to assess the VFP process for PD-AFO bending stiffness. A PD-AFO CAD model was customized for a healthy subject and tuned to four bending stiffness values via VFP. Two sets of each tuned model were fabricated via FDM using medical-grade polycarbonate (PC-ISO). Dimensional accuracy of the fabricated orthoses was excellent (average 0.51 ± 0.39 mm). Manufacturing precision ranged from 0.0 to 0.74 Nm/deg (average 0.30 ± 0.36 Nm/deg). Bending stiffness prediction accuracy was within 1 Nm/deg using the manufacturer provided PC-ISO elastic modulus (average 0.48 ± 0.35 Nm/deg). Using an experimentally derived PC-ISO elastic modulus improved the optimized bending stiffness prediction accuracy (average 0.29 ± 0.57 Nm/deg). Robustness of the derived modulus was tested by carrying out the VFP process for a disparate subject, tuning the PD-AFO model to five bending stiffness values. For this disparate subject, bending stiffness prediction accuracy was strong (average 0.20 ± 0.14 Nm/deg). Overall, the VFP process had excellent dimensional accuracy, good manufacturing precision, and strong prediction accuracy with the derived modulus. Implementing VFP as part of our PD-AFO customization and manufacturing framework, which also includes fit customization, provides a novel and powerful method to predictably tune and precisely manufacture orthoses with objectively customized fit and functional characteristics.

Manufacturing and test of 2G-HTS coils for rotating machines: Challenges, conductor requirements, realization

NASA Astrophysics Data System (ADS)

Oomen, Marijn; Herkert, Werner; Bayer, Dietmar; Kummeth, Peter; Nick, Wolfgang; Arndt, Tabea

2012-11-01

We investigate the use of 2nd-generation High-Temperature Superconductors (2G-HTSs) in the rotors of electrical motors and generators. For these devices the conductor must be wound into robust impregnated coils, which are operated in vacuum at temperatures around 30 K, in strong magnetic fields of about 2T. Differences in thermal contraction between the coil former, conductor constituents, impregnation resin, bandage and heat-sink materials (assembled at room temperature) cause mechanical stresses at operating temperature. Rotating-machine operation adds Lorentz forces and challenging centripetal accelerations up to thousands of g. Second generation-HTS conductors withstand large tensile stresses in axial direction and compression in normal direction. However, shear stresses, axial compression, and tension normal to the conductor can cause degradation in superconducting properties. Such stresses can be mitigated by correct choice of materials, coil lay-out and manufacturing process. A certain stress level will remain, which the conductor must withstand. We have manufactured many impregnated round and race-track coils, using different 2G-HTS conductors, and tested them at temperatures from 25 K to 77 K. Degradation of the superconductor in early coils was traced to the mentioned differences in thermal contraction, and was completely avoided in coils produced later. We will discuss appropriate coil-winding techniques to assure robust and reliable superconductor performance.

Two-sided friction stir riveting by extrusion: A process for joining dissimilar materials

DOE PAGES

Evans, William T.; Cox, Chase D.; Strauss, Alvin M.; ...

2016-06-25

Two-sided friction stir riveting (FSR) by extrusion is an innovative process developed to rapidly, efficiently, and securely join dissimilar materials. This process extends a previously developed one sided friction stir extrusion process to create a strong and robust joint by producing a continuous, rivet-like structure through a preformed hole in one of the materials with a simultaneous, two-sided friction stir spot weld. The two-sided FSR by extrusion process securely joins the dissimilar materials together and effectively locks them in place without the use of any separate materials or fasteners. Lastly, in this paper we demonstrate the process by joining aluminummore » to steel and illustrate its potential application to automotive and aerospace manufacturing processes.« less

Methods and Research for Multi-Component Cutting Force Sensing Devices and Approaches in Machining

PubMed Central

Liang, Qiaokang; Zhang, Dan; Wu, Wanneng; Zou, Kunlin

2016-01-01

Multi-component cutting force sensing systems in manufacturing processes applied to cutting tools are gradually becoming the most significant monitoring indicator. Their signals have been extensively applied to evaluate the machinability of workpiece materials, predict cutter breakage, estimate cutting tool wear, control machine tool chatter, determine stable machining parameters, and improve surface finish. Robust and effective sensing systems with capability of monitoring the cutting force in machine operations in real time are crucial for realizing the full potential of cutting capabilities of computer numerically controlled (CNC) tools. The main objective of this paper is to present a brief review of the existing achievements in the field of multi-component cutting force sensing systems in modern manufacturing. PMID:27854322

Simple and inexpensive microfluidic devices for the generation of monodisperse multiple emulsions

NASA Astrophysics Data System (ADS)

Li, Er Qiang; Zhang, Jia Ming; Thoroddsen, Sigurdur T.

2014-01-01

Droplet-based microfluidic devices have become a preferred versatile platform for various fields in physics, chemistry and biology. Polydimethylsiloxane soft lithography, the mainstay for fabricating microfluidic devices, usually requires the usage of expensive apparatus and a complex manufacturing procedure. Here, we report the design and fabrication of simple and inexpensive microfluidic devices based on microscope glass slides and pulled glass capillaries, for generating monodisperse multiple emulsions. The advantages of our method lie in a simple manufacturing procedure, inexpensive processing equipment and flexibility in the surface modification of the designed microfluidic devices. Different types of devices have been designed and tested and the experimental results demonstrated their robustness for preparing monodisperse single, double, triple and multi-component emulsions.

Methods and Research for Multi-Component Cutting Force Sensing Devices and Approaches in Machining.

PubMed

Liang, Qiaokang; Zhang, Dan; Wu, Wanneng; Zou, Kunlin

2016-11-16

Multi-component cutting force sensing systems in manufacturing processes applied to cutting tools are gradually becoming the most significant monitoring indicator. Their signals have been extensively applied to evaluate the machinability of workpiece materials, predict cutter breakage, estimate cutting tool wear, control machine tool chatter, determine stable machining parameters, and improve surface finish. Robust and effective sensing systems with capability of monitoring the cutting force in machine operations in real time are crucial for realizing the full potential of cutting capabilities of computer numerically controlled (CNC) tools. The main objective of this paper is to present a brief review of the existing achievements in the field of multi-component cutting force sensing systems in modern manufacturing.

A quality-by-design approach to risk reduction and optimization for human embryonic stem cell cryopreservation processes.

PubMed

Mitchell, Peter D; Ratcliffe, Elizabeth; Hourd, Paul; Williams, David J; Thomas, Robert J

2014-12-01

It is well documented that cryopreservation and resuscitation of human embryonic stem cells (hESCs) is complex and ill-defined, and often suffers poor cell recovery and increased levels of undesirable cell differentiation. In this study we have applied Quality-by-Design (QbD) concepts to the critical processes of slow-freeze cryopreservation and resuscitation of hESC colony cultures. Optimized subprocesses were linked together to deliver a controlled complete process. We have demonstrated a rapid, high-throughput, and stable system for measurement of cell adherence and viability as robust markers of in-process and postrecovery cell state. We observed that measurement of adherence and viability of adhered cells at 1 h postseeding was predictive of cell proliferative ability up to 96 h in this system. Application of factorial design defined the operating spaces for cryopreservation and resuscitation, critically linking the performance of these two processes. Optimization of both processes resulted in enhanced reattachment and post-thaw viability, resulting in substantially greater recovery of cryopreserved, pluripotent cell colonies. This study demonstrates the importance of QbD concepts and tools for rapid, robust, and low-risk process design that can inform manufacturing controls and logistics.

Zero point and zero suffix methods with robust ranking for solving fully fuzzy transportation problems

NASA Astrophysics Data System (ADS)

Ngastiti, P. T. B.; Surarso, Bayu; Sutimin

2018-05-01

Transportation issue of the distribution problem such as the commodity or goods from the supply tothe demmand is to minimize the transportation costs. Fuzzy transportation problem is an issue in which the transport costs, supply and demand are in the form of fuzzy quantities. Inthe case study at CV. Bintang Anugerah Elektrik, a company engages in the manufacture of gensets that has more than one distributors. We use the methods of zero point and zero suffix to investigate the transportation minimum cost. In implementing both methods, we use robust ranking techniques for the defuzzification process. The studyresult show that the iteration of zero suffix method is less than that of zero point method.

Monitoring cure properties of out-of-autoclave BMI composites using IFPI sensor

NASA Astrophysics Data System (ADS)

Kaur, Amardeep; Anandan, Sudharshan; Yuan, Lei; Watkins, Steve E.; Chandrashekhara, K.; Xiao, Hai; Phan, Nam

2016-04-01

A non-destructive technique for inspection of a Bismaleimide (BMI) composite is presented using an optical fiber sensor. High performance BMI composites are used for Aerospace application for their mechanical strength. They are also used as an alternative to toughened epoxy resins. A femtosecond-laser-inscribed Intrinsic Fabry-Perot Interferometer (IFPI) sensor is used to perform real time cure monitoring of a BMI composite. The composite is cured using the out-of-autoclave (OOA) process. The IFPI sensor was used for in-situ monitoring; different curing stages are analyzed throughout the curing process. Temperature-induced-strain was measured to analyze the cure properties. The IFPI structure comprises of two reflecting mirrors inscribed on the core of the fiber using a femtosecond-laser manufacturing process. The manufacturing process makes the sensor thermally stable and robust for embedded applications. The sensor can withstand very high temperatures of up to 850 °C. The temperature and strain sensitivities of embedded IFPI sensor were measured to be 1.4 pm/μepsilon and 0.6 pm/μepsilon respectively.

Factory-Calibrated Continuous Glucose Sensors: The Science Behind the Technology.

PubMed

Hoss, Udo; Budiman, Erwin Satrya

2017-05-01

The use of commercially available continuous glucose monitors for diabetes management requires sensor calibrations, which until recently are exclusively performed by the patient. A new development is the implementation of factory calibration for subcutaneous glucose sensors, which eliminates the need for user calibrations and the associated blood glucose tests. Factory calibration means that the calibration process is part of the sensor manufacturing process and performed under controlled laboratory conditions. The ability to move from a user calibration to factory calibration is based on several technical requirements related to sensor stability and the robustness of the sensor manufacturing process. The main advantages of factory calibration over the conventional user calibration are: (a) more convenience for the user, since no more fingersticks are required for calibration and (b) elimination of use errors related to the execution of the calibration process, which can lead to sensor inaccuracies. The FreeStyle Libre ™ and FreeStyle Libre Pro ™ flash continuous glucose monitoring systems are the first commercially available sensor systems using factory-calibrated sensors. For these sensor systems, no user calibrations are required throughout the sensor wear duration.

A novel approach of ensuring layout regularity correct by construction in advanced technologies

NASA Astrophysics Data System (ADS)

Ahmed, Shafquat Jahan; Vaderiya, Yagnesh; Gupta, Radhika; Parthasarathy, Chittoor; Marin, Jean-Claude; Robert, Frederic

2017-03-01

In advanced technology nodes, layout regularity has become a mandatory prerequisite to create robust designs less sensitive to variations in manufacturing process in order to improve yield and minimizing electrical variability. In this paper we describe a method for designing regular full custom layouts based on design and process co-optimization. The method includes various design rule checks that can be used on-the-fly during leaf-cell layout development. We extract a Layout Regularity Index (LRI) from the layouts based on the jogs, alignments and pitches used in the design for any given metal layer. Regularity Index of a layout is the direct indicator of manufacturing yield and is used to compare the relative health of different layout blocks in terms of process friendliness. The method has been deployed for 28nm and 40nm technology nodes for Memory IP and is being extended to other IPs (IO, standard-cell). We have quantified the gain of layout regularity with the deployed method on printability and electrical characteristics by process-variation (PV) band simulation analysis and have achieved up-to 5nm reduction in PV band.

Factory-Calibrated Continuous Glucose Sensors: The Science Behind the Technology

PubMed Central

Budiman, Erwin Satrya

2017-01-01

Abstract The use of commercially available continuous glucose monitors for diabetes management requires sensor calibrations, which until recently are exclusively performed by the patient. A new development is the implementation of factory calibration for subcutaneous glucose sensors, which eliminates the need for user calibrations and the associated blood glucose tests. Factory calibration means that the calibration process is part of the sensor manufacturing process and performed under controlled laboratory conditions. The ability to move from a user calibration to factory calibration is based on several technical requirements related to sensor stability and the robustness of the sensor manufacturing process. The main advantages of factory calibration over the conventional user calibration are: (a) more convenience for the user, since no more fingersticks are required for calibration and (b) elimination of use errors related to the execution of the calibration process, which can lead to sensor inaccuracies. The FreeStyle Libre™ and FreeStyle Libre Pro™ flash continuous glucose monitoring systems are the first commercially available sensor systems using factory-calibrated sensors. For these sensor systems, no user calibrations are required throughout the sensor wear duration. PMID:28541139

Aerogels Insulate Missions and Consumer Products

NASA Technical Reports Server (NTRS)

2008-01-01

Aspen Aerogels, of Northborough, Massachusetts, worked with NASA through an SBIR contract with Kennedy Space Center to develop a robust, flexible form of aerogel for cryogenic insulation for space shuttle launch applications. The company has since used the same manufacturing process developed under the SBIR award to expand its product offerings into the more commercial realms, making the naturally fragile aerogel available for the first time as a standard insulation that can be handled and installed just like standard insulation.

Advances in industrial biopharmaceutical batch process monitoring: Machine-learning methods for small data problems.

PubMed

Tulsyan, Aditya; Garvin, Christopher; Ündey, Cenk

2018-04-06

Biopharmaceutical manufacturing comprises of multiple distinct processing steps that require effective and efficient monitoring of many variables simultaneously in real-time. The state-of-the-art real-time multivariate statistical batch process monitoring (BPM) platforms have been in use in recent years to ensure comprehensive monitoring is in place as a complementary tool for continued process verification to detect weak signals. This article addresses a longstanding, industry-wide problem in BPM, referred to as the "Low-N" problem, wherein a product has a limited production history. The current best industrial practice to address the Low-N problem is to switch from a multivariate to a univariate BPM, until sufficient product history is available to build and deploy a multivariate BPM platform. Every batch run without a robust multivariate BPM platform poses risk of not detecting potential weak signals developing in the process that might have an impact on process and product performance. In this article, we propose an approach to solve the Low-N problem by generating an arbitrarily large number of in silico batches through a combination of hardware exploitation and machine-learning methods. To the best of authors' knowledge, this is the first article to provide a solution to the Low-N problem in biopharmaceutical manufacturing using machine-learning methods. Several industrial case studies from bulk drug substance manufacturing are presented to demonstrate the efficacy of the proposed approach for BPM under various Low-N scenarios. © 2018 Wiley Periodicals, Inc.

Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production.

PubMed

Baronsky-Probst, J; Möltgen, C-V; Kessler, W; Kessler, R W

2016-05-25

Hot melt extrusion (HME) is a well-known process within the plastic and food industries that has been utilized for the past several decades and is increasingly accepted by the pharmaceutical industry for continuous manufacturing. For tamper-resistant formulations of e.g. opioids, HME is the most efficient production technique. The focus of this study is thus to evaluate the manufacturability of the HME process for tamper-resistant formulations. Parameters such as the specific mechanical energy (SME), as well as the melt pressure and its standard deviation, are important and will be discussed in this study. In the first step, the existing process data are analyzed by means of multivariate data analysis. Key critical process parameters such as feed rate, screw speed, and the concentration of the API in the polymers are identified, and critical quality parameters of the tablet are defined. In the second step, a relationship between the critical material, product and process quality attributes are established by means of Design of Experiments (DoEs). The resulting SME and the temperature at the die are essential data points needed to indirectly qualify the degradation of the API, which should be minimal. NIR-spectroscopy is used to monitor the material during the extrusion process. In contrast to most applications in which the probe is directly integrated into the die, the optical sensor is integrated into the cooling line of the strands. This saves costs in the probe design and maintenance and increases the robustness of the chemometric models. Finally, a process measurement system is installed to monitor and control all of the critical attributes in real-time by means of first principles, DoE models, soft sensor models, and spectroscopic information. Overall, the process is very robust as long as the screw speed is kept low. Copyright © 2015 Elsevier B.V. All rights reserved.

Automatic Defect Detection for TFT-LCD Array Process Using Quasiconformal Kernel Support Vector Data Description

PubMed Central

Liu, Yi-Hung; Chen, Yan-Jen

2011-01-01

Defect detection has been considered an efficient way to increase the yield rate of panels in thin film transistor liquid crystal display (TFT-LCD) manufacturing. In this study we focus on the array process since it is the first and key process in TFT-LCD manufacturing. Various defects occur in the array process, and some of them could cause great damage to the LCD panels. Thus, how to design a method that can robustly detect defects from the images captured from the surface of LCD panels has become crucial. Previously, support vector data description (SVDD) has been successfully applied to LCD defect detection. However, its generalization performance is limited. In this paper, we propose a novel one-class machine learning method, called quasiconformal kernel SVDD (QK-SVDD) to address this issue. The QK-SVDD can significantly improve generalization performance of the traditional SVDD by introducing the quasiconformal transformation into a predefined kernel. Experimental results, carried out on real LCD images provided by an LCD manufacturer in Taiwan, indicate that the proposed QK-SVDD not only obtains a high defect detection rate of 96%, but also greatly improves generalization performance of SVDD. The improvement has shown to be over 30%. In addition, results also show that the QK-SVDD defect detector is able to accomplish the task of defect detection on an LCD image within 60 ms. PMID:22016625

Automatic defect detection for TFT-LCD array process using quasiconformal kernel support vector data description.

PubMed

Liu, Yi-Hung; Chen, Yan-Jen

2011-01-01

Defect detection has been considered an efficient way to increase the yield rate of panels in thin film transistor liquid crystal display (TFT-LCD) manufacturing. In this study we focus on the array process since it is the first and key process in TFT-LCD manufacturing. Various defects occur in the array process, and some of them could cause great damage to the LCD panels. Thus, how to design a method that can robustly detect defects from the images captured from the surface of LCD panels has become crucial. Previously, support vector data description (SVDD) has been successfully applied to LCD defect detection. However, its generalization performance is limited. In this paper, we propose a novel one-class machine learning method, called quasiconformal kernel SVDD (QK-SVDD) to address this issue. The QK-SVDD can significantly improve generalization performance of the traditional SVDD by introducing the quasiconformal transformation into a predefined kernel. Experimental results, carried out on real LCD images provided by an LCD manufacturer in Taiwan, indicate that the proposed QK-SVDD not only obtains a high defect detection rate of 96%, but also greatly improves generalization performance of SVDD. The improvement has shown to be over 30%. In addition, results also show that the QK-SVDD defect detector is able to accomplish the task of defect detection on an LCD image within 60 ms.

Concurrent use of magnetic bearings for rotor support and force sensing for the nondestructive evaluation of manufacturing processes

NASA Astrophysics Data System (ADS)

Kasarda, Mary; Imlach, Joseph; Balaji, P. A.; Marshall, Jeremy T.

2000-06-01

Active magnetic bearings are a proven technology in turbomachinery applications and they offer considerable promise for improving the performance of manufacturing processes. The Active Magnetic Bearing (AMB) is a feedback mechanism that supports a spinning shaft by levitating it in a magnetic field. AMBs have significantly higher surface speed capability than rolling element bearings and they eliminate the potential for product contamination by eliminating the requirement for bearing lubrication. In addition, one of the most promising capabilities for manufacturing applications is the ability of the AMB to act concurrently as both a support bearing and non-invasive force sensor. The feedback nature of the AMB allows for its use as a load cell to continuously measure shaft forces necessary for levitation based on information about the magnetic flux density in the air gaps. This measurement capability may be exploited to improve the process control of such products as textile fibers and photographic films where changes in shaft loads may indicate changes in product quality. This paper discusses the operation of AMBs and their potential benefits in manufacturing equipment along with results from research addressing accurate AMB force sensing performance in field applications. Specifically, results from the development of enhanced AMB measurement algorithms to better account for magnetic fringing and leakage effects to improve the accuracy of this technique are presented. Results from the development of a new on-line calibration procedure for robust in-situ calibration of AMBs in a field application such as a manufacturing plant scenario are also presented including results of Magnetic Finite Element Analysis (MFEA) verification of the procedure.

Holistic metrology qualification extension and its application to characterize overlay targets with asymmetric effects

NASA Astrophysics Data System (ADS)

Dos Santos Ferreira, Olavio; Sadat Gousheh, Reza; Visser, Bart; Lie, Kenrick; Teuwen, Rachel; Izikson, Pavel; Grzela, Grzegorz; Mokaberi, Babak; Zhou, Steve; Smith, Justin; Husain, Danish; Mandoy, Ram S.; Olvera, Raul

2018-03-01

Ever increasing need for tighter on-product overlay (OPO), as well as enhanced accuracy in overlay metrology and methodology, is driving semiconductor industry's technologists to innovate new approaches to OPO measurements. In case of High Volume Manufacturing (HVM) fabs, it is often critical to strive for both accuracy and robustness. Robustness, in particular, can be challenging in metrology since overlay targets can be impacted by proximity of other structures next to the overlay target (asymmetric effects), as well as symmetric stack changes such as photoresist height variations. Both symmetric and asymmetric contributors have impact on robustness. Furthermore, tweaking or optimizing wafer processing parameters for maximum yield may have an adverse effect on physical target integrity. As a result, measuring and monitoring physical changes or process abnormalities/artefacts in terms of new Key Performance Indicators (KPIs) is crucial for the end goal of minimizing true in-die overlay of the integrated circuits (ICs). IC manufacturing fabs often relied on CD-SEM in the past to capture true in-die overlay. Due to destructive and intrusive nature of CD-SEMs on certain materials, it's desirable to characterize asymmetry effects for overlay targets via inline KPIs utilizing YieldStar (YS) metrology tools. These KPIs can also be integrated as part of (μDBO) target evaluation and selection for final recipe flow. In this publication, the Holistic Metrology Qualification (HMQ) flow was extended to account for process induced (asymmetric) effects such as Grating Imbalance (GI) and Bottom Grating Asymmetry (BGA). Local GI typically contributes to the intrafield OPO whereas BGA typically impacts the interfield OPO, predominantly at the wafer edge. Stack height variations highly impact overlay metrology accuracy, in particular in case of multi-layer LithoEtch Litho-Etch (LELE) overlay control scheme. Introducing a GI impact on overlay (in nm) KPI check quantifies the grating imbalance impact on overlay, whereas optimizing for accuracy using self-reference captures the bottom grating asymmetry effect. Measuring BGA after each process step before exposure of the top grating helps to identify which specific step introduces the asymmetry in the bottom grating. By evaluating this set of KPI's to a BEOL LELE overlay scheme, we can enhance robustness of recipe selection and target selection. Furthermore, these KPIs can be utilized to highlight process and equipment abnormalities. In this work, we also quantified OPO results with a self-contained methodology called Triangle Method. This method can be utilized for LELE layers with a common target and reference. This allows validating general μDBO accuracy, hence reducing the need for CD-SEM verification.

New numerical approach for the modelling of machining applied to aeronautical structural parts

NASA Astrophysics Data System (ADS)

Rambaud, Pierrick; Mocellin, Katia

2018-05-01

The manufacturing of aluminium alloy structural aerospace parts involves several steps: forming (rolling, forging …etc), heat treatments and machining. Before machining, the manufacturing processes have embedded residual stresses into the workpiece. The final geometry is obtained during this last step, when up to 90% of the raw material volume is removed by machining. During this operation, the mechanical equilibrium of the part is in constant evolution due to the redistribution of the initial stresses. This redistribution is the main cause for workpiece deflections during machining and for distortions - after unclamping. Both may lead to non-conformity of the part regarding the geometrical and dimensional specifications and therefore to rejection of the part or additional conforming steps. In order to improve the machining accuracy and the robustness of the process, the effect of the residual stresses has to be considered for the definition of the machining process plan and even in the geometrical definition of the part. In this paper, the authors present two new numerical approaches concerning the modelling of machining of aeronautical structural parts. The first deals with the use of an immersed volume framework to model the cutting step, improving the robustness and the quality of the resulting mesh compared to the previous version. The second is about the mechanical modelling of the machining problem. The authors thus show that in the framework of rolled aluminium parts the use of a linear elasticity model is functional in the finite element formulation and promising regarding the reduction of computation times.

Single pass tangential flow filtration to debottleneck downstream processing for therapeutic antibody production.

PubMed

Dizon-Maspat, Jemelle; Bourret, Justin; D'Agostini, Anna; Li, Feng

2012-04-01

As the therapeutic monoclonal antibody (mAb) market continues to grow, optimizing production processes is becoming more critical in improving efficiencies and reducing cost-of-goods in large-scale production. With the recent trends of increasing cell culture titers from upstream process improvements, downstream capacity has become the bottleneck in many existing manufacturing facilities. Single Pass Tangential Flow Filtration (SPTFF) is an emerging technology, which is potentially useful in debottlenecking downstream capacity, especially when the pool tank size is a limiting factor. It can be integrated as part of an existing purification process, after a column chromatography step or a filtration step, without introducing a new unit operation. In this study, SPTFF technology was systematically evaluated for reducing process intermediate volumes from 2× to 10× with multiple mAbs and the impact of SPTFF on product quality, and process yield was analyzed. Finally, the potential fit into the typical 3-column industry platform antibody purification process and its implementation in a commercial scale manufacturing facility were also evaluated. Our data indicate that using SPTFF to concentrate protein pools is a simple, flexible, and robust operation, which can be implemented at various scales to improve antibody purification process capacity. Copyright © 2011 Wiley Periodicals, Inc.

Large-scale self-assembled zirconium phosphate smectic layers via a simple spray-coating process

NASA Astrophysics Data System (ADS)

Wong, Minhao; Ishige, Ryohei; White, Kevin L.; Li, Peng; Kim, Daehak; Krishnamoorti, Ramanan; Gunther, Robert; Higuchi, Takeshi; Jinnai, Hiroshi; Takahara, Atsushi; Nishimura, Riichi; Sue, Hung-Jue

2014-04-01

The large-scale assembly of asymmetric colloidal particles is used in creating high-performance fibres. A similar concept is extended to the manufacturing of thin films of self-assembled two-dimensional crystal-type materials with enhanced and tunable properties. Here we present a spray-coating method to manufacture thin, flexible and transparent epoxy films containing zirconium phosphate nanoplatelets self-assembled into a lamellar arrangement aligned parallel to the substrate. The self-assembled mesophase of zirconium phosphate nanoplatelets is stabilized by epoxy pre-polymer and exhibits rheology favourable towards large-scale manufacturing. The thermally cured film forms a mechanically robust coating and shows excellent gas barrier properties at both low- and high humidity levels as a result of the highly aligned and overlapping arrangement of nanoplatelets. This work shows that the large-scale ordering of high aspect ratio nanoplatelets is easier to achieve than previously thought and may have implications in the technological applications for similar materials.

The evolving role of supply chain management technology in healthcare.

PubMed

Langabeer, Jim

2005-01-01

The healthcare supply chain is a vast, disintegrated network of products and players, loosely held together by manual and people-intensive processes. Managing the flow of information, supplies, equipment, and services from manufacturers to distributors to providers of care is especially difficult in clinical supply chains, compared with more technology-intense industries like consumer goods or industrial manufacturing. As supplies move downstream towards hospitals and clinics, the quality and robustness of accompanying management and information systems used to manage these products deteriorates significantly. Technology that provides advanced planning, synchronization, and collaboration upstream at the large supply manufacturers and distributors rarely is used at even the world's larger and more sophisticated hospitals. This article outlines the current state of healthcare supply chain management technologies, addresses potential reasons for the lack of adoption of technologies and provides a roadmap for the evolution of technology for the future. This piece is based on both quantitative and qualitative research assessments of the healthcare supply chain conducted during the last two years.

Optimization of rotor shaft shrink fit method for motor using "Robust design"

NASA Astrophysics Data System (ADS)

Toma, Eiji

2018-01-01

This research is collaborative investigation with the general-purpose motor manufacturer. To review construction method in production process, we applied the parameter design method of quality engineering and tried to approach the optimization of construction method. Conventionally, press-fitting method has been adopted in process of fitting rotor core and shaft which is main component of motor, but quality defects such as core shaft deflection occurred at the time of press fitting. In this research, as a result of optimization design of "shrink fitting method by high-frequency induction heating" devised as a new construction method, its construction method was feasible, and it was possible to extract the optimum processing condition.

A carbon dioxide stripping model for mammalian cell culture in manufacturing scale bioreactors.

PubMed

Xing, Zizhuo; Lewis, Amanda M; Borys, Michael C; Li, Zheng Jian

2017-06-01

Control of carbon dioxide within the optimum range is important in mammalian bioprocesses at the manufacturing scale in order to ensure robust cell growth, high protein yields, and consistent quality attributes. The majority of bioprocess development work is done in laboratory bioreactors, in which carbon dioxide levels are more easily controlled. Some challenges in carbon dioxide control can present themselves when cell culture processes are scaled up, because carbon dioxide accumulation is a common feature due to longer gas-residence time of mammalian cell culture in large scale bioreactors. A carbon dioxide stripping model can be used to better understand and optimize parameters that are critical to cell culture processes at the manufacturing scale. The prevailing carbon dioxide stripping models in literature depend on mass transfer coefficients and were applicable to cell culture processes with low cell density or at stationary/cell death phase. However, it was reported that gas bubbles are saturated with carbon dioxide before leaving the culture, which makes carbon dioxide stripping no longer depend on a mass transfer coefficient in the new generation cell culture processes characterized by longer exponential growth phase, higher peak viable cell densities, and higher specific production rate. Here, we present a new carbon dioxide stripping model for manufacturing scale bioreactors, which is independent of carbon dioxide mass transfer coefficient, but takes into account the gas-residence time and gas CO 2 saturation time. The model was verified by CHO cell culture processes with different peak viable cell densities (7 to 12 × 10 6  cells mL -1 ) for two products in 5,000-L and 25,000-L bioreactors. The model was also applied to a next generation cell culture process to optimize cell culture conditions and reduce carbon dioxide levels at manufacturing scale. The model provides a useful tool to understand and better control cell culture carbon dioxide profiles for process development, scale up, and characterization. Biotechnol. Bioeng. 2017;114: 1184-1194. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Thermographic Microstructure Monitoring in Electron Beam Additive Manufacturing.

PubMed

Raplee, J; Plotkowski, A; Kirka, M M; Dinwiddie, R; Okello, A; Dehoff, R R; Babu, S S

2017-03-03

To reduce the uncertainty of build performance in metal additive manufacturing, robust process monitoring systems that can detect imperfections and improve repeatability are desired. One of the most promising methods for in situ monitoring is thermographic imaging. However, there is a challenge in using this technology due to the difference in surface emittance between the metal powder and solidified part being observed that affects the accuracy of the temperature data collected. The purpose of the present study was to develop a method for properly calibrating temperature profiles from thermographic data to account for this emittance change and to determine important characteristics of the build through additional processing. The thermographic data was analyzed to identify the transition of material from metal powder to a solid as-printed part. A corrected temperature profile was then assembled for each point using calibrations for these surface conditions. Using this data, the thermal gradient and solid-liquid interface velocity were approximated and correlated to experimentally observed microstructural variation within the part. This work shows that by using a method of process monitoring, repeatability of a build could be monitored specifically in relation to microstructure control.

Thermographic Microstructure Monitoring in Electron Beam Additive Manufacturing

DOE PAGES

Raplee, Jake B.; Plotkowski, Alex J.; Kirka, Michael M.; ...

2017-03-03

To reduce the uncertainty of build performance in metal additive manufacturing, robust process monitoring systems that can detect imperfections and improve repeatability are desired. One of the most promising methods for in-situ monitoring is thermographic imaging. However, there is a challenge in using this technology due to the difference in surface emittance between the metal powder and solidified part being observed that affects the accuracy of the temperature data collected. This developed a method for properly calibrating temperature profiles from thermographic data and then determining important characteristics of the build through additional processing. The thermographic data was analyzed to determinemore » the transition of material from metal powder to a solid as-printed part. A corrected temperature profile was then assembled for each point using calibrations for these surface conditions. Using this data, we calculated the thermal gradient and solid-liquid interface velocity and correlated it to microstructural variation within the part experimentally. This work shows that by using a method of process monitoring, repeatability of a build could be monitored specifically in relation to microstructure control.« less

Solid electrolyte material manufacturable by polymer processing methods

DOEpatents

Singh, Mohit; Gur, Ilan; Eitouni, Hany Basam; Balsara, Nitash Pervez

2012-09-18

The present invention relates generally to electrolyte materials. According to an embodiment, the present invention provides for a solid polymer electrolyte material that is ionically conductive, mechanically robust, and can be formed into desirable shapes using conventional polymer processing methods. An exemplary polymer electrolyte material has an elastic modulus in excess of 1.times.10.sup.6 Pa at 90 degrees C. and is characterized by an ionic conductivity of at least 1.times.10.sup.-5 Scm-1 at 90 degrees C. An exemplary material can be characterized by a two domain or three domain material system. An exemplary material can include material components made of diblock polymers or triblock polymers. Many uses are contemplated for the solid polymer electrolyte materials. For example, the present invention can be applied to improve Li-based batteries by means of enabling higher energy density, better thermal and environmental stability, lower rates of self-discharge, enhanced safety, lower manufacturing costs, and novel form factors.

Mass-manufacturable polymer microfluidic device for dual fiber optical trapping.

PubMed

De Coster, Diane; Ottevaere, Heidi; Vervaeke, Michael; Van Erps, Jürgen; Callewaert, Manly; Wuytens, Pieter; Simpson, Stephen H; Hanna, Simon; De Malsche, Wim; Thienpont, Hugo

2015-11-30

We present a microfluidic chip in Polymethyl methacrylate (PMMA) for optical trapping of particles in an 80µm wide microchannel using two counterpropagating single-mode beams. The trapping fibers are separated from the sample fluid by 70µm thick polymer walls. We calculate the optical forces that act on particles flowing in the microchannel using wave optics in combination with non-sequential ray-tracing and further mathematical processing. Our results are compared with a theoretical model and the Mie theory. We use a novel fabrication process that consists of a premilling step and ultraprecision diamond tooling for the manufacturing of the molds and double-sided hot embossing for replication, resulting in a robust microfluidic chip for optical trapping. In a proof-of-concept demonstration, we show the trapping capabilities of the hot embossed chip by trapping spherical beads with a diameter of 6µm, 8µm and 10µm and use the power spectrum analysis of the trapped particle displacements to characterize the trap strength.

Magnetically assisted slip casting of bioinspired heterogeneous composites

NASA Astrophysics Data System (ADS)

Le Ferrand, Hortense; Bouville, Florian; Niebel, Tobias P.; Studart, André R.

2015-11-01

Natural composites are often heterogeneous to fulfil functional demands. Manufacturing analogous materials remains difficult, however, owing to the lack of adequate and easily accessible processing tools. Here, we report an additive manufacturing platform able to fabricate complex-shaped parts exhibiting bioinspired heterogeneous microstructures with locally tunable texture, composition and properties, as well as unprecedentedly high volume fractions of inorganic phase (up to 100%). The technology combines an aqueous-based slip-casting process with magnetically directed particle assembly to create programmed microstructural designs using anisotropic stiff platelets in a ceramic, metal or polymer functional matrix. Using quantitative tools to control the casting kinetics and the temporal pattern of the applied magnetic fields, we demonstrate that this approach is robust and can be exploited to design and fabricate heterogeneous composites with thus far inaccessible microstructures. Proof-of-concept examples include bulk composites with periodic patterns of microreinforcement orientation, and tooth-like bilayer parts with intricate shapes exhibiting site-specific composition and texture.

Global Value Chain and Manufacturing Analysis on Geothermal Power Plant Turbines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akar, Sertac; Augustine, Chad; Kurup, Parthiv

In this study, we have undertaken a robust analysis of the global supply chain and manufacturing costs for components of Organic Rankine Cycle (ORC) Turboexpander and steam turbines used in geothermal power plants. We collected a range of market data influencing manufacturing from various data sources and determined the main international manufacturers in the industry. The data includes the manufacturing cost model to identify requirements for equipment, facilities, raw materials, and labor. We analyzed three different cases; 1) 1 MW geothermal ORC Turboexpander 2) 5 MW ORC Turboexpander 3) 20 MW geothermal Steam Turbine

The Use of Multidimensional Image-Based Analysis to Accurately Monitor Cell Growth in 3D Bioreactor Culture

PubMed Central

Baradez, Marc-Olivier; Marshall, Damian

2011-01-01

The transition from traditional culture methods towards bioreactor based bioprocessing to produce cells in commercially viable quantities for cell therapy applications requires the development of robust methods to ensure the quality of the cells produced. Standard methods for measuring cell quality parameters such as viability provide only limited information making process monitoring and optimisation difficult. Here we describe a 3D image-based approach to develop cell distribution maps which can be used to simultaneously measure the number, confluency and morphology of cells attached to microcarriers in a stirred tank bioreactor. The accuracy of the cell distribution measurements is validated using in silico modelling of synthetic image datasets and is shown to have an accuracy >90%. Using the cell distribution mapping process and principal component analysis we show how cell growth can be quantitatively monitored over a 13 day bioreactor culture period and how changes to manufacture processes such as initial cell seeding density can significantly influence cell morphology and the rate at which cells are produced. Taken together, these results demonstrate how image-based analysis can be incorporated in cell quality control processes facilitating the transition towards bioreactor based manufacture for clinical grade cells. PMID:22028809

The use of multidimensional image-based analysis to accurately monitor cell growth in 3D bioreactor culture.

PubMed

Baradez, Marc-Olivier; Marshall, Damian

2011-01-01

The transition from traditional culture methods towards bioreactor based bioprocessing to produce cells in commercially viable quantities for cell therapy applications requires the development of robust methods to ensure the quality of the cells produced. Standard methods for measuring cell quality parameters such as viability provide only limited information making process monitoring and optimisation difficult. Here we describe a 3D image-based approach to develop cell distribution maps which can be used to simultaneously measure the number, confluency and morphology of cells attached to microcarriers in a stirred tank bioreactor. The accuracy of the cell distribution measurements is validated using in silico modelling of synthetic image datasets and is shown to have an accuracy >90%. Using the cell distribution mapping process and principal component analysis we show how cell growth can be quantitatively monitored over a 13 day bioreactor culture period and how changes to manufacture processes such as initial cell seeding density can significantly influence cell morphology and the rate at which cells are produced. Taken together, these results demonstrate how image-based analysis can be incorporated in cell quality control processes facilitating the transition towards bioreactor based manufacture for clinical grade cells.

A Multi-Agent Approach to the Simulation of Robotized Manufacturing Systems

NASA Astrophysics Data System (ADS)

Foit, K.; Gwiazda, A.; Banaś, W.

2016-08-01

The recent years of eventful industry development, brought many competing products, addressed to the same market segment. The shortening of a development cycle became a necessity if the company would like to be competitive. Because of switching to the Intelligent Manufacturing model the industry search for new scheduling algorithms, while the traditional ones do not meet the current requirements. The agent-based approach has been considered by many researchers as an important way of evolution of modern manufacturing systems. Due to the properties of the multi-agent systems, this methodology is very helpful during creation of the model of production system, allowing depicting both processing and informational part. The complexity of such approach makes the analysis impossible without the computer assistance. Computer simulation still uses a mathematical model to recreate a real situation, but nowadays the 2D or 3D virtual environments or even virtual reality have been used for realistic illustration of the considered systems. This paper will focus on robotized manufacturing system and will present the one of possible approaches to the simulation of such systems. The selection of multi-agent approach is motivated by the flexibility of this solution that offers the modularity, robustness and autonomy.

EUV mask pilot line at Intel Corporation

NASA Astrophysics Data System (ADS)

Stivers, Alan R.; Yan, Pei-Yang; Zhang, Guojing; Liang, Ted; Shu, Emily Y.; Tejnil, Edita; Lieberman, Barry; Nagpal, Rajesh; Hsia, Kangmin; Penn, Michael; Lo, Fu-Chang

2004-12-01

The introduction of extreme ultraviolet (EUV) lithography into high volume manufacturing requires the development of a new mask technology. In support of this, Intel Corporation has established a pilot line devoted to encountering and eliminating barriers to manufacturability of EUV masks. It concentrates on EUV-specific process modules and makes use of the captive standard photomask fabrication capability of Intel Corporation. The goal of the pilot line is to accelerate EUV mask development to intersect the 32nm technology node. This requires EUV mask technology to be comparable to standard photomask technology by the beginning of the silicon wafer process development phase for that technology node. The pilot line embodies Intel's strategy to lead EUV mask development in the areas of the mask patterning process, mask fabrication tools, the starting material (blanks) and the understanding of process interdependencies. The patterning process includes all steps from blank defect inspection through final pattern inspection and repair. We have specified and ordered the EUV-specific tools and most will be installed in 2004. We have worked with International Sematech and others to provide for the next generation of EUV-specific mask tools. Our process of record is run repeatedly to ensure its robustness. This primes the supply chain and collects information needed for blank improvement.

CFD Analysis of the Oscillating Flow within a Stirling Engine with an Additively Manufactured Foil Type Regenerator

NASA Astrophysics Data System (ADS)

Qiu, Songgang; Solomon, Laura

2017-11-01

The simplistic design, fuel independence, and robustness of Stirling convertors makes them the ideal choice for use in solar power and combined heat and power (CHP) applications. A lack of moving parts and the use of novel flexure bearings allows free-piston type Stirling engines to run in excess of ten years without degradation or maintenance. The key component to their overall efficiency is the regenerator. While a foil type regenerator outperforms a sintered random fiber regenerator, limitation in manufacturing and keeping uniform spacing between the foils has limited their overall use. However, with the advent of additive manufacturing, a robust foil type regenerator can be cheaply manufactured without traditional limitations. Currently, a CFD analysis of the oscillating internal flow within the novel design was conducted to evaluate the flow loses within the system. Particularly the pressure drop across the regenerator in comparison to a traditionally used random fiber regenerator. Additionally, the heat transfer and flow over the tubular heater hear was evaluated. The results of the investigation will be used to optimize the operation of the next generation of additively manufactured Stirling convertors. This research was supported by ARPA-E and West Virginia University.

The Highly Robust Electrical Interconnects and Ultrasensitive Biosensors Based on Embedded Carbon Nanotube Arrays

NASA Technical Reports Server (NTRS)

Li, Jun; Cassell, Alan; Koehne, Jessica; Chen, Hua; Ng, Hou Tee; Ye, Qi; Stevens, Ramsey; Han, Jie; Meyyappan, M.

2003-01-01

We report on our recent breakthroughs in two different applications using well-aligned carbon nanotube (CNT) arrays on Si chips, including (1) a novel processing solution for highly robust electrical interconnects in integrated circuit manufacturing, and (2) the development of ultrasensitive electrochemical DNA sensors. Both of them rely on the invention of a bottom-up fabrication scheme which includes six steps, including: (a) lithographic patterning, (b) depositing bottom conducting contacts, (c) depositing metal catalysts, (d) CNT growth by plasma enhanced chemical vapor deposition (PECVD), (e) dielectric gap-filling, and (f) chemical mechanical polishing (CMP). Such processes produce a stable planarized surface with only the open end of CNTs exposed, whch can be further processed or modified for different applications. By depositing patterned top contacts, the CNT can serve as vertical interconnects between the two conducting layers. This method is fundamentally different fiom current damascene processes and avoids problems associated with etching and filling of high aspect ratio holes at nanoscales. In addition, multiwalled CNTs (MWCNTs) are highly robust and can carry a current density of 10(exp 9) A/square centimeters without degradation. It has great potential to help extending the current Si technology. The embedded MWCNT array without the top contact layer can be also used as a nanoelectrode array in electrochemical biosensors. The cell time-constant and sensitivity can be dramatically improved. By functionalizing the tube ends with specific oligonucleotide probes, specific DNA targets can be detected with electrochemical methods down to subattomoles.

Manufacturing the Gas Diffusion Layer for PEM Fuel Cell Using a Novel 3D Printing Technique and Critical Assessment of the Challenges Encountered

PubMed Central

Singamneni, Sarat; Ramos, Maximiano; Al-Jumaily, Ahmed M

2017-01-01

The conventional gas diffusion layer (GDL) of polymer electrolyte membrane (PEM) fuel cells incorporates a carbon-based substrate, which suffers from electrochemical oxidation as well as mechanical degradation, resulting in reduced durability and performance. In addition, it involves a complex manufacturing process to produce it. The proposed technique aims to resolve both these issues by an advanced 3D printing technique, namely selective laser sintering (SLS). In the proposed work, polyamide (PA) is used as the base powder and titanium metal powder is added at an optimised level to enhance the electrical conductivity, thermal, and mechanical properties. The application of selective laser sintering to fabricate a robust gas diffusion substrate for PEM fuel cell applications is quite novel and is attempted here for the first time. PMID:28773156

Manufacturing the Gas Diffusion Layer for PEM Fuel Cell Using a Novel 3D Printing Technique and Critical Assessment of the Challenges Encountered.

PubMed

Jayakumar, Arunkumar; Singamneni, Sarat; Ramos, Maximiano; Al-Jumaily, Ahmed M; Pethaiah, Sethu Sundar

2017-07-14

The conventional gas diffusion layer (GDL) of polymer electrolyte membrane (PEM) fuel cells incorporates a carbon-based substrate, which suffers from electrochemical oxidation as well as mechanical degradation, resulting in reduced durability and performance. In addition, it involves a complex manufacturing process to produce it. The proposed technique aims to resolve both these issues by an advanced 3D printing technique, namely selective laser sintering (SLS). In the proposed work, polyamide (PA) is used as the base powder and titanium metal powder is added at an optimised level to enhance the electrical conductivity, thermal, and mechanical properties. The application of selective laser sintering to fabricate a robust gas diffusion substrate for PEM fuel cell applications is quite novel and is attempted here for the first time.

SOFT ROBOTICS. A 3D-printed, functionally graded soft robot powered by combustion.

PubMed

Bartlett, Nicholas W; Tolley, Michael T; Overvelde, Johannes T B; Weaver, James C; Mosadegh, Bobak; Bertoldi, Katia; Whitesides, George M; Wood, Robert J

2015-07-10

Roboticists have begun to design biologically inspired robots with soft or partially soft bodies, which have the potential to be more robust and adaptable, and safer for human interaction, than traditional rigid robots. However, key challenges in the design and manufacture of soft robots include the complex fabrication processes and the interfacing of soft and rigid components. We used multimaterial three-dimensional (3D) printing to manufacture a combustion-powered robot whose body transitions from a rigid core to a soft exterior. This stiffness gradient, spanning three orders of magnitude in modulus, enables reliable interfacing between rigid driving components (controller, battery, etc.) and the primarily soft body, and also enhances performance. Powered by the combustion of butane and oxygen, this robot is able to perform untethered jumping. Copyright © 2015, American Association for the Advancement of Science.

Design for robustness of unique, multi-component engineering systems

NASA Astrophysics Data System (ADS)

Shelton, Kenneth A.

2007-12-01

The purpose of this research is to advance the science of conceptual designing for robustness in unique, multi-component engineering systems. Robustness is herein defined as the ability of an engineering system to operate within a desired performance range even if the actual configuration has differences from specifications within specified tolerances. These differences are caused by three sources, namely manufacturing errors, system degradation (operational wear and tear), and parts availability. Unique, multi-component engineering systems are defined as systems produced in unique or very small production numbers. They typically have design and manufacturing costs on the order of billions of dollars, and have multiple, competing performance objectives. Design time for these systems must be minimized due to competition, high manpower costs, long manufacturing times, technology obsolescence, and limited available manpower expertise. Most importantly, design mistakes cannot be easily corrected after the systems are operational. For all these reasons, robustness of these systems is absolutely critical. This research examines the space satellite industry in particular. Although inherent robustness assurance is absolutely critical, it is difficult to achieve in practice. The current state of the art for robustness in the industry is to overdesign components and subsystems with redundancy and margin. The shortfall is that it is not known if the added margins were either necessary or sufficient given the risk management preferences of the designer or engineering system customer. To address this shortcoming, new assessment criteria to evaluate robustness in design concepts have been developed. The criteria are comprised of the "Value Distance", addressing manufacturing errors and system degradation, and "Component Distance", addressing parts availability. They are based on an evolutionary computation format that uses a string of alleles to describe the components in the design concept. These allele values are unitless themselves, but map to both configuration descriptions and attribute values. The Value Distance and Component Distance are metrics that measure the relative differences between two design concepts using the allele values, and all differences in a population of design concepts are calculated relative to a reference design, called the "base design". The base design is the top-ranked member of the population in weighted terms of robustness and performance. Robustness is determined based on the change in multi-objective performance as Value Distance and Component Distance (and thus differences in design) increases. It is assessed as acceptable if differences in design configurations up to specified tolerances result in performance changes that remain within a specified performance range. The design configuration difference tolerances and performance range together define the designer's risk management preferences for the final design concepts. Additionally, a complementary visualization capability was developed, called the "Design Solution Topography". This concept allows the visualization of a population of design concepts, and is a 3-axis plot where each point represents an entire design concept. The axes are the Value Distance, Component Distance and Performance Objective. The key benefit of the Design Solution Topography is that it allows the designer to visually identify and interpret the overall robustness of the current population of design concepts for a particular performance objective. In a multi-objective problem, each performance objective has its own Design Solution Topography view. These new concepts are implemented in an evolutionary computation-based conceptual designing method called the "Design for Robustness Method" that produces robust design concepts. The design procedures associated with this method enable designers to evaluate and ensure robustness in selected designs that also perform within a desired performance range. The method uses an evolutionary computation-based procedure to generate populations of large numbers of alternative design concepts, which are assessed for robustness using the Value Distance, Component Distance and Design Solution Topography procedures. The Design for Robustness Method provides a working conceptual designing structure in which to implement and gain the benefits of these new concepts. In the included experiments, the method was used on several mathematical examples to demonstrate feasibility, which showed favorable results as compared to existing known methods. Furthermore, it was tested on a real-world satellite conceptual designing problem to illustrate the applicability and benefits to industry. Risk management insights were demonstrated for the robustness-related issues of manufacturing errors, operational degradation, parts availability, and impacts based on selections of particular types of components.

Simulation Based Acquisition for NASA's Office of Exploration Systems

NASA Technical Reports Server (NTRS)

Hale, Joe

2004-01-01

In January 2004, President George W. Bush unveiled his vision for NASA to advance U.S. scientific, security, and economic interests through a robust space exploration program. This vision includes the goal to extend human presence across the solar system, starting with a human return to the Moon no later than 2020, in preparation for human exploration of Mars and other destinations. In response to this vision, NASA has created the Office of Exploration Systems (OExS) to develop the innovative technologies, knowledge, and infrastructures to explore and support decisions about human exploration destinations, including the development of a new Crew Exploration Vehicle (CEV). Within the OExS organization, NASA is implementing Simulation Based Acquisition (SBA), a robust Modeling & Simulation (M&S) environment integrated across all acquisition phases and programs/teams, to make the realization of the President s vision more certain. Executed properly, SBA will foster better informed, timelier, and more defensible decisions throughout the acquisition life cycle. By doing so, SBA will improve the quality of NASA systems and speed their development, at less cost and risk than would otherwise be the case. SBA is a comprehensive, Enterprise-wide endeavor that necessitates an evolved culture, a revised spiral acquisition process, and an infrastructure of advanced Information Technology (IT) capabilities. SBA encompasses all project phases (from requirements analysis and concept formulation through design, manufacture, training, and operations), professional disciplines, and activities that can benefit from employing SBA capabilities. SBA capabilities include: developing and assessing system concepts and designs; planning manufacturing, assembly, transport, and launch; training crews, maintainers, launch personnel, and controllers; planning and monitoring missions; responding to emergencies by evaluating effects and exploring solutions; and communicating across the OExS enterprise, within the Government, and with the general public. The SBA process features empowered collaborative teams (including industry partners) to integrate requirements, acquisition, training, operations, and sustainment. The SBA process also utilizes an increased reliance on and investment in M&S to reduce design risk. SBA originated as a joint Industry and Department of Defense (DoD) initiative to define and integrate an acquisition process that employs robust, collaborative use of M&S technology across acquisition phases and programs. The SBA process was successfully implemented in the Air Force s Joint Strike Fighter (JSF) Program.

ATMAD: robust image analysis for Automatic Tissue MicroArray De-arraying.

PubMed

Nguyen, Hoai Nam; Paveau, Vincent; Cauchois, Cyril; Kervrann, Charles

2018-04-19

Over the last two decades, an innovative technology called Tissue Microarray (TMA), which combines multi-tissue and DNA microarray concepts, has been widely used in the field of histology. It consists of a collection of several (up to 1000 or more) tissue samples that are assembled onto a single support - typically a glass slide - according to a design grid (array) layout, in order to allow multiplex analysis by treating numerous samples under identical and standardized conditions. However, during the TMA manufacturing process, the sample positions can be highly distorted from the design grid due to the imprecision when assembling tissue samples and the deformation of the embedding waxes. Consequently, these distortions may lead to severe errors of (histological) assay results when the sample identities are mismatched between the design and its manufactured output. The development of a robust method for de-arraying TMA, which localizes and matches TMA samples with their design grid, is therefore crucial to overcome the bottleneck of this prominent technology. In this paper, we propose an Automatic, fast and robust TMA De-arraying (ATMAD) approach dedicated to images acquired with brightfield and fluorescence microscopes (or scanners). First, tissue samples are localized in the large image by applying a locally adaptive thresholding on the isotropic wavelet transform of the input TMA image. To reduce false detections, a parametric shape model is considered for segmenting ellipse-shaped objects at each detected position. Segmented objects that do not meet the size and the roundness criteria are discarded from the list of tissue samples before being matched with the design grid. Sample matching is performed by estimating the TMA grid deformation under the thin-plate model. Finally, thanks to the estimated deformation, the true tissue samples that were preliminary rejected in the early image processing step are recognized by running a second segmentation step. We developed a novel de-arraying approach for TMA analysis. By combining wavelet-based detection, active contour segmentation, and thin-plate spline interpolation, our approach is able to handle TMA images with high dynamic, poor signal-to-noise ratio, complex background and non-linear deformation of TMA grid. In addition, the deformation estimation produces quantitative information to asset the manufacturing quality of TMAs.

Model Development and Process Analysis for Lean Cellular Design Planning in Aerospace Assembly and Manufacturing

NASA Astrophysics Data System (ADS)

Hilburn, Monty D.

Successful lean manufacturing and cellular manufacturing execution relies upon a foundation of leadership commitment and strategic planning built upon solid data and robust analysis. The problem for this study was to create and employ a simple lean transformation planning model and review process that could be used to identify functional support staff resources required to plan and execute lean manufacturing cells within aerospace assembly and manufacturing sites. The lean planning model was developed using available literature for lean manufacturing kaizen best practices and validated through a Delphi panel of lean experts. The resulting model and a standardized review process were used to assess the state of lean transformation planning at five sites of an international aerospace manufacturing and assembly company. The results of the three day, on-site review were compared with baseline plans collected from each of the five sites to determine if there analyzed, with focus on three critical areas of lean planning: the number and type of manufacturing cells identified, the number, type, and duration of planned lean and continuous kaizen events, and the quantity and type of functional staffing resources planned to support the kaizen schedule. Summarized data of the baseline and on-site reviews was analyzed with descriptive statistics. ANOVAs and paired-t tests at 95% significance level were conducted on the means of data sets to determine if null hypotheses related to cell, kaizen event, and support resources could be rejected. The results of the research found significant differences between lean transformation plans developed by site leadership and plans developed utilizing the structured, on-site review process and lean transformation planning model. The null hypothesis that there was no difference between the means of pre-review and on-site cell counts was rejected, as was the null hypothesis that there was no significant difference in kaizen event plans. These factors are critical inputs into the support staffing resources calculation used by the lean planning model. Null hypothesis related to functional support staff resources was rejected for most functional groups, indicating that the baseline site plan inadequately provided for cross-functional staff involvement to support the lean transformation plan. Null hypotheses related to total lean transformation staffing could not be rejected, indicating that while total staffing plans were not significantly different than plans developed during the on-site review and through the use of the lean planning model, the allocation of staffing among various functional groups such as engineering, production, and materials planning was an issue. The on-site review process and simple lean transformation plan developed was determined to be useful in identifying short-comings in lean transformation planning within aerospace manufacturing and assembly sites. It was concluded that the differences uncovered were likely contributing factors affecting the effectiveness of aerospace manufacturing sites' implementation of lean cellular manufacturing.

Robust Low-Cost Cathode for Commercial Applications

NASA Technical Reports Server (NTRS)

Patterson, Michael J.

2007-01-01

Under funding from the NASA Commercial Technology Office, a cathode assembly was designed, developed, fabricated, and tested for use in plasma sources for ground-based materials processing applications. The cathode development activity relied on the large prior NASA investment and successful development of high-current, high-efficiency, long-life hollow cathodes for use on the International Space Station Plasma Contactor System. The hollow cathode was designed and fabricated based on known engineering criteria and manufacturing processes for compatibility with the requirements of the plasma source. The transfer of NASA GRC-developed hollow cathode technology for use as an electron emitter in the commercial plasma source is anticipated to yield a significant increase in process control, while eliminating the present issues of electron emitter lifetime and contamination.

Microelectromechanical resonator and method for fabrication

DOEpatents

Wittwer, Jonathan W [Albuquerque, NM; Olsson, Roy H [Albuquerque, NM

2009-11-10

A method is disclosed for the robust fabrication of a microelectromechanical (MEM) resonator. In this method, a pattern of holes is formed in the resonator mass with the position, size and number of holes in the pattern being optimized to minimize an uncertainty .DELTA.f in the resonant frequency f.sub.0 of the MEM resonator due to manufacturing process variations (e.g. edge bias). A number of different types of MEM resonators are disclosed which can be formed using this method, including capacitively transduced Lame, wineglass and extensional resonators, and piezoelectric length-extensional resonators.

Microelectromechanical resonator and method for fabrication

DOEpatents

Wittwer, Jonathan W [Albuquerque, NM; Olsson, Roy H [Albuquerque, NM

2010-01-26

A method is disclosed for the robust fabrication of a microelectromechanical (MEM) resonator. In this method, a pattern of holes is formed in the resonator mass with the position, size and number of holes in the pattern being optimized to minimize an uncertainty .DELTA.f in the resonant frequency f.sub.0 of the MEM resonator due to manufacturing process variations (e.g. edge bias). A number of different types of MEM resonators are disclosed which can be formed using this method, including capacitively transduced Lame, wineglass and extensional resonators, and piezoelectric length-extensional resonators.

The Design of Fault Tolerant Quantum Dot Cellular Automata Based Logic

NASA Technical Reports Server (NTRS)

Armstrong, C. Duane; Humphreys, William M.; Fijany, Amir

2002-01-01

As transistor geometries are reduced, quantum effects begin to dominate device performance. At some point, transistors cease to have the properties that make them useful computational components. New computing elements must be developed in order to keep pace with Moore s Law. Quantum dot cellular automata (QCA) represent an alternative paradigm to transistor-based logic. QCA architectures that are robust to manufacturing tolerances and defects must be developed. We are developing software that allows the exploration of fault tolerant QCA gate architectures by automating the specification, simulation, analysis and documentation processes.

Optical Fiber Design And Fabrication: Discussion On Recent Developments

NASA Astrophysics Data System (ADS)

Roy, Philippe; Devautour, Mathieu; Lavoute, Laure; Gaponov, Dmitry; Brasse, Gurvan; Hautreux, Stéphanie; Février, Sébastien; Restoin, Christine; Auguste, Jean-Louis; Gérôme, Frédéric; Humbert, Georges; Blondy, Jean-Marc

2008-10-01

Level of emitted power and beam quality of singlemode fiber lasers have been drastically increased at the expense of loss due to bend sensitivity, simplicity of manufacturing and packaging. Furthermore, the extension of the spectral coverage was primarily explored by exploiting non-linear effects, neglecting numerous possible transitions of rare earths. Through different research areas, we demonstrate the possibilities offered by new fiber designs and alternative methods of manufacturing. Photonic Band Gap fibers reconcile diffraction limited beam and large mode area with low bending loss. 80% slope efficiency is demonstrated together with a robust propagation allowing the fiber to be tightly bent until wounding radii as small as 6 cm. Highly ytterbium doped multimode core surrounded by high refractive index rods fiber exhibits a transverse singlemode behavior under continuous wave laser regime. A robust LP01 mode is observed and filtering effect is clearly observed. A non CVD process based on silica sand vitrification allows the synthesis of large and highly doped core with high index homogeneity, opening the way to design of efficient large mode area fiber lasers. 74% slope efficiency is measured, demonstrating the good quality of the core material. Finally, the use of rare earth (Er3+) doped zirconia nanocrystals in silica matrix offers a large panel of ignored energy transitions for visible or off-usual band of emission.

Trial-Run of a Junction-Box Attachment Test for Use in Photovoltaic Module Qualification: Preprint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, D. C.; Deibert, S. L.; Wohlgemuth, J. H.

Engineering robust adhesion of the junction box (j-box) is a hurdle typically encountered by photovoltaic module manufacturers during product development and manufacturing process control. There are historical incidences of adverse effects (e.g., fires) caused when the j-box/adhesive/module system has failed in the field. The addition of a weight to the j-box during the 'damp-heat,' 'thermal-cycle,' or 'creep' tests within the IEC qualification protocol is proposed to verify the basic robustness of the adhesion system. The details of the proposed test are described, in addition to a trial-run of the test procedure. The described experiments examine four moisture-cured silicones, four foammore » tapes, and a hot-melt adhesive used in conjunction with glass, KPE, THV, and TPE substrates. For the purpose of validating the experiment, j-boxes were adhered to a substrate, loaded with a prescribed weight, and then subjected to aging. The replicate mock-modules were aged in an environmental chamber (at 85 degrees C/85% relative humidity for 1000 hours; then 100 degrees C/<10% relative humidity for 200 hours) or fielded in Golden (CO), Miami (FL), and Phoenix (AZ) for one year. Attachment strength tests, including pluck and shear test geometries, were also performed on smaller component specimens.« less

Trial Run of a Junction-Box Attachment Test for Use in Photovoltaic Module Qualification (Presentation)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, D.; Deibert, S.; Wohlgemuth, J.

Engineering robust adhesion of the junction-box (j-box) is a hurdle typically encountered by photovoltaic (PV) module manufacturers during product development and manufacturing process control. There are historical incidences of adverse effects (e.g., fires), caused when the j-box/adhesive/module system has failed in the field. The addition of a weight to the j-box during the 'damp-heat', 'thermal-cycle', or 'creep' tests within the IEC qualification protocol is proposed to verify the basic robustness of the adhesion system. The details of the proposed test are described, in addition to a trial run of the test procedure. The described experiments examine 4 moisture-cured silicones, 4more » foam tapes, and a hot-melt adhesive used in conjunction with glass, KPE, THV, and TPE substrates. For the purpose of validating the experiment, j-boxes were adhered to a substrate, loaded with a prescribed weight, and then subjected to aging. The replicate mock-modules were aged in an environmental chamber (at 85 deg C/85% relative humidity for 1000 hours; then 100 degrees C/<10% relative humidity for 200 hours) or fielded in Golden, Miami, and Phoenix for 1 year. Attachment strength tests, including pluck and shear test geometries, were also performed on smaller component specimens.« less

Robustness of assembly supply chain networks by considering risk propagation and cascading failure

NASA Astrophysics Data System (ADS)

Tang, Liang; Jing, Ke; He, Jie; Stanley, H. Eugene

2016-10-01

An assembly supply chain network (ASCN) is composed of manufacturers located in different geographical regions. To analyze the robustness of this ASCN when it suffers from catastrophe disruption events, we construct a cascading failure model of risk propagation. In our model, different disruption scenarios s are considered and the probability equation of all disruption scenarios is developed. Using production capability loss as the robustness index (RI) of an ASCN, we conduct a numerical simulation to assess its robustness. Through simulation, we compare the network robustness at different values of linking intensity and node threshold and find that weak linking intensity or high node threshold increases the robustness of the ASCN. We also compare network robustness levels under different disruption scenarios.

Minding the Gap: Investing in a Skilled Manufacturing Workforce

ERIC Educational Resources Information Center

Richard, Alan

2015-01-01

Advanced manufacturing is growing and thriving in the United States. Companies are in great need of reliable employees who can communicate well, effectively make decisions, and are interested in long-term careers with opportunity for advancement. Employers have identified a need for a more robust talent pipeline to narrow America's skills gap--a…

Characterization, optimisation and process robustness of a co-processed mannitol for the development of orally disintegrating tablets.

PubMed

Soh, Josephine Lay Peng; Grachet, Maud; Whitlock, Mark; Lukas, Timothy

2013-02-01

This is a study to fully assess a commercially available co-processed mannitol for its usefulness as an off-the-shelf excipient for developing orally disintegrating tablets (ODTs) by direct compression on a pilot scale (up to 4 kg). This work encompassed material characterization, formulation optimisation and process robustness. Overall, this co-processed mannitol possessed favourable physical attributes including low hygroscopicity and compactibility. Two design-of-experiments (DoEs) were used to screen and optimise the placebo formulation. Xylitol and crospovidone concentrations were found to have the most significant impact on disintegration time (p < 0.05). Higher xylitol concentrations retarded disintegration. Avicel PH102 promoted faster disintegration than PH101, at higher levels of xylitol. Without xylitol, higher crospovidone concentrations yielded faster disintegration and reduced tablet friability. Lubrication sensitivity studies were later conducted at two fill loads, three levels for lubricant concentration and number of blend rotations. Even at 75% fill load, the design space plot showed that 1.5% lubricant and 300 blend revolutions were sufficient to manufacture ODTs with ≤ 0.1% friability and disintegrated within 15 s. This study also describes results using a modified disintegration method based on the texture analyzer as an alternative to the USP method.

Amine control for DUV lithography: identifying hidden sources

NASA Astrophysics Data System (ADS)

Kishkovich, Oleg P.; Larson, Carl E.

2000-06-01

The impact of airborne basic molecular contamination (MB) on the performance of chemically amplified (CA) resist systems has been a long standing problem. Low ppb levels of MB may be sufficient for robust 0.25 micrometer lithography with today's advanced CA resist systems combined with adequate chemical air filtration. However, with minimum CD targets heading below 150 nm, the introduction of new resist chemistries for Next Generation Lithography, and the trend towards thinner resists, the impact of MB at low and sub-ppb levels again becomes a critical manufacturing issue. Maximizing process control at aggressive feature sizes requires that the level of MB be maintained below a certain limit, which depends on such parameters as the sensitivity of the CA resist, the type of production tools, product mix, and process characteristics. Three approaches have been identified to reduce the susceptibility of CA resists to MB: effective chemical air filtration, modifications to resist chemistry/processing and cleanroom protocols involving MB monitoring and removal of MB sources from the fab. The final MB concentration depends on the effectiveness of filtration resources and on the total pollution originating from different sources in and out of the cleanroom. There are many well-documented sources of MB. Among these are: ambient air; polluted exhaust from other manufacturing areas re-entering the cleanroom through make-up air handlers; manufacturing process chemicals containing volatile molecular bases; certain cleanroom construction materials, such as paint and ceiling tiles; and volatile, humidifier system boiler additives (corrosion inhibitors), such as morpholine, cyclohexylamine, and dimethylaminoethanol. However, there is also an indeterminate number of other 'hidden' pollution sources, which are neither obvious nor well-documented. None of these sources are new, but they had little impact on earlier semiconductor manufacturing processes because the contamination levels are low enough that they were tolerable. The purpose of this article is to investigate some of these frequently overlooked sources of basic molecular contamination and to thereby increase the reader's awareness of their potential risks.

Picosecond and femtosecond lasers for industrial material processing

NASA Astrophysics Data System (ADS)

Mayerhofer, R.; Serbin, J.; Deeg, F. W.

2016-03-01

Cold laser materials processing using ultra short pulsed lasers has become one of the most promising new technologies for high-precision cutting, ablation, drilling and marking of almost all types of material, without causing unwanted thermal damage to the part. These characteristics have opened up new application areas and materials for laser processing, allowing previously impossible features to be created and also reducing the amount of post-processing required to an absolute minimum, saving time and cost. However, short pulse widths are only one part of thee story for industrial manufacturing processes which focus on total costs and maximum productivity and production yield. Like every other production tool, ultra-short pulse lasers have too provide high quality results with maximum reliability. Robustness and global on-site support are vital factors, as well ass easy system integration.

20 years of KVH fiber optic gyro technology: the evolution from large, low performance FOGs to compact, precise FOGs and FOG-based inertial systems

NASA Astrophysics Data System (ADS)

Napoli, Jay

2016-05-01

Precision fiber optic gyroscopes (FOGs) are critical components for an array of platforms and applications ranging from stabilization and pointing orientation of payloads and platforms to navigation and control for unmanned and autonomous systems. In addition, FOG-based inertial systems provide extremely accurate data for geo-referencing systems. Significant improvements in the performance of FOGs and FOG-based inertial systems at KVH are due, in large part, to advancements in the design and manufacture of optical fiber, as well as in manufacturing operations and signal processing. Open loop FOGs, such as those developed and manufactured by KVH Industries, offer tactical-grade performance in a robust, small package. The success of KVH FOGs and FOG-based inertial systems is due to innovations in key fields, including the development of proprietary D-shaped fiber with an elliptical core, and KVH's unique ThinFiber. KVH continually improves its FOG manufacturing processes and signal processing, which result in improved accuracies across its entire FOG product line. KVH acquired its FOG capabilities, including its patented E•Core fiber, when the company purchased Andrew Corporation's Fiber Optic Group in 1997. E•Core fiber is unique in that the light-guiding core - critical to the FOG's performance - is elliptically shaped. The elliptical core produces a fiber that has low loss and high polarization-maintaining ability. In 2010, KVH developed its ThinFiber, a 170-micron diameter fiber that retains the full performance characteristics of E•Core fiber. ThinFiber has enabled the development of very compact, high-performance open-loop FOGs, which are also used in a line of FOG-based inertial measurement units and inertial navigation systems.

Statistical Methods for Quality Control of Steel Coils Manufacturing Process using Generalized Linear Models

NASA Astrophysics Data System (ADS)

García-Díaz, J. Carlos

2009-11-01

Fault detection and diagnosis is an important problem in process engineering. Process equipments are subject to malfunctions during operation. Galvanized steel is a value added product, furnishing effective performance by combining the corrosion resistance of zinc with the strength and formability of steel. Fault detection and diagnosis is an important problem in continuous hot dip galvanizing and the increasingly stringent quality requirements in automotive industry has also demanded ongoing efforts in process control to make the process more robust. When faults occur, they change the relationship among these observed variables. This work compares different statistical regression models proposed in the literature for estimating the quality of galvanized steel coils on the basis of short time histories. Data for 26 batches were available. Five variables were selected for monitoring the process: the steel strip velocity, four bath temperatures and bath level. The entire data consisting of 48 galvanized steel coils was divided into sets. The first training data set was 25 conforming coils and the second data set was 23 nonconforming coils. Logistic regression is a modeling tool in which the dependent variable is categorical. In most applications, the dependent variable is binary. The results show that the logistic generalized linear models do provide good estimates of quality coils and can be useful for quality control in manufacturing process.

The operation of large computer-controlled manufacturing systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Upton, D.M.

1988-01-01

This work examines methods for operation of large computer-controlled manufacturing systems, with more than 50 or so disparate CNC machines in congregation. The central theme is the development of a distributed control system, which requires minimal central supervision, and allows manufacturing system re-configuration without extensive control software re-writes. Provision is made for machines to learn from their experience and provide estimates of the time necessary to effect various tasks. Routing is opportunistic, with varying degrees of myopia depending on the prevailing situation. Necessary curtailments of opportunism are built in to the system, in order to provide a society of machinesmore » that operate in unison rather than in chaos. Negotiation and contention resolution are carried out using a UHF radio communications network, along with processing capability on both pallets and tools. Graceful and robust error recovery is facilitated by ensuring adequate pessimistic consideration of failure modes at each stage in the scheme. Theoretical models are developed and an examination is made of fundamental characteristics of auction-based scheduling methods.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lherbier, Louis, W.; Novotnak, David, J.; Herling, Darrell, R.

Hot forming processes such as forging, die casting and glass forming require tooling that is subjected to high temperatures during the manufacturing of components. Current tooling is adversely affected by prolonged exposure at high temperatures. Initial studies were conducted to determine the root cause of tool failures in a number of applications. Results show that tool failures vary and depend on the operating environment under which they are used. Major root cause failures include (1) thermal softening, (2) fatigue and (3) tool erosion, all of which are affected by process boundary conditions such as lubrication, cooling, process speed, etc. Whilemore » thermal management is a key to addressing tooling failures, it was clear that new tooling materials with superior high temperature strength could provide improved manufacturing efficiencies. These efficiencies are based on the use of functionally graded materials (FGM), a new subset of hybrid tools with customizable properties that can be fabricated using advanced powder metallurgy manufacturing technologies. Modeling studies of the various hot forming processes helped identify the effect of key variables such as stress, temperature and cooling rate and aid in the selection of tooling materials for specific applications. To address the problem of high temperature strength, several advanced powder metallurgy nickel and cobalt based alloys were selected for evaluation. These materials were manufactured into tooling using two relatively new consolidation processes. One process involved laser powder deposition (LPD) and the second involved a solid state dynamic powder consolidation (SSDPC) process. These processes made possible functionally graded materials (FGM) that resulted in shaped tooling that was monolithic, bi-metallic or substrate coated. Manufacturing of tooling with these processes was determined to be robust and consistent for a variety of materials. Prototype and production testing of FGM tooling showed the benefits of the nickel and cobalt based powder metallurgy alloys in a number of applications evaluated. Improvements in tool life ranged from three (3) to twenty (20) or more times than currently used tooling. Improvements were most dramatic where tool softening and deformation were the major cause of tool failures in hot/warm forging applications. Significant improvement was also noted in erosion of aluminum die casting tooling. Cost and energy savings can be realized as a result of increased tooling life, increased productivity and a reduction in scrap because of improved dimensional controls. Although LPD and SSDPC tooling usually have higher acquisition costs, net tooling costs per component produced drops dramatically with superior tool performance. Less energy is used to manufacture the tooling because fewer tools are required and less recycling of used tools are needed for the hot forming process. Energy is saved during the component manufacturing cycle because more parts can be produced in shorter periods of time. Energy is also saved by minimizing heating furnace idling time because of less downtime for tooling changes.« less

Thermographic Microstructure Monitoring in Electron Beam Additive Manufacturing

PubMed Central

Raplee, J.; Plotkowski, A.; Kirka, M. M.; Dinwiddie, R.; Okello, A.; Dehoff, R. R.; Babu, S. S.

2017-01-01

To reduce the uncertainty of build performance in metal additive manufacturing, robust process monitoring systems that can detect imperfections and improve repeatability are desired. One of the most promising methods for in situ monitoring is thermographic imaging. However, there is a challenge in using this technology due to the difference in surface emittance between the metal powder and solidified part being observed that affects the accuracy of the temperature data collected. The purpose of the present study was to develop a method for properly calibrating temperature profiles from thermographic data to account for this emittance change and to determine important characteristics of the build through additional processing. The thermographic data was analyzed to identify the transition of material from metal powder to a solid as-printed part. A corrected temperature profile was then assembled for each point using calibrations for these surface conditions. Using this data, the thermal gradient and solid-liquid interface velocity were approximated and correlated to experimentally observed microstructural variation within the part. This work shows that by using a method of process monitoring, repeatability of a build could be monitored specifically in relation to microstructure control. PMID:28256595

Lessons from industry: one school's transformation toward "lean" curricular governance.

PubMed

Stratton, Terry D; Rudy, David W; Sauer, Marlene J; Perman, Jay A; Jennings, C Darrell

2007-04-01

As medical education grapples with organizational calls for centralized curricular oversight, programs may be compelled to respond by establishing highly vertical, stacked governance structures. Although these models offer discrete advantages over the horizontal, compartmentalized structures they are designed to replace, they pose new challenges to ensuring curricular quality and the educational innovations that drive the curricula. The authors describe a hybrid quality-assurance (QA) governance structure introduced in 2003 at the University of Kentucky College of Medicine (UKCOM) that ensures centralized curricular oversight of the educational product while allowing individualized creative control over the educational process. Based on a Lean production model, this approach draws on industry experiences that strategically separate institutional accountability (management) for a quality curriculum from the decision-making processes required to ensure it (production). In so doing, the authors acknowledge general similarities and key differences between overseeing the manufacture of a complex product versus the education of a physician-emphasizing the structured, sequential, and measurable nature of each process. Further, the authors briefly trace the emergence of quality approaches in manufacturing and discuss the philosophical changes that accompany transition to an institutional governance system that relies on vigorous, robust performance measures to offer continuous feedback on curricular quality.

Wafer-level manufacturing technology of glass microlenses

NASA Astrophysics Data System (ADS)

Gossner, U.; Hoeftmann, T.; Wieland, R.; Hansch, W.

2014-08-01

In high-tech products, there is an increasing demand to integrate glass lenses into complex micro systems. Especially in the lighting industry LEDs and laser diodes used for automotive applications require encapsulated micro lenses. To enable low-cost production, manufacturing of micro lenses on wafer level base using a replication technology is a key technology. This requires accurate forming of thousands of lenses with a diameter of 1-2 mm on a 200 mm wafer compliant with mass production. The article will discuss the technical aspects of a lens manufacturing replication process and the challenges, which need to be solved: choice of an appropriate master for replication, thermally robust interlayer coating, choice of replica glass, bonding and separation procedure. A promising approach for the master substrate material is based on a lens structured high-quality glass wafer with high melting point covered by a coating layer of amorphous silicon or germanium. This layer serves as an interlayer for the glass bonding process. Low pressure chemical vapor deposition and plasma enhanced chemical vapor deposition processes allow a deposition of layer coatings with different hydrogen and doping content influencing their chemical and physical behavior. A time reduced molding process using a float glass enables the formation of high quality lenses while preserving the recyclability of the mother substrate. The challenge is the separation of the replica from the master mold. An overview of chemical methods based on optimized etching of coating layer through small channels will be given and the impact of glass etching on surface roughness is discussed.

Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part I: from three-dimensional cell growth to biomimetics of in vivo development.

PubMed

Lenas, Petros; Moos, Malcolm; Luyten, Frank P

2009-12-01

Recent advances in developmental biology, systems biology, and network science are converging to poise the heretofore largely empirical field of tissue engineering on the brink of a metamorphosis into a rigorous discipline based on universally accepted engineering principles of quality by design. Failure of more simplistic approaches to the manufacture of cell-based therapies has led to increasing appreciation of the need to imitate, at least to some degree, natural mechanisms that control cell fate and differentiation. The identification of many of these mechanisms, which in general are based on cell signaling pathways, is an important step in this direction. Some well-accepted empirical concepts of developmental biology, such as path-dependence, robustness, modularity, and semiautonomy of intermediate tissue forms, that appear sequentially during tissue development are starting to be incorporated in process design.

Fast and accurate metrology of multi-layered ceramic materials by an automated boundary detection algorithm developed for optical coherence tomography data

PubMed Central

Ekberg, Peter; Su, Rong; Chang, Ernest W.; Yun, Seok Hyun; Mattsson, Lars

2014-01-01

Optical coherence tomography (OCT) is useful for materials defect analysis and inspection with the additional possibility of quantitative dimensional metrology. Here, we present an automated image-processing algorithm for OCT analysis of roll-to-roll multilayers in 3D manufacturing of advanced ceramics. It has the advantage of avoiding filtering and preset modeling, and will, thus, introduce a simplification. The algorithm is validated for its capability of measuring the thickness of ceramic layers, extracting the boundaries of embedded features with irregular shapes, and detecting the geometric deformations. The accuracy of the algorithm is very high, and the reliability is better than 1 µm when evaluating with the OCT images using the same gauge block step height reference. The method may be suitable for industrial applications to the rapid inspection of manufactured samples with high accuracy and robustness. PMID:24562018

2016 Summer Series - Jason Dunn - The Future of Making Things in Space

NASA Image and Video Library

2016-08-04

Manufacturing of tools is why humans survive. Inkjet printer technology has revolutionized the world of printing anything and led to 3D printers that allow rapid prototyping and manufacturing of tools. Getting materials to space is costly and the ability to manufacture on demand will make space exploration and space utilization more robust and affordable. Jason Dunn will discuss Made In Space’s achievements in bringing 3D printers to the International Space Station and their future role in space exploration.

ANN-PSO Integrated Optimization Methodology for Intelligent Control of MMC Machining

NASA Astrophysics Data System (ADS)

Chandrasekaran, Muthumari; Tamang, Santosh

2017-08-01

Metal Matrix Composites (MMC) show improved properties in comparison with non-reinforced alloys and have found increased application in automotive and aerospace industries. The selection of optimum machining parameters to produce components of desired surface roughness is of great concern considering the quality and economy of manufacturing process. In this study, a surface roughness prediction model for turning Al-SiCp MMC is developed using Artificial Neural Network (ANN). Three turning parameters viz., spindle speed ( N), feed rate ( f) and depth of cut ( d) were considered as input neurons and surface roughness was an output neuron. ANN architecture having 3 -5 -1 is found to be optimum and the model predicts with an average percentage error of 7.72 %. Particle Swarm Optimization (PSO) technique is used for optimizing parameters to minimize machining time. The innovative aspect of this work is the development of an integrated ANN-PSO optimization method for intelligent control of MMC machining process applicable to manufacturing industries. The robustness of the method shows its superiority for obtaining optimum cutting parameters satisfying desired surface roughness. The method has better convergent capability with minimum number of iterations.

Additive Manufacturing of Catalytically Active Living Materials.

PubMed

Saha, Abhijit; Johnston, Trevor G; Shafranek, Ryan T; Goodman, Cassandra J; Zalatan, Jesse G; Storti, Duane W; Ganter, Mark A; Nelson, Alshakim

2018-04-25

Living materials, which are composites of living cells residing in a polymeric matrix, are designed to utilize the innate functionalities of the cells to address a broad range of applications such as fermentation and biosensing. Herein, we demonstrate the additive manufacturing of catalytically active living materials (AMCALM) for continuous fermentation. A multi-stimuli-responsive yeast-laden hydrogel ink, based on F127-dimethacrylate, was developed and printed using a direct-write 3D printer. The reversible stimuli-responsive behaviors of the polymer hydrogel inks to temperature and pressure are critical, as they enabled the facile incorporation of yeast cells and subsequent fabrication of 3D lattice constructs. Subsequent photo-cross-linking of the printed polymer hydrogel afforded a robust elastic material. These yeast-laden living materials were metabolically active in the fermentation of glucose into ethanol for 2 weeks in a continuous batch process without significant reduction in efficiency (∼90% yield of ethanol). This cell immobilization platform may potentially be applicable toward other genetically modified yeast strains to produce other high-value chemicals in a continuous biofermentation process.

Solid-state supercapacitors with rationally designed heterogeneous electrodes fabricated by large area spray processing for wearable energy storage applications.

PubMed

Huang, Chun; Zhang, Jin; Young, Neil P; Snaith, Henry J; Grant, Patrick S

2016-05-10

Supercapacitors are in demand for short-term electrical charge and discharge applications. Unlike conventional supercapacitors, solid-state versions have no liquid electrolyte and do not require robust, rigid packaging for containment. Consequently they can be thinner, lighter and more flexible. However, solid-state supercapacitors suffer from lower power density and where new materials have been developed to improve performance, there remains a gap between promising laboratory results that usually require nano-structured materials and fine-scale processing approaches, and current manufacturing technology that operates at large scale. We demonstrate a new, scalable capability to produce discrete, multi-layered electrodes with a different material and/or morphology in each layer, and where each layer plays a different, critical role in enhancing the dynamics of charge/discharge. This layered structure allows efficient utilisation of each material and enables conservative use of hard-to-obtain materials. The layered electrode shows amongst the highest combinations of energy and power densities for solid-state supercapacitors. Our functional design and spray manufacturing approach to heterogeneous electrodes provide a new way forward for improved energy storage devices.

Color sensor and neural processor on one chip

NASA Astrophysics Data System (ADS)

Fiesler, Emile; Campbell, Shannon R.; Kempem, Lother; Duong, Tuan A.

1998-10-01

Low-cost, compact, and robust color sensor that can operate in real-time under various environmental conditions can benefit many applications, including quality control, chemical sensing, food production, medical diagnostics, energy conservation, monitoring of hazardous waste, and recycling. Unfortunately, existing color sensor are either bulky and expensive or do not provide the required speed and accuracy. In this publication we describe the design of an accurate real-time color classification sensor, together with preprocessing and a subsequent neural network processor integrated on a single complementary metal oxide semiconductor (CMOS) integrated circuit. This one-chip sensor and information processor will be low in cost, robust, and mass-producible using standard commercial CMOS processes. The performance of the chip and the feasibility of its manufacturing is proven through computer simulations based on CMOS hardware parameters. Comparisons with competing methodologies show a significantly higher performance for our device.

Strategy for design NIR calibration sets based on process spectrum and model space: An innovative approach for process analytical technology.

PubMed

Cárdenas, V; Cordobés, M; Blanco, M; Alcalà, M

2015-10-10

The pharmaceutical industry is under stringent regulations on quality control of their products because is critical for both, productive process and consumer safety. According to the framework of "process analytical technology" (PAT), a complete understanding of the process and a stepwise monitoring of manufacturing are required. Near infrared spectroscopy (NIRS) combined with chemometrics have lately performed efficient, useful and robust for pharmaceutical analysis. One crucial step in developing effective NIRS-based methodologies is selecting an appropriate calibration set to construct models affording accurate predictions. In this work, we developed calibration models for a pharmaceutical formulation during its three manufacturing stages: blending, compaction and coating. A novel methodology is proposed for selecting the calibration set -"process spectrum"-, into which physical changes in the samples at each stage are algebraically incorporated. Also, we established a "model space" defined by Hotelling's T(2) and Q-residuals statistics for outlier identification - inside/outside the defined space - in order to select objectively the factors to be used in calibration set construction. The results obtained confirm the efficacy of the proposed methodology for stepwise pharmaceutical quality control, and the relevance of the study as a guideline for the implementation of this easy and fast methodology in the pharma industry. Copyright © 2015 Elsevier B.V. All rights reserved.

Optimization of Tape Winding Process Parameters to Enhance the Performance of Solid Rocket Nozzle Throat Back Up Liners using Taguchi's Robust Design Methodology

NASA Astrophysics Data System (ADS)

Nath, Nayani Kishore

2017-08-01

The throat back up liners is used to protect the nozzle structural members from the severe thermal environment in solid rocket nozzles. The throat back up liners is made with E-glass phenolic prepregs by tape winding process. The objective of this work is to demonstrate the optimization of process parameters of tape winding process to achieve better insulative resistance using Taguchi's robust design methodology. In this method four control factors machine speed, roller pressure, tape tension, tape temperature that were investigated for the tape winding process. The presented work was to study the cogency and acceptability of Taguchi's methodology in manufacturing of throat back up liners. The quality characteristic identified was Back wall temperature. Experiments carried out using L 9 ' (34) orthogonal array with three levels of four different control factors. The test results were analyzed using smaller the better criteria for Signal to Noise ratio in order to optimize the process. The experimental results were analyzed conformed and successfully used to achieve the minimum back wall temperature of the throat back up liners. The enhancement in performance of the throat back up liners was observed by carrying out the oxy-acetylene tests. The influence of back wall temperature on the performance of throat back up liners was verified by ground firing test.

Challenges and Opportunities in Reactive Processing and Applications of Advanced Ceramic Materials

NASA Technical Reports Server (NTRS)

Singh, Mrityunjay

2003-01-01

Recently, there has been a great deal of interest in the research, development, and commercialization of innovative synthesis and processing technologies for advanced ceramics and composite materials. Reactive processing approaches have been actively considered due to their robustness, flexibility, and affordability. A wide variety of silicon carbide-based advanced ceramics and composites are currently being fabricated using the processing approaches involving reactive infiltration of liquid and gaseous species into engineered fibrous or microporous carbon performs. The microporous carbon performs have been fabricated using the temperature induced phase separation and pyrolysis of two phase organic (resin-pore former) mixtures and fiber reinforcement of carbon and ceramic particulate bodies. In addition, pyrolyzed native plant cellulose tissues also provide unique carbon templates for manufacturing of non-oxide and oxide ceramics. In spite of great interest in this technology due to their affordability and robustness, there is a lack of scientific basis for process understanding and many technical challenges still remain. The influence of perform properties and other parameters on the resulting microstructure and properties of final material is not well understood. In this presentation, mechanism of silicon-carbon reaction in various systems and the effect of perform microstructure on the mechanical properties of advanced silicon carbide based materials will be discussed. Various examples of applications of reactively processed advanced silicon carbide ceramics and composite materials will be presented.

Challenges in teaching modern manufacturing technologies

NASA Astrophysics Data System (ADS)

Ngaile, Gracious; Wang, Jyhwen; Gau, Jenn-Terng

2015-07-01

Teaching of manufacturing courses for undergraduate engineering students has become a challenge due to industrial globalisation coupled with influx of new innovations, technologies, customer-driven products. This paper discusses development of a modern manufacturing course taught concurrently in three institutions where students collaborate in executing various projects. Lectures are developed to contain materials featuring advanced manufacturing technologies, R&D trends in manufacturing. Pre- and post-surveys were conducted by an external evaluator to assess the impact of the course on increase in student's knowledge of manufacturing; increase students' preparedness and confidence in effective communication and; increase students' interest in pursuing additional academic studies and/or a career path in manufacturing and high technology. The surveyed data indicate that the students perceived significant gains in manufacturing knowledge and preparedness in effective communication. The study also shows that implementation of a collaborative course within multiple institutions requires a robust and collective communication platform.

Axiomatic Design and Fabrication of Composite Structures - Applications in Robots, Machine Tools, and Automobiles

NASA Astrophysics Data System (ADS)

Lee, Dai Gil; Suh, Nam Pyo

2005-11-01

The idea that materials can be designed to satisfy specific performance requirements is relatively new. With high-performance composites, however, the entire process of designing and fabricating a part can be worked out before manufacturing. The purpose of this book is to present an integrated approach to the design and manufacturing of products from advanced composites. It shows how the basic behavior of composites and their constitutive relationships can be used during the design stage, which minimizes the complexity of manufacturing composite parts and reduces the repetitive "design-build-test" cycle. Designing it right the first time is going to determine the competitiveness of a company, the reliability of the part, the robustness of fabrication processes, and ultimately, the cost and development time of composite parts. Most of all, it should expand the use of advanced composite parts in fields that use composites only to a limited extent at this time. To achieve these goals, this book presents the design and fabrication of novel composite parts made for machine tools and other applications like robots and automobiles. This book is suitable as a textbook for graduate courses in the design and fabrication of composites. It will also be of interest to practicing engineers learning about composites and axiomatic design. A CD-ROM is included in every copy of the book, containing Axiomatic CLPT software. This program, developed by the authors, will assist readers in calculating material properties from the microstructure of the composite. This book is part of the Oxford Series on Advanced Manufacturing.

Quality-by-design III: application of near-infrared spectroscopy to monitor roller compaction in-process and product quality attributes of immediate release tablets.

PubMed

Kona, Ravikanth; Fahmy, Raafat M; Claycamp, Gregg; Polli, James E; Martinez, Marilyn; Hoag, Stephen W

2015-02-01

The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller compaction process parameters, compression force (CFt), and formulation variables identified from our earlier studies were evaluated in more detail. Multivariate principal component analysis (PCA) and partial least square (PLS) models were developed during the development stage and used as a control tool to predict the quality of granules and tablets. Validated models were used to monitor and control batches manufactured at different sites to assess their robustness to change. The results showed that roll pressure (RP) and CFt played a critical role in the quality of the granules and the finished product within the range tested. Replacing binder source did not statistically influence the quality attributes of the granules and tablets. However, lubricant type has significantly impacted the granule size. Blend uniformity, crushing force, disintegration time during the manufacturing was predicted using validated PLS regression models with acceptable standard error of prediction (SEP) values, whereas the models resulted in higher SEP for batches obtained from different manufacturing site. From this study, we were able to identify critical factors which could impact the quality attributes of the CIP IR tablets. In summary, we demonstrated the ability of near-infrared spectroscopy coupled with chemometrics as a powerful tool to monitor critical quality attributes (CQA) identified during formulation development.

Making On-the-Job Training Work: Lessons from the Boeing Manufacturing On-the-Job Training Project

ERIC Educational Resources Information Center

Kobes, Deborah

2013-01-01

The need to build a more robust workforce development pipeline is evident in the hundreds of thousands of job openings in our nation's advanced manufacturing industry. Rapid technological change has created a severe skills gap, compounded by a pending wave of retirements due to the aging of the workforce. These challenges are particularly…

A QRM Discussion of Microbial Contamination of Non-sterile Drug Products, Using FDA and EMA Warning Letters Recorded between 2008 and 2016.

PubMed

Santos, Ana M C; Doria, Mara S; Meirinhos-Soares, Luís; Almeida, António J; Menezes, José C

2018-01-01

Microbial quality control of non-sterile drug products has been a concern to regulatory agencies and the pharmaceutical industry since the 1960s. Despite being an old challenge to companies, microbial contamination still affects a high number of manufacturers of non-sterile products. Consequences go well beyond the obvious direct costs related to batch rejections or product recalls, as human lives and a company's reputation are significantly impacted if such events occur. To better manage risk and establish effective mitigation strategies, it is necessary to understand the microbial hazards involved in non-sterile drug products manufacturing, be able to evaluate their potential impact on final product quality, and apply mitigation actions. Herein we discuss the most likely root causes involved in microbial contaminations referenced in warning letters issued by US health authorities and non-compliance reports issued by European health authorities over a period of several years. The quality risk management tools proposed were applied to the data gathered from those databases, and a generic risk ranking was provided based on a panel of non-sterile drug product manufacturers that was assembled and given the opportunity to perform the risk assessments. That panel identified gaps and defined potential mitigation actions, based on their own experience of potential risks expected for their processes. Major findings clearly indicate that the manufacturers affected by the warning letters should focus their attention on process improvements and microbial control strategies, especially those related to microbial analysis and raw material quality control. Additionally, the WLs considered frequently referred to failures in quality-related issues, which indicates that the quality commitment should be reinforced at most companies to avoid microbiological contaminations. LAY ABSTRACT: Microbial contamination of drug products affects the quality of non-sterile drug products produced by numerous manufacturers, representing a major risk to patients. It is necessary to understand the microbial hazards involved in the manufacturing process and evaluate their impact on final product quality so that effective prevention strategies can be implemented. A risk-based classification of most likely root causes for microbial contamination found in the warning letters issued by the US Food and Drug Administration and the European Medicines Agency is proposed. To validate the likely root causes extracted from the warning letters, a subject matter expert panel made of several manufacturers was formed and consulted. A quality risk management approach to assess microbiological contamination of non-sterile drug products is proposed for the identification of microbial hazards involved in the manufacturing process. To enable ranking of microbial contamination risks, quality risk management metrics related to criticality and overall risk were applied. The results showed that manufacturers of non-sterile drug products should improve their microbial control strategy, with special attention to quality controls of raw materials, primary containers, and closures. Besides that, they should invest in a more robust quality system and culture. As a start, manufacturers may consider investigating their specific microbiological risks, adressing their sites' own microbial ecology, type of manufacturing processes, and dosage form characteristics, as these may lead to increased contamination risks. Authorities should allow and enforce innovative, more comprehensive, and more effective approaches to in-process contamination monitoring and controls. © PDA, Inc. 2018.

Optical microsystem for analyzing engine lubricants

NASA Astrophysics Data System (ADS)

Scott, Andrew J.; Mabesa, Jose R., Jr.; Gorsich, David; Rathgeb, Brian; Said, Ali A.; Dugan, Mark; Haddock, Tom F.; Bado, Philippe W.

2004-12-01

It is possible to dramatically improve the performance, reliability, and maintainability of vehicles and other similarly complex equipment if improved sensing and diagnostics systems are available. Each year military and commercial maintenance personnel unnecessarily replace, at scheduled intervals, significant amounts of lubricant fluids in vehicles, weapon systems, and supporting equipment. Personnel draw samples of fluids and send them to test labs for analysis to determine if replacement is necessary. Systematic use of either on-board (embedded) lubricant quality analysis capabilities will save millions of dollars each year in avoided fluid changes, saved labor, prevented damage to mechanical components while providing associated environmental benefits. This paper discusses the design, the manufacturing, and the evaluation of robust optical sensors designed to monitor the condition of industrial fluids. The sensors reported are manufactured from bulk fused silica substrates. They incorporate three-dimensional micro fluidic circuitry side-by-side with three-dimensional wave guided optical networks. The manufacturing of the optical waveguides are completed using a direct-write process based on the use of femtosecond laser pulses to locally alter the structure of the glass substrate at the nano-level. The microfluidic circuitry is produced using the same femtosecond laser based process, followed by an anisotropic wet chemical etching step. Data will be presented regarding the use of these sensors to monitor the quality of engine oil and possibly some other vehicle lubricants such as hydraulic oil.

Risk mitigation strategies for viral contamination of biotechnology products: consideration of best practices.

PubMed

Rosenberg, Amy S; Cherney, Barry; Brorson, Kurt; Clouse, Kathleen; Kozlowski, Steven; Hughes, Patricia; Friedman, Rick

2011-01-01

CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda, MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA) Viral contamination of biotech product facilities is a potentially devastating manufacturing risk and, unfortunately, is more common than is generally reported or previously appreciated. Although viral contaminants of biotech products are thought to originate principally from biological raw materials, all potential process risks merit evaluation. Limitations to existing methods for virus detection are becoming evident as emerging viruses have contaminated facilities and disrupted supplies of critical products. New technologies, such as broad-based polymerase chain reaction screens for multiple virus types, are increasingly becoming available to detect adventitious viral contamination and thus, mitigate risks to biotech products and processes. Further, the industry embrace of quality risk management that promotes improvements in testing stratagems, enhanced viral inactivation methods for raw materials, implementation and standardization of robust viral clearance procedures, and efforts to learn from both epidemiologic screening of raw material sources and from the experience of other manufacturers with regard to this problem will serve to enhance the safety of biotech products available to patients. Based on this evolving landscape, we propose a set of principles for manufacturers of biotech products: Pillars of Risk Mitigation for Viral Contamination of Biotech Products.

TiO x -Based Thermoelectric Modules: Manufacturing, Properties, and Operational Behavior

NASA Astrophysics Data System (ADS)

Martin, Hans-Peter; Pönicke, Andreas; Kluge, Martin; Sichert, Ina; Rost, Axel; Conze, Susan; Wätzig, Katja; Schilm, Jochen; Michaelis, Alexander

2016-03-01

Substoichiometric titanium oxides are attractive thermoelectric materials for high-temperature modules. Their advantages are availability, economy, and safety. This paper gives results of thermoelectric data on scale-up titanium suboxides, manufacturing technologies of TiO x modules, glass coating as an option for oxidation protection, and test results of TiO x modules. The thermoelectric efficiency of TiO x is low compared with established thermoelectric materials. However, TiO x is very attractive for economic reasons, and there are still expectations for efficiency rise by modification of the material's microstructure. TiO x can be produced in large quantities of several tens of kilograms. A manufacturing process for TiO x -based unileg n-type modules has been established, including all technological steps. The design of the TiO x -based modules was optimized for the thermoelectric conversion process and thermal robustness. A test device was used for experimental analysis with maximum temperature of 600°C at the hot side and 100°C at the cold side. This initial test revealed similar power output and internal resistance of all fabricated modules. Furthermore, thermal cycles with increasing and decreasing temperatures at the hot side were realized to characterize the reliability and stability of the modules. Additionally, modules were tested in a hot gas test rig to simulate the thermal stresses during power generation in the exhaust line of a passenger car.

Tolerancing aspheres based on manufacturing knowledge

NASA Astrophysics Data System (ADS)

Wickenhagen, S.; Kokot, S.; Fuchs, U.

2017-10-01

A standard way of tolerancing optical elements or systems is to perform a Monte Carlo based analysis within a common optical design software package. Although, different weightings and distributions are assumed they are all counting on statistics, which usually means several hundreds or thousands of systems for reliable results. Thus, employing these methods for small batch sizes is unreliable, especially when aspheric surfaces are involved. The huge database of asphericon was used to investigate the correlation between the given tolerance values and measured data sets. The resulting probability distributions of these measured data were analyzed aiming for a robust optical tolerancing process.

Tolerancing aspheres based on manufacturing statistics

NASA Astrophysics Data System (ADS)

Wickenhagen, S.; Möhl, A.; Fuchs, U.

2017-11-01

A standard way of tolerancing optical elements or systems is to perform a Monte Carlo based analysis within a common optical design software package. Although, different weightings and distributions are assumed they are all counting on statistics, which usually means several hundreds or thousands of systems for reliable results. Thus, employing these methods for small batch sizes is unreliable, especially when aspheric surfaces are involved. The huge database of asphericon was used to investigate the correlation between the given tolerance values and measured data sets. The resulting probability distributions of these measured data were analyzed aiming for a robust optical tolerancing process.

Method for automatically evaluating a transition from a batch manufacturing technique to a lean manufacturing technique

DOEpatents

Ivezic, Nenad; Potok, Thomas E.

2003-09-30

A method for automatically evaluating a manufacturing technique comprises the steps of: receiving from a user manufacturing process step parameters characterizing a manufacturing process; accepting from the user a selection for an analysis of a particular lean manufacturing technique; automatically compiling process step data for each process step in the manufacturing process; automatically calculating process metrics from a summation of the compiled process step data for each process step; and, presenting the automatically calculated process metrics to the user. A method for evaluating a transition from a batch manufacturing technique to a lean manufacturing technique can comprise the steps of: collecting manufacturing process step characterization parameters; selecting a lean manufacturing technique for analysis; communicating the selected lean manufacturing technique and the manufacturing process step characterization parameters to an automatic manufacturing technique evaluation engine having a mathematical model for generating manufacturing technique evaluation data; and, using the lean manufacturing technique evaluation data to determine whether to transition from an existing manufacturing technique to the selected lean manufacturing technique.

Materials and Process Activities for NASA's Composite Crew Module

NASA Technical Reports Server (NTRS)

Polis, Daniel L.

2012-01-01

In January 2007, the NASA Administrator and Associate Administrator for the Exploration Systems Mission Directorate chartered the NASA Engineering and Safety Center (NESC) to design, build, and test a full-scale Composite Crew Module (CCM). The overall goal of the CCM project was to develop a team from the NASA family with hands-on experience in composite design, manufacturing, and testing in anticipation of future space exploration systems being made of composite materials. The CCM project was planned to run concurrently with the Orion project s baseline metallic design within the Constellation Program so that features could be compared and discussed without inducing risk to the overall Program. The materials and process activities were prioritized based on a rapid prototype approach. This approach focused developmental activities on design details with greater risk and uncertainty, such as out-of-autoclave joining, over some of the more traditional lamina and laminate building block levels. While process development and associated building block testing were performed, several anomalies were still observed at the full-scale level due to interactions between process robustness and manufacturing scale-up. This paper describes the process anomalies that were encountered during the CCM development and the subsequent root cause investigations that led to the final design solutions. These investigations highlight the importance of full-scale developmental work early in the schedule of a complex composite design/build project.

Development and Characterization of Mechanically Robust, 3D-Printable Photopolymers

NASA Astrophysics Data System (ADS)

Sycks, Dalton George

3D printing has seen an explosion of interest and growth in recent years, especially within the biomedical space. Prized for its efficiency, ability to produce complex geometries, and facile material processing, additive manufacturing is rapidly being used to create medical devices ranging from orthopedic implants to tissue scaffolds. However, 3D printing is currently limited to a select few material choices, especially when one considers soft tissue replacement or augmentation. To this end, my research focuses on developing material systems that are simultaneously 1) 3D printable, 2) biocompatible, and 3) mechanically robust with properties appropriate for soft-tissue replacement or augmentation applications. Two systems were developed toward this goal: an interpenetrating network (IPN) hydrogel consisting of covalently crosslinked poly (ethylene glycol) diacrylate (PEGDA) and ionically crosslinked brown sodium alginate, and semi-crystalline thiol-ene photopolymers containing spiroacetal molecules in the polymer main-chain backbone. In addition to successfully being incorporated into existing 3D printing systems (extrusion-deposition for the PEGDA-alginate hydrogel and digital light processing for the thiol-ene polymers) both systems exhibited biocompatibility and superior thermomechanical properties such as tensile modulus, failure strain, and toughness. This work offers two fully-developed, novel polymer platforms with outstanding performance; further, structure-property relationships are highlighted and discussed on a molecular and morphological level to provide material insights that are useful to researchers and engineers in the design of highly tuned and mechanically robust polymers.

Robustness of solvent/detergent treatment of plasma derivatives: a data collection from Plasma Protein Therapeutics Association member companies.

PubMed

Dichtelmüller, Herbert O; Biesert, Lothar; Fabbrizzi, Fabrizio; Gajardo, Rodrigo; Gröner, Albrecht; von Hoegen, Ilka; Jorquera, Juan I; Kempf, Christoph; Kreil, Thomas R; Pifat, Dominique; Osheroff, Wendy; Poelsler, Gerhard

2009-09-01

Solvent/detergent (S/D) treatment is an established virus inactivation technology that has been applied in the manufacture of medicinal products derived from human plasma for more than 20 years. Data on the inactivation of enveloped viruses by S/D treatment collected from seven Plasma Protein Therapeutics Association member companies demonstrate the robustness, reliability, and efficacy of this virus inactivation method. The results from 308 studies reflecting production conditions as well as technical variables significantly beyond the product release specification were evaluated for virus inactivation, comprising different combinations of solvent and detergent (tri(n-butyl) phosphate [TNBP]/Tween 80, TNBP/Triton X-100, TNBP/Na-cholate) and different products (Factor [F]VIII, F IX, and intravenous and intramuscular immunoglobulins). Neither product class, process temperature, protein concentration, nor pH value has a significant impact on virus inactivation. A variable that did appear to be critical was the concentration of solvent and detergent. The data presented here demonstrate the robustness of virus inactivation by S/D treatment for a broad spectrum of enveloped test viruses and process variables. Our data substantiate the fact that no transmission of viruses such as human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or of other enveloped viruses was reported for licensed plasma derivatives since the introduction of S/D treatment.

Amyris, Inc. Integrated Biorefinery Project Summary Final Report - Public Version

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gray, David; Sato, Suzanne; Garcia, Fernando

The Amyris pilot-scale Integrated Biorefinery (IBR) leveraged Amyris synthetic biology and process technology experience to upgrade Amyris’s existing Emeryville, California pilot plant and fermentation labs to enable development of US-based production capabilities for renewable diesel fuel and alternative chemical products. These products were derived semi-synthetically from high-impact biomass feedstocks via microbial fermentation to the 15-carbon intermediate farnesene, with subsequent chemical finishing to farnesane. The Amyris IBR team tested and provided methods for production of diesel and alternative chemical products from sweet sorghum, and other high-impact lignocellulosic feedstocks, at pilot scale. This enabled robust techno-economic analysis (TEA), regulatory approvals, and amore » basis for full-scale manufacturing processes and facility design.« less

A quality-by-design study for an immediate-release tablet platform: examining the relative impact of active pharmaceutical ingredient properties, processing methods, and excipient variability on drug product quality attributes.

PubMed

Kushner, Joseph; Langdon, Beth A; Hicks, Ian; Song, Daniel; Li, Fasheng; Kathiria, Lalji; Kane, Anil; Ranade, Gautam; Agarwal, Kam

2014-02-01

The impact of filler-lubricant particle size ratio variation (3.4-41.6) on the attributes of an immediate-release tablet was compared with the impacts of the manufacturing method used (direct compression or dry granulation) and drug loading (1%, 5%, and 25%), particle size (D[4,3]: 8-114 μm), and drug type (theophylline or ibuprofen). All batches were successfully manufactured, except for direct compression of 25% drug loading of 8 μm (D[4,3]) drug, which exhibited very poor flow properties. All manufactured tablets possessed adequate quality attributes: tablet weight uniformity <4% RSD, tablet potency: 94%-105%, content uniformity <6% RSD, acceptance value ≤ 15, solid fraction: 0.82-0.86, tensile strength >1 MPa, friability ≤ 0.2% weight loss, and disintegration time < 4 min. The filler-lubricant particle size ratio exhibited the greatest impact on blend and granulation particle size and granulation flow, whereas drug property variation dominated blend flow, ribbon solid fraction, and tablet quality attributes. Although statistically significant effects were observed, the results of this study suggest that the manufacturability and performance of this immediate-release tablet formulation is robust to a broad range of variation in drug properties, both within-grade and extra-grade excipient particle size variations, and the choice of manufacturing method. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Defining process design space for a hydrophobic interaction chromatography (HIC) purification step: application of quality by design (QbD) principles.

PubMed

Jiang, Canping; Flansburg, Lisa; Ghose, Sanchayita; Jorjorian, Paul; Shukla, Abhinav A

2010-12-15

The concept of design space has been taking root under the quality by design paradigm as a foundation of in-process control strategies for biopharmaceutical manufacturing processes. This paper outlines the development of a design space for a hydrophobic interaction chromatography (HIC) process step. The design space included the impact of raw material lot-to-lot variability and variations in the feed stream from cell culture. A failure modes and effects analysis was employed as the basis for the process characterization exercise. During mapping of the process design space, the multi-dimensional combination of operational variables were studied to quantify the impact on process performance in terms of yield and product quality. Variability in resin hydrophobicity was found to have a significant influence on step yield and high-molecular weight aggregate clearance through the HIC step. A robust operating window was identified for this process step that enabled a higher step yield while ensuring acceptable product quality. © 2010 Wiley Periodicals, Inc.

Production of erythrocytes from directly isolated or Delta1 Notch ligand expanded CD34+ hematopoietic progenitor cells: process characterization, monitoring and implications for manufacture.

PubMed

Glen, Katie E; Workman, Victoria L; Ahmed, Forhad; Ratcliffe, Elizabeth; Stacey, Adrian J; Thomas, Robert J

2013-09-01

Economic ex vivo manufacture of erythrocytes at 10(12) cell doses requires an efficiently controlled bio-process capable of extensive proliferation and high terminal density. High-resolution characterization of the process would identify production strategies for increased efficiency, monitoring and control. CD34(+) cord blood cells or equivalent cells that had been pre-expanded for 7 days with Delta1 Notch ligand were placed in erythroid expansion and differentiation conditions in a micro-scale ambr suspension bioreactor. Multiple culture parameters were varied, and phenotype markers and metabolites measured to identify conserved trends and robust monitoring markers. The cells exhibited a bi-modal erythroid differentiation pattern with an erythroid marker peak after 2 weeks and 3 weeks of culture; differentiation was comparatively weighted toward the second peak in Delta1 pre-expanded cells. Both differentiation events were strengthened by omission of stem cell factor and dexamethasone. The cumulative cell proliferation and death, or directly measured CD45 expression, enabled monitoring of proliferative rate of the cells. The metabolic activities of the cultures (glucose, glutamine and ammonia consumption or production) were highly variable but exhibited systematic change synchronized with the change in differentiation state. Erythroid differentiation chronology is partly determined by the heterogeneous CD34(+) progenitor compartment with implications for input control; Delta1 ligand-mediated progenitor culture can alter differentiation profile with control benefits for engineering production strategy. Differentiation correlated changes in cytokine response, markers and metabolic state will enable scientifically designed monitoring and timing of manufacturing process steps. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Vibration Sensor Monitoring of Nickel-Titanium Alloy Turning for Machinability Evaluation.

PubMed

Segreto, Tiziana; Caggiano, Alessandra; Karam, Sara; Teti, Roberto

2017-12-12

Nickel-Titanium (Ni-Ti) alloys are very difficult-to-machine materials causing notable manufacturing problems due to their unique mechanical properties, including superelasticity, high ductility, and severe strain-hardening. In this framework, the aim of this paper is to assess the machinability of Ni-Ti alloys with reference to turning processes in order to realize a reliable and robust in-process identification of machinability conditions. An on-line sensor monitoring procedure based on the acquisition of vibration signals was implemented during the experimental turning tests. The detected vibration sensorial data were processed through an advanced signal processing method in time-frequency domain based on wavelet packet transform (WPT). The extracted sensorial features were used to construct WPT pattern feature vectors to send as input to suitably configured neural networks (NNs) for cognitive pattern recognition in order to evaluate the correlation between input sensorial information and output machinability conditions.

Vibration Sensor Monitoring of Nickel-Titanium Alloy Turning for Machinability Evaluation

PubMed Central

Segreto, Tiziana; Karam, Sara; Teti, Roberto

2017-01-01

Nickel-Titanium (Ni-Ti) alloys are very difficult-to-machine materials causing notable manufacturing problems due to their unique mechanical properties, including superelasticity, high ductility, and severe strain-hardening. In this framework, the aim of this paper is to assess the machinability of Ni-Ti alloys with reference to turning processes in order to realize a reliable and robust in-process identification of machinability conditions. An on-line sensor monitoring procedure based on the acquisition of vibration signals was implemented during the experimental turning tests. The detected vibration sensorial data were processed through an advanced signal processing method in time-frequency domain based on wavelet packet transform (WPT). The extracted sensorial features were used to construct WPT pattern feature vectors to send as input to suitably configured neural networks (NNs) for cognitive pattern recognition in order to evaluate the correlation between input sensorial information and output machinability conditions. PMID:29231864

Allogeneic Cell Therapy Bioprocess Economics and Optimization: Single-Use Cell Expansion Technologies

PubMed Central

Simaria, Ana S; Hassan, Sally; Varadaraju, Hemanthram; Rowley, Jon; Warren, Kim; Vanek, Philip; Farid, Suzanne S

2014-01-01

For allogeneic cell therapies to reach their therapeutic potential, challenges related to achieving scalable and robust manufacturing processes will need to be addressed. A particular challenge is producing lot-sizes capable of meeting commercial demands of up to 109 cells/dose for large patient numbers due to the current limitations of expansion technologies. This article describes the application of a decisional tool to identify the most cost-effective expansion technologies for different scales of production as well as current gaps in the technology capabilities for allogeneic cell therapy manufacture. The tool integrates bioprocess economics with optimization to assess the economic competitiveness of planar and microcarrier-based cell expansion technologies. Visualization methods were used to identify the production scales where planar technologies will cease to be cost-effective and where microcarrier-based bioreactors become the only option. The tool outputs also predict that for the industry to be sustainable for high demand scenarios, significant increases will likely be needed in the performance capabilities of microcarrier-based systems. These data are presented using a technology S-curve as well as windows of operation to identify the combination of cell productivities and scale of single-use bioreactors required to meet future lot sizes. The modeling insights can be used to identify where future R&D investment should be focused to improve the performance of the most promising technologies so that they become a robust and scalable option that enables the cell therapy industry reach commercially relevant lot sizes. The tool outputs can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes needed as products proceed through the development pathway. Biotechnol. Bioeng. 2014;111: 69–83. © 2013 Wiley Periodicals, Inc. PMID:23893544

Allogeneic cell therapy bioprocess economics and optimization: single-use cell expansion technologies.

PubMed

Simaria, Ana S; Hassan, Sally; Varadaraju, Hemanthram; Rowley, Jon; Warren, Kim; Vanek, Philip; Farid, Suzanne S

2014-01-01

For allogeneic cell therapies to reach their therapeutic potential, challenges related to achieving scalable and robust manufacturing processes will need to be addressed. A particular challenge is producing lot-sizes capable of meeting commercial demands of up to 10(9) cells/dose for large patient numbers due to the current limitations of expansion technologies. This article describes the application of a decisional tool to identify the most cost-effective expansion technologies for different scales of production as well as current gaps in the technology capabilities for allogeneic cell therapy manufacture. The tool integrates bioprocess economics with optimization to assess the economic competitiveness of planar and microcarrier-based cell expansion technologies. Visualization methods were used to identify the production scales where planar technologies will cease to be cost-effective and where microcarrier-based bioreactors become the only option. The tool outputs also predict that for the industry to be sustainable for high demand scenarios, significant increases will likely be needed in the performance capabilities of microcarrier-based systems. These data are presented using a technology S-curve as well as windows of operation to identify the combination of cell productivities and scale of single-use bioreactors required to meet future lot sizes. The modeling insights can be used to identify where future R&D investment should be focused to improve the performance of the most promising technologies so that they become a robust and scalable option that enables the cell therapy industry reach commercially relevant lot sizes. The tool outputs can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes needed as products proceed through the development pathway. © 2013 Wiley Periodicals, Inc.

Simple laser vision sensor calibration for surface profiling applications

NASA Astrophysics Data System (ADS)

Abu-Nabah, Bassam A.; ElSoussi, Adnane O.; Al Alami, Abed ElRahman K.

2016-09-01

Due to the relatively large structures in the Oil and Gas industry, original equipment manufacturers (OEMs) have been implementing custom-designed laser vision sensor (LVS) surface profiling systems as part of quality control in their manufacturing processes. The rough manufacturing environment and the continuous movement and misalignment of these custom-designed tools adversely affect the accuracy of laser-based vision surface profiling applications. Accordingly, Oil and Gas businesses have been raising the demand from the OEMs to implement practical and robust LVS calibration techniques prior to running any visual inspections. This effort introduces an LVS calibration technique representing a simplified version of two known calibration techniques, which are commonly implemented to obtain a calibrated LVS system for surface profiling applications. Both calibration techniques are implemented virtually and experimentally to scan simulated and three-dimensional (3D) printed features of known profiles, respectively. Scanned data is transformed from the camera frame to points in the world coordinate system and compared with the input profiles to validate the introduced calibration technique capability against the more complex approach and preliminarily assess the measurement technique for weld profiling applications. Moreover, the sensitivity to stand-off distances is analyzed to illustrate the practicality of the presented technique.

Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT).

PubMed

Aksu, Buket; De Beer, Thomas; Folestad, Staffan; Ketolainen, Jarkko; Lindén, Hans; Lopes, Joao Almeida; de Matas, Marcel; Oostra, Wim; Rantanen, Jukka; Weimer, Marco

2012-09-29

Substantial changes in Pharmaceutical R&D strategy are required to address existing issues of low productivity, imminent patent expirations and pressures on pricing. Moves towards personalized healthcare and increasing diversity in the nature of portfolios including the rise of biopharmaceuticals however have the potential to provide considerable challenges to the establishment of cost effective and robust supply chains. To guarantee product quality and surety of supply for essential medicines it is necessary that manufacturing science keeps pace with advances in pharmaceutical R&D. In this position paper, the EUFEPS QbD and PAT Sciences network make recommendations that European industry, academia and health agencies focus attention on delivering step changes in science and technology in a number of key themes. These subject areas, all underpinned by the sciences allied to QbD and PAT, include product design and development for personalized healthcare, continuous-processing in pharmaceutical product manufacture, quantitative quality risk assessment for pharmaceutical development including life cycle management and the downstream processing of biopharmaceutical products. Plans are being established to gain commitment for inclusion of these themes into future funding priorities for the Innovative Medicines Initiative (IMI). Copyright © 2012 Elsevier B.V. All rights reserved.

Effect of replacement of tin doped indium oxide (ITO) by ZnO: analysis of environmental impact categories

NASA Astrophysics Data System (ADS)

Ziemińska-Stolarska, Aleksandra; Barecka, Magda; Zbiciński, Ireneusz

2017-10-01

Abundant use of natural resources is doubtlessly one of the greatest challenges of sustainable development. Process alternatives, which enable sustainable manufacturing of valuable products from more accessible resources, are consequently required. One of examples of limited resources is Indium, currently broadly used for tin doped indium oxide (ITO) for production of transparent conductive films (TCO) in electronics industry. Therefore, candidates for Indium replacement, which would offer as good performance as the industrial state-of-the-art technology based on ITO are widely studied. However, the environmental impact of new layers remains unknown. Hence, this paper studies the environmental effect of ITO replacement by zinc oxide (ZnO) by means life cycle assessment (LCA) methodology. The analysis enables to quantify the environmental impact over the entire period of life cycle of products—during manufacturing, use phase and waste generation. The analysis was based on experimental data for deposition process. Further, analysis of different impact categories was performed in order to determine specific environmental effects related to technology change. What results from the analysis, is that ZnO is a robust alternative material for ITO replacement regarding environmental load and energy efficiency of deposition process which is also crucial for sustainable TCO layer production.

Improving near-infrared prediction model robustness with support vector machine regression: a pharmaceutical tablet assay example.

PubMed

Igne, Benoît; Drennen, James K; Anderson, Carl A

2014-01-01

Changes in raw materials and process wear and tear can have significant effects on the prediction error of near-infrared calibration models. When the variability that is present during routine manufacturing is not included in the calibration, test, and validation sets, the long-term performance and robustness of the model will be limited. Nonlinearity is a major source of interference. In near-infrared spectroscopy, nonlinearity can arise from light path-length differences that can come from differences in particle size or density. The usefulness of support vector machine (SVM) regression to handle nonlinearity and improve the robustness of calibration models in scenarios where the calibration set did not include all the variability present in test was evaluated. Compared to partial least squares (PLS) regression, SVM regression was less affected by physical (particle size) and chemical (moisture) differences. The linearity of the SVM predicted values was also improved. Nevertheless, although visualization and interpretation tools have been developed to enhance the usability of SVM-based methods, work is yet to be done to provide chemometricians in the pharmaceutical industry with a regression method that can supplement PLS-based methods.

The integrated simulation and assessment of the impacts of process change in biotherapeutic antibody production.

PubMed

Chhatre, Sunil; Jones, Carl; Francis, Richard; O'Donovan, Kieran; Titchener-Hooker, Nigel; Newcombe, Anthony; Keshavarz-Moore, Eli

2006-01-01

Growing commercial pressures in the pharmaceutical industry are establishing a need for robust computer simulations of whole bioprocesses to allow rapid prediction of the effects of changes made to manufacturing operations. This paper presents an integrated process simulation that models the cGMP manufacture of the FDA-approved biotherapeutic CroFab, an IgG fragment used to treat rattlesnake envenomation (Protherics U.K. Limited, Blaenwaun, Ffostrasol, Llandysul, Wales, U.K.). Initially, the product is isolated from ovine serum by precipitation and centrifugation, before enzymatic digestion of the IgG to produce FAB and FC fragments. These are purified by ion exchange and affinity chromatography to remove the FC and non-specific FAB fragments from the final venom-specific FAB product. The model was constructed in a discrete event simulation environment and used to determine the potential impact of a series of changes to the process, such as increasing the step efficiencies or volumes of chromatographic matrices, upon product yields and process times. The study indicated that the overall FAB yield was particularly sensitive to changes in the digestive and affinity chromatographic step efficiencies, which have a predicted 30% greater impact on process FAB yield than do the precipitation or centrifugation stages. The study showed that increasing the volume of affinity matrix has a negligible impact upon total process time. Although results such as these would require experimental verification within the physical constraints of the process and the facility, the model predictions are still useful in allowing rapid "what-if" scenario analysis of the likely impacts of process changes within such an integrated production process.

Design for the automation of composite wind turbine blade manufacture

NASA Astrophysics Data System (ADS)

Polcari, M. J.; White, K. D.; Sherwood, J. A.

2016-10-01

The majority of large wind turbine blades are manufactured from textile-reinforced resin-infused composites using an open mold. The placement of the textile reinforcements in the mold is traditionally accomplished by a manual process where dozens of workers hand place each dry fabric in the mold. Depending on the level of skill and experience of each worker and the relative complexity of the mold geometry, local areas may exhibit out-of-plane wrinkling and in-plane waviness. Fabric imperfections such as these can adversely impact the strength and stiffness of the blade, thereby compromising its durability in service. In an effort to reduce the variabilities associated with a manual-labor process, an automated piecewise shifting method has been proposed for fabric placement. This automated layup method saves time on the preform process and reduces variability from blade to blade. In the current research the automated shifting layup method is investigated using a robust and easy-to-use finite element modelling approach. User-defined material models utilizing a mesoscopic unit-cell modeling approach are linked with Abaqus to capture the evolution of the fabric shear stiffness and changes in the fiber orientations during the fabric-placement process. The simulation approach is demonstrated for the geometry of the trailing edge of a typical wind turbine blade. The simulation considers the mechanical behavior of the fabric and reliably predicts fabric deformation and failure zones.

Design for a Manufacturing Method for Memristor-Based Neuromorphic Computing Processors

DTIC Science & Technology

2013-03-01

DESIGN FOR A MANUFACTURING METHOD FOR MEMRISTOR- BASED NEUROMORPHIC COMPUTING PROCESSORS UNIVERSITY OF PITTSBURGH MARCH 2013...BASED NEUROMORPHIC COMPUTING PROCESSORS 5a. CONTRACT NUMBER FA8750-11-1-0271 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER 62788F 6. AUTHOR(S...synapses and implemented a neuromorphic computing system based on our proposed synapse designs. The robustness of our system is also evaluated by

A meta-model based approach for rapid formability estimation of continuous fibre reinforced components

NASA Astrophysics Data System (ADS)

Zimmerling, Clemens; Dörr, Dominik; Henning, Frank; Kärger, Luise

2018-05-01

Due to their high mechanical performance, continuous fibre reinforced plastics (CoFRP) become increasingly important for load bearing structures. In many cases, manufacturing CoFRPs comprises a forming process of textiles. To predict and optimise the forming behaviour of a component, numerical simulations are applied. However, for maximum part quality, both the geometry and the process parameters must match in mutual regard, which in turn requires numerous numerically expensive optimisation iterations. In both textile and metal forming, a lot of research has focused on determining optimum process parameters, whilst regarding the geometry as invariable. In this work, a meta-model based approach on component level is proposed, that provides a rapid estimation of the formability for variable geometries based on pre-sampled, physics-based draping data. Initially, a geometry recognition algorithm scans the geometry and extracts a set of doubly-curved regions with relevant geometry parameters. If the relevant parameter space is not part of an underlying data base, additional samples via Finite-Element draping simulations are drawn according to a suitable design-table for computer experiments. Time saving parallel runs of the physical simulations accelerate the data acquisition. Ultimately, a Gaussian Regression meta-model is built from the data base. The method is demonstrated on a box-shaped generic structure. The predicted results are in good agreement with physics-based draping simulations. Since evaluations of the established meta-model are numerically inexpensive, any further design exploration (e.g. robustness analysis or design optimisation) can be performed in short time. It is expected that the proposed method also offers great potential for future applications along virtual process chains: For each process step along the chain, a meta-model can be set-up to predict the impact of design variations on manufacturability and part performance. Thus, the method is considered to facilitate a lean and economic part and process design under consideration of manufacturing effects.

Fault region localization (FRL): collaborative product and process improvement based on field performance

NASA Astrophysics Data System (ADS)

Mannar, Kamal; Ceglarek, Darek

2005-11-01

Customer feedback in the form of warranty/field performance is an important and direct indicator of quality and robustness of a product. Linking warranty information to manufacturing measurements can identify key design parameters and process variables (DPs and PVs) that are related to warranty failures. Warranty data has been traditionally used in reliability studies to determine failure distributions and warranty cost. This paper proposes a novel Fault Region Localization (FRL) methodology to map warranty failures to manufacturing measurements (hence to DPs/PVs) to diagnose warranty failures and perform tolerance revaluation. The FRL methodology consists of two parts: 1. Identifying relations between warranty failures and DPs and PVs using the Generalized Rough Set (GRS) method. GRS is a supervised learning technique to identify specific DPs and PVs related to the given warranty failures and then determining the corresponding Warranty Fault Regions (WFR), Normal Region (NR) and Boundary region (BND). GRS expands traditional Rough Set method by allowing inclusion of noise and uncertainty of warranty data classes. 2. Revaluating the original tolerances of DPs/PVs based on the WFR and BND region identified. The FRL methodology is illustrated using case studies based on two warranty failures from the electronics industry.

Controlling Fiber Morphology in Simultaneous Centrifugal Spinning and Photopolymerization

NASA Astrophysics Data System (ADS)

Fang, Yichen; Dulaney, Austin; Ellison, Christopher

2015-03-01

Current synthetic fiber manufacturing technologies use either solvent or heat to transform a solid preformed polymer into a liquid before applying a force to draw the liquid into fiber. While the use of solvent poses concerns regarding process safety and environmental impact, the use of heat may also lead to polymer degradation and excessive energy consumption. To address these critical challenges, here we present an alternative fiber manufacturing method that encompasses extruding a monomer solution through an orifice, drawing it using centrifugal Forcespinning and polymerizing the monomer jet into solid fiber in flight using UV initiated thiol-ene chemistry. This method not only negates the use of both heat and solvent, but also produces fibers that are highly crosslinked, mechanically robust, and thermally stable. In this process, the balance between curing kinetics, fiber flight time, and solution viscoelasticity is essential. Studies were conducted to quantitatively investigate the effect of these factors on fiber formation and morphology. An operating diagram was developed to show how the intricate interplay of these factors led to the formation of smooth fibers and other undesirable fiber defects, such as beads-on-string, fused fibers, and droplets.

Solid-state supercapacitors with rationally designed heterogeneous electrodes fabricated by large area spray processing for wearable energy storage applications

PubMed Central

Huang, Chun; Zhang, Jin; Young, Neil P.; Snaith, Henry J.; Grant, Patrick S.

2016-01-01

Supercapacitors are in demand for short-term electrical charge and discharge applications. Unlike conventional supercapacitors, solid-state versions have no liquid electrolyte and do not require robust, rigid packaging for containment. Consequently they can be thinner, lighter and more flexible. However, solid-state supercapacitors suffer from lower power density and where new materials have been developed to improve performance, there remains a gap between promising laboratory results that usually require nano-structured materials and fine-scale processing approaches, and current manufacturing technology that operates at large scale. We demonstrate a new, scalable capability to produce discrete, multi-layered electrodes with a different material and/or morphology in each layer, and where each layer plays a different, critical role in enhancing the dynamics of charge/discharge. This layered structure allows efficient utilisation of each material and enables conservative use of hard-to-obtain materials. The layered electrode shows amongst the highest combinations of energy and power densities for solid-state supercapacitors. Our functional design and spray manufacturing approach to heterogeneous electrodes provide a new way forward for improved energy storage devices. PMID:27161379

3D printing and milling a real-time PCR device for infectious disease diagnostics.

PubMed

Mulberry, Geoffrey; White, Kevin A; Vaidya, Manjusha; Sugaya, Kiminobu; Kim, Brian N

2017-01-01

Diagnosing infectious diseases using quantitative polymerase chain reaction (qPCR) offers a conclusive result in determining the infection, the strain or type of pathogen, and the level of infection. However, due to the high-cost instrumentation involved and the complexity in maintenance, it is rarely used in the field to make a quick turnaround diagnosis. In order to provide a higher level of accessibility than current qPCR devices, a set of 3D manufacturing methods is explored as a possible option to fabricate a low-cost and portable qPCR device. The key advantage of this approach is the ability to upload the digital format of the design files on the internet for wide distribution so that people at any location can simply download and feed into their 3D printers for quick manufacturing. The material and design are carefully selected to minimize the number of custom parts that depend on advanced manufacturing processes which lower accessibility. The presented 3D manufactured qPCR device is tested with 20-μL samples that contain various concentrations of lentivirus, the same type as HIV. A reverse-transcription step is a part of the device's operation, which takes place prior to the qPCR step to reverse transcribe the target RNA from the lentivirus into complementary DNA (cDNA). This is immediately followed by qPCR which quantifies the target sequence molecules in the sample during the PCR amplification process. The entire process of thermal control and time-coordinated fluorescence reading is automated by closed-loop feedback and a microcontroller. The resulting device is portable and battery-operated, with a size of 12 × 7 × 6 cm3 and mass of only 214 g. By uploading and sharing the design files online, the presented low-cost qPCR device may provide easier access to a robust diagnosis protocol for various infectious diseases, such as HIV and malaria.

3D printing and milling a real-time PCR device for infectious disease diagnostics

PubMed Central

Mulberry, Geoffrey; White, Kevin A.; Vaidya, Manjusha; Sugaya, Kiminobu

2017-01-01

Diagnosing infectious diseases using quantitative polymerase chain reaction (qPCR) offers a conclusive result in determining the infection, the strain or type of pathogen, and the level of infection. However, due to the high-cost instrumentation involved and the complexity in maintenance, it is rarely used in the field to make a quick turnaround diagnosis. In order to provide a higher level of accessibility than current qPCR devices, a set of 3D manufacturing methods is explored as a possible option to fabricate a low-cost and portable qPCR device. The key advantage of this approach is the ability to upload the digital format of the design files on the internet for wide distribution so that people at any location can simply download and feed into their 3D printers for quick manufacturing. The material and design are carefully selected to minimize the number of custom parts that depend on advanced manufacturing processes which lower accessibility. The presented 3D manufactured qPCR device is tested with 20-μL samples that contain various concentrations of lentivirus, the same type as HIV. A reverse-transcription step is a part of the device’s operation, which takes place prior to the qPCR step to reverse transcribe the target RNA from the lentivirus into complementary DNA (cDNA). This is immediately followed by qPCR which quantifies the target sequence molecules in the sample during the PCR amplification process. The entire process of thermal control and time-coordinated fluorescence reading is automated by closed-loop feedback and a microcontroller. The resulting device is portable and battery-operated, with a size of 12 × 7 × 6 cm3 and mass of only 214 g. By uploading and sharing the design files online, the presented low-cost qPCR device may provide easier access to a robust diagnosis protocol for various infectious diseases, such as HIV and malaria. PMID:28586401

RFID identity theft and countermeasures

NASA Astrophysics Data System (ADS)

Herrigel, Alexander; Zhao, Jian

2006-02-01

This paper reviews the ICAO security architecture for biometric passports. An attack enabling RFID identity theft for a later misuse is presented. Specific countermeasures against this attack are described. Furthermore, it is shown that robust high capacity digital watermarking for the embedding and retrieving of binary digital signature data can be applied as an effective mean against RFID identity theft. This approach requires only minimal modifications of the passport manufacturing process and is an enhancement of already proposed solutions. The approach may also be applied in combination with a RFID as a backup solution (damaged RFID chip) to verify with asymmetric cryptographic techniques the authenticity and the integrity of the passport data.

Chemochromic Detector for Sensing Gas Leakage and Process for Producing the Same

NASA Technical Reports Server (NTRS)

Williams, Martha K. (Inventor); Roberson, Luke B. (Inventor); Smith, Trent M. (Inventor); Tate, LaNetra Clayton (Inventor); Captain, Janine E. (Inventor)

2014-01-01

A chemochromic sensor for detecting a combustible gas, such as hydrogen, includes a chemochromic pigment mechanically mixed with a polymer and molded into a rigid or pliable shape. In a preferred embodiment, the chemochromic detector is within the material which is molded into a manufactured part, said part becoming the detector itself. The detector is robust and easily modifiable for a variety of applications and environmental conditions, such as atmospheres of inert gas, hydrogen gas, or mixtures of gases, or in environments that have variable temperature, including high temperatures such as above 100 C. and low temperatures such as below -196 C.

Feasibility of using continuous chromatography in downstream processing: Comparison of costs and product quality for a hybrid process vs. a conventional batch process.

PubMed

Ötes, Ozan; Flato, Hendrik; Winderl, Johannes; Hubbuch, Jürgen; Capito, Florian

2017-10-10

The protein A capture step is the main cost-driver in downstream processing, with high attrition costs especially when using protein A resin not until end of resin lifetime. Here we describe a feasibility study, transferring a batch downstream process to a hybrid process, aimed at replacing batch protein A capture chromatography with a continuous capture step, while leaving the polishing steps unchanged to minimize required process adaptations compared to a batch process. 35g of antibody were purified using the hybrid approach, resulting in comparable product quality and step yield compared to the batch process. Productivity for the protein A step could be increased up to 420%, reducing buffer amounts by 30-40% and showing robustness for at least 48h continuous run time. Additionally, to enable its potential application in a clinical trial manufacturing environment cost of goods were compared for the protein A step between hybrid process and batch process, showing a 300% cost reduction, depending on processed volumes and batch cycles. Copyright © 2017 Elsevier B.V. All rights reserved.

Strain hardening behavior during manufacturing of tube shapes by hydroforming

NASA Astrophysics Data System (ADS)

Park, Hyun Kyu; Yi, Hyae Kyung; Van Tyne, Chester J.; Moon, Young Hoon

2009-12-01

Safe and robust process design relies on knowledge of the evolution of the mechanical properties in a tube during hydroforming. The manufacturing of tubular shapes generally consists of three main stages: bending, preforming, and expansion. The latter is usually called hydroforming. As a result of these three steps, the final product's strain hardening history is nonlinear. In the present study, the strain hardening behavior during hydroforming was experimentally investigated. The variation of local flow stress and/or local hardness was used as an index of the strain hardening during the various steps and the local flow stress and/or local hardness were used with respective correlations to determine the effective strain. The strain hardening behavior during hydroforming after preforming has been successfully analyzed by using the relationships between hardness, flow stress, and effective strain for variable pre-strains prior to hydroforming. The comparison of predicted hardness with measured hardness confirms that the methodology used in this study is feasible, and that the strain hardening behavior can be quantitatively estimated with good accuracy.

A Magnetic Bead-Integrated Chip for the Large Scale Manufacture of Normalized esiRNAs

PubMed Central

Wang, Zhao; Huang, Huang; Zhang, Hanshuo; Sun, Changhong; Hao, Yang; Yang, Junyu; Fan, Yu; Xi, Jianzhong Jeff

2012-01-01

The chemically-synthesized siRNA duplex has become a powerful and widely used tool for RNAi loss-of-function studies, but suffers from a high off-target effect problem. Recently, endoribonulease-prepared siRNA (esiRNA) has been shown to be an attractive alternative due to its lower off-target effect and cost effectiveness. However, the current manufacturing method for esiRNA is complicated, mainly in regards to purification and normalization on a large-scale level. In this study, we present a magnetic bead-integrated chip that can immobilize amplification or transcription products on beads and accomplish transcription, digestion, normalization and purification in a robust and convenient manner. This chip is equipped to manufacture ready-to-use esiRNAs on a large-scale level. Silencing specificity and efficiency of these esiRNAs were validated at the transcriptional, translational and functional levels. Manufacture of several normalized esiRNAs in a single well, including those silencing PARP1 and BRCA1, was successfully achieved, and the esiRNAs were subsequently utilized to effectively investigate their synergistic effect on cell viability. A small esiRNA library targeting 68 tyrosine kinase genes was constructed for a loss-of-function study, and four genes were identified in regulating the migration capability of Hela cells. We believe that this approach provides a more robust and cost-effective choice for manufacturing esiRNAs than current approaches, and therefore these heterogeneous RNA strands may have utility in most intensive and extensive applications. PMID:22761791

Ultraviolet Light Surface Treatment as an Environmentally Benign Process for Production, Maintenance and Repair of Military Composite Structures

NASA Astrophysics Data System (ADS)

Drzal, Lawrence T.

2002-02-01

The principal objective of this work is to develop a low-cost, high-speed, environmentally benign, dry surface treatment method for production, and repair of military composite structures using ultraviolet (UV) light in ambient air. The potential advantage of this method is that it would eliminate volatile organic wastes (VOCs), reduce or eliminate the use of solutions and detergents, and provide a robust surface that would enhance or eliminate the use of solutions and detergents, and provide a robust surface that would enhance the wetting and spreading of paints, coatings and adhesives on polymeric and inorganic surfaces treated by this method. A manufacturing base for UV production equipment is in place although not for this application. There is a need for development of an environmentally friendly, cost effective as well as a robust surface treatment method that can clean a surface as well as create a beneficial chemistry for painting and produce optimum adhesive bonding of polymers, polymer composites and metal surfaces. With this in mind, three main technical objectives were sought in the work. The first objective was to determine the usefulness of UV and UV/O(3) to surface treatments to clean and chemically modify the surface of typical PMCs used in DOD systems. The second objective was to determine the effectiveness of this surface preparation for production and/or repair of adhesively bonded, painted and/or coated polymer matrix composite structures. Finally, a determination of the environmental and performance benefits of this method as a new environmentally benign processing method for the production and/or re air of adhesively SERDP, SERDP collection, robust surface, polymeric surface, inorganic surface, volatile organic compounds (VOC) emissions.

Harnessing QbD, Programming Languages, and Automation for Reproducible Biology.

PubMed

Sadowski, Michael I; Grant, Chris; Fell, Tim S

2016-03-01

Building robust manufacturing processes from biological components is a task that is highly complex and requires sophisticated tools to describe processes, inputs, and measurements and administrate management of knowledge, data, and materials. We argue that for bioengineering to fully access biological potential, it will require application of statistically designed experiments to derive detailed empirical models of underlying systems. This requires execution of large-scale structured experimentation for which laboratory automation is necessary. This requires development of expressive, high-level languages that allow reusability of protocols, characterization of their reliability, and a change in focus from implementation details to functional properties. We review recent developments in these areas and identify what we believe is an exciting trend that promises to revolutionize biotechnology. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Novel Nanotube Manufacturing Streamlines Production

NASA Technical Reports Server (NTRS)

2007-01-01

Nanotubes have novel qualities that make them uniquely qualified for a plethora of uses, including applications in electronics, optics, and other scientific and industrial fields. The NASA process for creating these nanostructures involves using helium arc welding to vaporize an amorphous carbon rod and then form nanotubes by depositing the vapor onto a water-cooled carbon cathode, which then yields bundles, or ropes, of single-walled nanotubes at a rate of 2 grams per hour using a single setup. This eliminates costs associated with the use of metal catalysts, including the cost of product purification, resulting in a relatively inexpensive, high-quality, very pure end product. While managing to be less expensive, safer, and simpler, the process also increases the quality of the nanotubes. Goddard's Innovative Partnerships Program (IPP) Office promoted the technology, and in 2005, Boise-based Idaho Space Materials Inc. (ISM) was formed and applied for a nonexclusive license for the single-walled carbon nanotube (SWCNT) manufacturing technology. ISM commercialized its products, and the inexpensive, robust nanotubes are now in the hands of the scientists who will create the next generation of composite polymers, metals, and ceramics that will impact the way we live. In fact, researchers are examining ways for these newfound materials to be used in the manufacture of transistors and fuel cells, large screen televisions, ultra-sensitive sensors, high-resolution atomic force microscopy probes, supercapacitors, transparent conducting films, drug carriers, catalysts, and advanced composite materials, to name just a few of the myriad technologies to benefit.

Robust Joining and Assembly Technologies for Ceramic Matrix Composites: Technical Challenges and Opportunities

NASA Technical Reports Server (NTRS)

Mrityunjay, Singh; Gray, Hugh R. (Technical Monitor)

2002-01-01

Fiber reinforced ceramic matrix composites are under active consideration for use in a wide variety of high temperature applications within the aeronautics, energy, process, and nuclear industries. The engineering designs require fabrication and manufacturing of complex shaped parts. In many instances, it is more economical to build up complex shapes by Joining simple geometrical shapes. Thus, joining and attachment have been recognized as enabling technologies for successful utilization of ceramic components in various demanding applications. In this presentation, various challenges and opportunities in design, fabrication, and testing of high temperature joints in ceramic matrix composites will be presented. Various joint design philosophies and design issues in joining of composites will be discussed along with an affordable, robust ceramic joining technology (ARCJoinT). A wide variety of ceramic composites, in different shapes and sizes, have been joined using this technology. Microstructure and mechanical properties of joints will be reported. Current status of various ceramic joining technologies and future prospects for their applications will also be discussed.

Analytical technologies for influenza virus-like particle candidate vaccines: challenges and emerging approaches

PubMed Central

2013-01-01

Influenza virus-like particle vaccines are one of the most promising ways to respond to the threat of future influenza pandemics. VLPs are composed of viral antigens but lack nucleic acids making them non-infectious which limit the risk of recombination with wild-type strains. By taking advantage of the advancements in cell culture technologies, the process from strain identification to manufacturing has the potential to be completed rapidly and easily at large scales. After closely reviewing the current research done on influenza VLPs, it is evident that the development of quantification methods has been consistently overlooked. VLP quantification at all stages of the production process has been left to rely on current influenza quantification methods (i.e. Hemagglutination assay (HA), Single Radial Immunodiffusion assay (SRID), NA enzymatic activity assays, Western blot, Electron Microscopy). These are analytical methods developed decades ago for influenza virions and final bulk influenza vaccines. Although these methods are time-consuming and cumbersome they have been sufficient for the characterization of final purified material. Nevertheless, these analytical methods are impractical for in-line process monitoring because VLP concentration in crude samples generally falls out of the range of detection for these methods. This consequently impedes the development of robust influenza-VLP production and purification processes. Thus, development of functional process analytical techniques, applicable at every stage during production, that are compatible with different production platforms is in great need to assess, optimize and exploit the full potential of novel manufacturing platforms. PMID:23642219

Autonomous Agents for Dynamic Process Planning in the Flexible Manufacturing System

NASA Astrophysics Data System (ADS)

Nik Nejad, Hossein Tehrani; Sugimura, Nobuhiro; Iwamura, Koji; Tanimizu, Yoshitaka

Rapid changes of market demands and pressures of competition require manufacturers to maintain highly flexible manufacturing systems to cope with a complex manufacturing environment. This paper deals with development of an agent-based architecture of dynamic systems for incremental process planning in the manufacturing systems. In consideration of alternative manufacturing processes and machine tools, the process plans and the schedules of the manufacturing resources are generated incrementally and dynamically. A negotiation protocol is discussed, in this paper, to generate suitable process plans for the target products real-timely and dynamically, based on the alternative manufacturing processes. The alternative manufacturing processes are presented by the process plan networks discussed in the previous paper, and the suitable process plans are searched and generated to cope with both the dynamic changes of the product specifications and the disturbances of the manufacturing resources. We initiatively combine the heuristic search algorithms of the process plan networks with the negotiation protocols, in order to generate suitable process plans in the dynamic manufacturing environment.

A proposed holistic approach to on-chip, off-chip, test, and package interconnections

NASA Astrophysics Data System (ADS)

Bartelink, Dirk J.

1998-11-01

The term interconnection has traditionally implied a `robust' connection from a transistor or a group of transistors in an IC to the outside world, usually a PC board. Optimum system utilization is done from outside the IC. As an alternative, this paper addresses `unimpeded' transistor-to-transistor interconnection aimed at reaching the high circuit densities and computational capabilities of neighboring IC's. In this view, interconnections are not made to some human-centric place outside the IC world requiring robustness—except for system input and output connections. This unimpeded interconnect style is currently available only through intra-chip signal traces in `system-on-a-chip' implementations, as exemplified by embedded DRAMs. Because the traditional off-chip penalty in performance and wiring density is so large, a merging of complex process technologies is the only option today. It is suggested that, for system integration to move forward, the traditional robustness requirement inherited from conventional packaging interconnect and IC manufacturing test must be discarded. Traditional system assembly from vendor parts requires robustness under shipping, inspection and assembly. The trend toward systems on a chip signifies willingness by semiconductor companies to design and fabricate whole systems in house, so that `in-house' chip-to-chip assembly is not beyond reach. In this scenario, bare chips never leave the controlled environment of the IC fabricator while the two major contributors to off-chip signal penalty, ESD protection and the need to source a 50-ohm test head, are avoided. With in-house assembly, ESD protection can be eliminated with the precautions already familiar in plasma etching. Test interconnection impacts the fundamentals of IC manufacturing, particularly with clock speeds approaching 1GHz, and cannot be an afterthought. It should be an integral part of the chip-to-chip interconnection bandwidth optimization, because—as we must recognize—test is also performed using IC's. A system interconnection is proposed using multiple chips fabricated with conventional silicon processes, including MEMS technology. The system resembles an MCM that can be joined without committing to final assembly to perform at-speed testing. 50-Ohm test probes never load the circuit; only intended neighboring chips are ever connected. A `back-plane' chip provides the connection layers for both inter- and intra-chip signals and also serves as the probe card, in analogy with membrane probes now used for single-chip testing. Intra-chip connections, which require complicated connections during test that exactly match the product, are then properly made and all waveforms and loading conditions under test will be identical to those of the product. The major benefit is that all front-end chip technologies can be merged—logic, memory, RF, even passives. ESD protection is required only on external system connections. Manufacturing test information will accurately characterize process faults and thus avoid the Known-Good-Die problem that has slowed the arrival of conventional MCM's.

Transcriptomics as a tool for assessing the scalability of mammalian cell perfusion systems.

PubMed

Jayapal, Karthik P; Goudar, Chetan T

2014-01-01

DNA microarray-based transcriptomics have been used to determine the time course of laboratory and manufacturing-scale perfusion bioreactors in an attempt to characterize cell physiological state at these two bioreactor scales. Given the limited availability of genomic data for baby hamster kidney (BHK) cells, a Chinese hamster ovary (CHO)-based microarray was used following a feasibility assessment of cross-species hybridization. A heat shock experiment was performed using both BHK and CHO cells and resulting DNA microarray data were analyzed using a filtering criteria of perfect match (PM)/single base mismatch (MM) > 1.5 and PM-MM > 50 to exclude probes with low specificity or sensitivity for cross-species hybridizations. For BHK cells, 8910 probe sets (39 %) passed the cutoff criteria, whereas 12,961 probe sets (56 %) passed the cutoff criteria for CHO cells. Yet, the data from BHK cells allowed distinct clustering of heat shock and control samples as well as identification of biologically relevant genes as being differentially expressed, indicating the utility of cross-species hybridization. Subsequently, DNA microarray analysis was performed on time course samples from laboratory- and manufacturing-scale perfusion bioreactors that were operated under the same conditions. A majority of the variability (37 %) was associated with the first principal component (PC-1). Although PC-1 changed monotonically with culture duration, the trends were very similar in both the laboratory and manufacturing-scale bioreactors. Therefore, despite time-related changes to the cell physiological state, transcriptomic fingerprints were similar across the two bioreactor scales at any given instance in culture. Multiple genes were identified with time-course expression profiles that were very highly correlated (> 0.9) with bioprocess variables of interest. Although the current incomplete annotation limits the biological interpretation of these observations, their full potential may be realized in due course when richer genomic data become available. By taking a pragmatic approach of transcriptome fingerprinting, we have demonstrated the utility of systems biology to support the comparability of laboratory and manufacturing-scale perfusion systems. Scale-down model qualification is the first step in process characterization and hence is an integral component of robust regulatory filings. Augmenting the current paradigm, which relies primarily on cell culture and product quality information, with gene expression data can help make a substantially stronger case for similarity. With continued advances in systems biology approaches, we expect them to be seamlessly integrated into bioprocess development, which can translate into more robust and high yielding processes that can ultimately reduce cost of care for patients.

Monitoring of laser material processing using machine integrated low-coherence interferometry

NASA Astrophysics Data System (ADS)

Kunze, Rouwen; König, Niels; Schmitt, Robert

2017-06-01

Laser material processing has become an indispensable tool in modern production. With the availability of high power pico- and femtosecond laser sources, laser material processing is advancing into applications, which demand for highest accuracies such as laser micro milling or laser drilling. In order to enable narrow tolerance windows, a closedloop monitoring of the geometrical properties of the processed work piece is essential for achieving a robust manufacturing process. Low coherence interferometry (LCI) is a high-precision measuring principle well-known from surface metrology. In recent years, we demonstrated successful integrations of LCI into several different laser material processing methods. Within this paper, we give an overview about the different machine integration strategies, that always aim at a complete and ideally telecentric integration of the measurement device into the existing beam path of the processing laser. Thus, highly accurate depth measurements within machine coordinates and a subsequent process control and quality assurance are possible. First products using this principle have already found its way to the market, which underlines the potential of this technology for the monitoring of laser material processing.

ILT optimization of EUV masks for sub-7nm lithography

NASA Astrophysics Data System (ADS)

Hooker, Kevin; Kuechler, Bernd; Kazarian, Aram; Xiao, Guangming; Lucas, Kevin

2017-06-01

The 5nm and 7nm technology nodes will continue recent scaling trends and will deliver significantly smaller minimum features, standard cell areas and SRAM cell areas vs. the 10nm node. There are tremendous economic pressures to shrink each subsequent technology, though in a cost-effective and performance enhancing manner. IC manufacturers are eagerly awaiting EUV so that they can more aggressively shrink their technology than they could by using complicated MPT. The current 0.33NA EUV tools and processes also have their patterning limitations. EUV scanner lenses, scanner sources, masks and resists are all relatively immature compared to the current lithography manufacturing baseline of 193i. For example, lens aberrations are currently several times larger (as a function of wavelength) in EUV scanners than for 193i scanners. Robustly patterning 16nm L/S fully random logic metal patterns and 40nm pitch random logic rectangular contacts with 0.33NA EUV are tough challenges that will benefit from advanced OPC/RET. For example, if an IC manufacturer can push single exposure device layer resolution 10% tighter using improved ILT to avoid using DPT, there will be a significant cost and process complexity benefit to doing so. ILT is well known to have considerable benefits in finding flexible 193i mask pattern solutions to improve process window, improve 2D CD control, improve resolution in low K1 lithography regime and help to delay the introduction of DPT. However, ILT has not previously been applied to EUV lithography. In this paper, we report on new developments which extend ILT method to EUV lithography and we characterize the benefits seen vs. traditional EUV OPC/RET methods.

Quality risk management of top spray fluidized bed process for antihypertensive drug formulation with control strategy engendered by Box-behnken experimental design space.

PubMed

Mukharya, Amit; Patel, Paresh U; Shenoy, Dinesh; Chaudhary, Shivang

2013-01-01

Lacidipine (LCDP) is a very low soluble and highly biovariable calcium channel blocker used in the treatment of hypertension. To increase its apparent solubility and to reduce its biovariability, solid dispersion fluid bed processing technology was explored, as it produces highly dispersible granules with a characteristic porous structure that enhances dispersibility, wettability, blend uniformity (by dissolving and spraying a solution of actives), flow ability and compressibility of granules for tableting and reducing variability by uniform drug-binder solution distribution on carrier molecules. Main object of this quality risk management (QRM) study is to provide a sophisticated "robust and rugged" Fluidized Bed Process (FBP) for the preparation of LCDP tablets with desired quality (stability) and performance (dissolution) by quality by design (QbD) concept. THIS STUDY IS PRINCIPALLY FOCUSING ON THOROUGH MECHANISTIC UNDERSTANDING OF THE FBP BY WHICH IT IS DEVELOPED AND SCALED UP WITH A KNOWLEDGE OF THE CRITICAL RISKS INVOLVED IN MANUFACTURING PROCESS ANALYZED BY RISK ASSESSMENT TOOLS LIKE: Qualitative Initial Risk-based Matrix Analysis (IRMA) and Quantitative Failure Mode Effective Analysis (FMEA) to identify and rank parameters with potential to have an impact on In Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical Process Parameters (CPPs) were further refined by DoE and MVDA to develop design space with Real Time Release Testing (RTRT) that leads to implementation of a control strategy to achieve consistent finished product quality at lab scale itself to prevent possible product failure at larger manufacturing scale.

Quality risk management of top spray fluidized bed process for antihypertensive drug formulation with control strategy engendered by Box-behnken experimental design space

PubMed Central

Mukharya, Amit; Patel, Paresh U; Shenoy, Dinesh; Chaudhary, Shivang

2013-01-01

Introduction: Lacidipine (LCDP) is a very low soluble and highly biovariable calcium channel blocker used in the treatment of hypertension. To increase its apparent solubility and to reduce its biovariability, solid dispersion fluid bed processing technology was explored, as it produces highly dispersible granules with a characteristic porous structure that enhances dispersibility, wettability, blend uniformity (by dissolving and spraying a solution of actives), flow ability and compressibility of granules for tableting and reducing variability by uniform drug-binder solution distribution on carrier molecules. Materials and Methods: Main object of this quality risk management (QRM) study is to provide a sophisticated “robust and rugged” Fluidized Bed Process (FBP) for the preparation of LCDP tablets with desired quality (stability) and performance (dissolution) by quality by design (QbD) concept. Results and Conclusion: This study is principally focusing on thorough mechanistic understanding of the FBP by which it is developed and scaled up with a knowledge of the critical risks involved in manufacturing process analyzed by risk assessment tools like: Qualitative Initial Risk-based Matrix Analysis (IRMA) and Quantitative Failure Mode Effective Analysis (FMEA) to identify and rank parameters with potential to have an impact on In Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical Process Parameters (CPPs) were further refined by DoE and MVDA to develop design space with Real Time Release Testing (RTRT) that leads to implementation of a control strategy to achieve consistent finished product quality at lab scale itself to prevent possible product failure at larger manufacturing scale. PMID:23799202

Ordinal optimization and its application to complex deterministic problems

NASA Astrophysics Data System (ADS)

Yang, Mike Shang-Yu

1998-10-01

We present in this thesis a new perspective to approach a general class of optimization problems characterized by large deterministic complexities. Many problems of real-world concerns today lack analyzable structures and almost always involve high level of difficulties and complexities in the evaluation process. Advances in computer technology allow us to build computer models to simulate the evaluation process through numerical means, but the burden of high complexities remains to tax the simulation with an exorbitant computing cost for each evaluation. Such a resource requirement makes local fine-tuning of a known design difficult under most circumstances, let alone global optimization. Kolmogorov equivalence of complexity and randomness in computation theory is introduced to resolve this difficulty by converting the complex deterministic model to a stochastic pseudo-model composed of a simple deterministic component and a white-noise like stochastic term. The resulting randomness is then dealt with by a noise-robust approach called Ordinal Optimization. Ordinal Optimization utilizes Goal Softening and Ordinal Comparison to achieve an efficient and quantifiable selection of designs in the initial search process. The approach is substantiated by a case study in the turbine blade manufacturing process. The problem involves the optimization of the manufacturing process of the integrally bladed rotor in the turbine engines of U.S. Air Force fighter jets. The intertwining interactions among the material, thermomechanical, and geometrical changes makes the current FEM approach prohibitively uneconomical in the optimization process. The generalized OO approach to complex deterministic problems is applied here with great success. Empirical results indicate a saving of nearly 95% in the computing cost.

Development and Industrialization of InGaN/GaN LEDs on Patterned Sapphire Substrates for Low Cost Emitter Architecture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flemish, Joseph; Soer, Wouter

2015-11-30

Patterned sapphire substrate (PSS) technology has proven to be an effective approach to improve efficacy and reduce cost of light-emitting diodes (LEDs). The volume emission from the transparent substrate leads to high package efficiency, while the simple and robust architecture of PSS-based LEDs enables low cost. PSS substrates have gained wide use in mid-power LEDs over the past years. In this project, Lumileds has developed and industrialized PSS and epitaxy technology for high- power flip-chip LEDs to bring these benefits to a broader range of applications and accelerate the adoption of energy-efficient solid-state lighting (SSL). PSS geometries were designed formore » highly efficient light extraction in a flip-chip architecture and high-volume manufacturability, and corresponding sapphire patterning and epitaxy manufacturing processes were integrally developed. Concurrently, device and package architectures were developed to take advantage of the PSS flip-chip die in different types of products that meet application needs. The developed PSS and epitaxy technology has been fully implemented in manufacturing at Lumileds’ San Jose, CA location, and incorporated in illumination-grade LED products that have been successfully introduced to the market, including LUXEON Q and LUXEON FlipChip White.« less

Practical considerations in clinical strategy to support the development of injectable drug-device combination products for biologics.

PubMed

Li, Zhaoyang; Easton, Rachael

2018-01-01

The development of an injectable drug-device combination (DDC) product for biologics is an intricate and evolving process that requires substantial investments of time and money. Consequently, the commercial dosage form(s) or presentation(s) are often not ready when pivotal trials commence, and it is common to have drug product changes (manufacturing process or presentation) during clinical development. A scientifically sound and robust bridging strategy is required in order to introduce these changes into the clinic safely. There is currently no single developmental paradigm, but a risk-based hierarchical approach has been well accepted. The rigor required of a bridging package depends on the level of risk associated with the changes. Clinical pharmacokinetic/pharmacodynamic comparability or outcome studies are only required when important changes occur at a late stage. Moreover, an injectable DDC needs to be user-centric, and usability assessment in real-world clinical settings may be required to support the approval of a DDC. In this review, we discuss the common issues during the manufacturing process and presentation development of an injectable DDC and practical considerations in establishing a clinical strategy to address these issues, including key elements of clinical studies. We also analyze the current practice in the industry and review relevant and status of regulatory guidance in the DDC field.

Practical considerations in clinical strategy to support the development of injectable drug-device combination products for biologics

PubMed Central

Easton, Rachael

2018-01-01

ABSTRACT The development of an injectable drug-device combination (DDC) product for biologics is an intricate and evolving process that requires substantial investments of time and money. Consequently, the commercial dosage form(s) or presentation(s) are often not ready when pivotal trials commence, and it is common to have drug product changes (manufacturing process or presentation) during clinical development. A scientifically sound and robust bridging strategy is required in order to introduce these changes into the clinic safely. There is currently no single developmental paradigm, but a risk-based hierarchical approach has been well accepted. The rigor required of a bridging package depends on the level of risk associated with the changes. Clinical pharmacokinetic/pharmacodynamic comparability or outcome studies are only required when important changes occur at a late stage. Moreover, an injectable DDC needs to be user-centric, and usability assessment in real-world clinical settings may be required to support the approval of a DDC. In this review, we discuss the common issues during the manufacturing process and presentation development of an injectable DDC and practical considerations in establishing a clinical strategy to address these issues, including key elements of clinical studies. We also analyze the current practice in the industry and review relevant and status of regulatory guidance in the DDC field. PMID:29035675

A new approach for high performance fiber manufacturing via simultaneous fiber spinning and UV initiated polymerization

NASA Astrophysics Data System (ADS)

Ellison, Chris

Synthetic fibers have been manufactured for decades using solvents or heat to reduce the viscosity of pre-formed polymers and promote drawing. However, nature has engineered spiders and silkworms with benign ways of making silk fibers with high strength and toughness. Conceptually, their approach of chemically linking small functional units (i.e., proteins) into long chain molecules and solid fibrillar structures ``on-demand'' is fundamentally different from current synthetic fiber manufacturing methods. Drawing inspiration from nature, a method will be described that uses light to trigger a thiol-ene photopolymerization to rapidly transform reactive liquid mixtures into solid thread-like structures as they are forced out of a capillary at high speeds. Besides being manufactured without using solvents/volatile components or heat, these fibers are mechanically robust and have excellent chemical and thermal stability due to their crosslinked nature. During processing, the balance between curing kinetics, fiber flight time, and monomer mixture viscoelasticity is essential for the formation of defect free fibers. This work focuses on developing a universal operating diagram to show how the intricate interplay of gel time, flight time, and fluid relaxation time leads to the formation of uniform fibers and other undesirable fiber morphologies such as beads-on-string, fused fibers, non-uniform fibers, and droplets. This predictive capability enables adaptation of this spinning concept to all existing fiber spinning platforms, and customization of monomer formulations to target desired properties.

A PageRank-based reputation model for personalised manufacturing service recommendation

NASA Astrophysics Data System (ADS)

Zhang, W. Y.; Zhang, S.; Guo, S. S.

2017-05-01

The number of manufacturing services for cross-enterprise business collaborations is increasing rapidly because of the explosive growth of Web service technologies. This trend demands intelligent and robust models to address information overload in order to enable efficient discovery of manufacturing services. In this paper, we present a personalised manufacturing service recommendation approach, which combines a PageRank-based reputation model and a collaborative filtering technique in a unified framework for recommending the right manufacturing services to an active service user for supply chain deployment. The novel aspect of this research is adapting the PageRank algorithm to a network of service-oriented multi-echelon supply chain in order to determine both user reputation and service reputation. In addition, it explores the use of these methods in alleviating data sparsity and cold start problems that hinder traditional collaborative filtering techniques. A case study is conducted to validate the practicality and effectiveness of the proposed approach in recommending the right manufacturing services to active service users.

Plasma jet printing for flexible substrates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gandhiraman, Ram P.; Singh, Eric; Diaz-Cartagena, Diana C.

2016-03-21

Recent interest in flexible electronics and wearable devices has created a demand for fast and highly repeatable printing processes suitable for device manufacturing. Robust printing technology is critical for the integration of sensors and other devices on flexible substrates such as paper and textile. An atmospheric pressure plasma-based printing process has been developed to deposit different types of nanomaterials on flexible substrates. Multiwalled carbon nanotubes were deposited on paper to demonstrate site-selective deposition as well as direct printing without any type of patterning. Plasma-printed nanotubes were compared with non-plasma-printed samples under similar gas flow and other experimental conditions and foundmore » to be denser with higher conductivity. The utility of the nanotubes on the paper substrate as a biosensor and chemical sensor was demonstrated by the detection of dopamine, a neurotransmitter, and ammonia, respectively.« less

Practicing safe cell culture: applied process designs for minimizing virus contamination risk.

PubMed

Kiss, Robert D

2011-01-01

CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda, MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA) Genentech responded to a virus contamination in its biologics manufacturing facility by developing and implementing a series of barriers specifically designed to prevent recurrence of this significant and impactful event. The barriers included steps to inactivate or remove potential virus particles from the many raw materials used in cell culture processing. Additionally, analytical testing barriers provided protection of the downstream processing areas should a culture contamination occur, and robust virus clearance capability provided further assurance of virus safety should a low level contamination go undetected. This conference proceeding will review Genentech's approach, and lessons learned, in minimizing virus contamination risk in cell culture processes through multiple layers of targeted barriers designed to deliver biologics products with high success rates.

Characterizing the impact of pressure on virus filtration processes and establishing design spaces to ensure effective parvovirus removal.

PubMed

Strauss, Daniel; Goldstein, Joshua; Hongo-Hirasaki, Tomoko; Yokoyama, Yoshiro; Hirotomi, Naokatsu; Miyabayashi, Tomoyuki; Vacante, Dominick

2017-09-01

Virus filtration provides robust removal of potential viral contaminants and is a critical step during the manufacture of biotherapeutic products. However, recent studies have shown that small virus removal can be impacted by low operating pressure and depressurization. To better understand the impact of these conditions and to define robust virus filtration design spaces, we conducted multivariate analyses to evaluate parvovirus removal over wide ranges of operating pressure, solution pH, and conductivity for three mAb products on Planova™ BioEX and 20N filters. Pressure ranges from 0.69 to 3.43 bar (10.0-49.7 psi) for Planova BioEX filters and from 0.50 to 1.10 bar (7.3 to 16.0 psi) for Planova 20N filters were identified as ranges over which effective removal of parvovirus is achieved for different products over wide ranges of pH and conductivity. Viral clearance at operating pressure below the robust pressure range suggests that effective parvovirus removal can be achieved at low pressure but that Minute virus of mice (MVM) logarithmic reduction value (LRV) results may be impacted by product and solution conditions. These results establish robust design spaces for Planova BioEX and 20N filters where high parvovirus clearance can be expected for most antibody products and provide further understanding of viral clearance mechanisms. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1294-1302, 2017. © 2017 American Institute of Chemical Engineers.

Using cell structures to develop functional nanomaterials and nanostructures--case studies of actin filaments and microtubules.

PubMed

Wu, Kevin Chia-Wen; Yang, Chung-Yao; Cheng, Chao-Min

2014-04-25

This article is based on the continued development of biologically relevant elements (i.e., actin filaments and microtubules in living cells) as building blocks to create functional nanomaterials and nanostructures that can then be used to manufacture nature-inspired small-scale devices or systems. Here, we summarize current progress in the field and focus specifically on processes characterized by (1) robustness and ease of use, (2) inexpensiveness, and (3) potential expandability to mass production. This article, we believe, will provide scientists and engineers with a more comprehensive understanding of how to mine biological materials and natural design features to construct functional materials and devices.

Development and technology transfer of Haemophilus influenzae type b conjugate vaccines for developing countries.

PubMed

Beurret, Michel; Hamidi, Ahd; Kreeftenberg, Hans

2012-07-13

This paper describes the development of a Haemophilus influenzae type b (Hib) conjugate vaccine at the National Institute for Public Health and the Environment/Netherlands Vaccine Institute (RIVM/NVI, Bilthoven, The Netherlands), and the subsequent transfer of its production process to manufacturers in developing countries. In 1998, at the outset of the project, the majority of the world's children were not immunized against Hib because of the high price and limited supply of the conjugate vaccines, due partly to the fact that local manufacturers in developing countries did not master the Hib conjugate production technology. To address this problem, the RIVM/NVI has developed a robust Hib conjugate vaccine production process based on a proven model, and transferred this technology to several partners in India, Indonesia, Korea and China. As a result, emerging manufacturers in developing countries acquired modern technologies previously unavailable to them. This has in turn facilitated their approach to producing other conjugate vaccines. As an additional spin-off from the project, a World Health Organization (WHO) Hib quality control (QC) course was designed and conducted at the RIVM/NVI, resulting in an increased regulatory capacity for conjugate vaccines in developing countries at the National Regulatory Authority (NRA) level. For the local populations, this has translated into an increased and sustainable supply of affordable Hib conjugate-containing combination vaccines. During the course of this project, developing countries have demonstrated their ability to produce large quantities of high-quality modern vaccines after a successful transfer of the technology. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Classification Scheme for Smart Manufacturing Systems’ Performance Metrics

PubMed Central

Lee, Y. Tina; Kumaraguru, Senthilkumaran; Jain, Sanjay; Robinson, Stefanie; Helu, Moneer; Hatim, Qais Y.; Rachuri, Sudarsan; Dornfeld, David; Saldana, Christopher J.; Kumara, Soundar

2017-01-01

This paper proposes a classification scheme for performance metrics for smart manufacturing systems. The discussion focuses on three such metrics: agility, asset utilization, and sustainability. For each of these metrics, we discuss classification themes, which we then use to develop a generalized classification scheme. In addition to the themes, we discuss a conceptual model that may form the basis for the information necessary for performance evaluations. Finally, we present future challenges in developing robust, performance-measurement systems for real-time, data-intensive enterprises. PMID:28785744

Advanced Ablative Insulators and Methods of Making Them

NASA Technical Reports Server (NTRS)

Congdon, William M.

2005-01-01

Advanced ablative (more specifically, charring) materials that provide temporary protection against high temperatures, and advanced methods of designing and manufacturing insulators based on these materials, are undergoing development. These materials and methods were conceived in an effort to replace the traditional thermal-protection systems (TPSs) of re-entry spacecraft with robust, lightweight, better-performing TPSs that can be designed and manufactured more rapidly and at lower cost. These materials and methods could also be used to make improved TPSs for general aerospace, military, and industrial applications.

Diminishing Manufacturing Sources and Material Shortages: A Guidebook of Best Practices for Implementing a Robust DMSMS Management Program

DTIC Science & Technology

2012-08-01

EOL ) notices or other indicators of potential discontinuance. DMSMS monitoring and surveil- lance should begin as early as possible during the...throughout the duration of the program, when either the program receives a new EOL notice di- rectly, or the output of the program’s predictive tools or...OEM DMSMS mitigation efforts underway • OCM part number • Sources of active manufacturing • Actual or projected EOL • Function (active versus

Development and manufacture of an investigational human living dermal equivalent (ICX-SKN).

PubMed

Flasza, Marzena; Kemp, Paul; Shering, David; Qiao, Jizeng; Marshall, Damian; Bokta, Ausha; Johnson, Penny A

2007-11-01

To design and manufacture an investigational living skin graft replacement (ICX-SKN) that is able to incorporate into the host, providing healing by primary intent without the need for a second intervention. The ICX-SKN skin graft replacement has been designed as an allogeneic dermal substitute comprising an extracellular matrix composed largely of human collagen and human dermal fibroblast cells (HDFs). ICX-SKN is first formed by casting a provisional matrix of fibrin, into which HDFs are seeded. Through a process of maturation, HDFs are induced to lay down collagen and other extracellular matrix materials and, as the construct matures, the original fibrin is largely replaced by collagen, which provides tensile strength and flexibility to the construct. In order to design a product and manufacturing system that lends itself to large-scale production the process was developed as a discontinuous process consisting of four stages: 1. batch casting and maturation of the initial construct (pSKN), 2. freeze-drying of pSKN to produce a second intermediate (dSKN), 3. sterilization by gamma-irradiation of dSKN to produce a third intermediate (sSKN), and finally, 4. repopulation of sSKN by fresh HDFs to produce the final product, ICX-SKN skin graft replacement. Preliminary characterization of ICX-SKN and its application in a preclinical model are described. The 7-week maturation period resulted in a construct (pSKN) with robust handling properties, which was composed mainly of human collagen I. Following development of a process for freeze-drying and subsequent sterilization, the matrix was successfully repopulated with fresh HDFs. In addition, it was demonstrated that human keratinocytes attached and differentiated on the matrix. Application of human keratinocytes to the repopulated constructs (ICX-SKN) resulted in expression of markers of basement membranes that was largely dependent on the presence of living HDFs on the constructs. ICX-SKN graft replacements applied to excision wounds in mice healed and were rapidly re-epithelialized. ICX-SKN has been developed as a platform product that can be used as a skin graft replacement and the process by which it is manufactured has been designed for the product to be available to the end-user off-the-shelf and for ease-of-use in practice.

Bridging the gap between PAT concepts and implementation: An integrated software platform for fermentation.

PubMed

Chopda, Viki R; Gomes, James; Rathore, Anurag S

2016-01-01

Bioreactor control significantly impacts both the amount and quality of the product being manufactured. The complexity of the control strategy that is implemented increases with reactor size, which may vary from thousands to tens of thousands of litres in commercial manufacturing. The Process Analytical Technology (PAT) initiative has highlighted the need for having robust monitoring tools and effective control schemes that are capable of taking real time information about the critical quality attributes (CQA) and the critical process parameters (CPP) and executing immediate response as soon as a deviation occurs. However, the limited flexibility that present commercial software packages offer creates a hurdle. Visual programming environments have gradually emerged as potential alternatives to the available text based languages. This paper showcases development of an integrated programme using a visual programming environment for a Sartorius BIOSTAT® B Plus 5L bioreactor through which various peripheral devices are interfaced. The proposed programme facilitates real-time access to data and allows for execution of control actions to follow the desired trajectory. Major benefits of such integrated software system include: (i) improved real time monitoring and control; (ii) reduced variability; (iii) improved performance; (iv) reduced operator-training time; (v) enhanced knowledge management; and (vi) easier PAT implementation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The influence of target erosion grade in the optoelectronic properties of AZO coatings growth by magnetron sputtering

NASA Astrophysics Data System (ADS)

Zubizarreta, C.; G-Berasategui, E.; Ciarsolo, I.; Barriga, J.; Gaspar, D.; Martins, R.; Fortunato, E.

2016-09-01

Aluminum-doped zinc oxide (AZO) transparent conductor coating has emerged as promising substitute to tin-doped indium oxide (ITO) as electrode in optoelectronic applications such as photovoltaics or light emitting diodes (LEDs). Besides its high transmission in the visible spectral region and low resistivity, AZO presents a main advantage over other candidates such as graphene, carbon nanotubes or silver nanowires; it can be deposited using the technology industrially implemented to manufacture ITO layers, the magnetron sputtering (MS). This is a productive, reliable and green manufacturing technique. But to guarantee the robustness, reproducibility and reliability of the process there are still some issues to be addressed, such as the effect and control of the target state. In this paper a thorough study of the influence of the target erosion grade in developed coatings has been performed. AZO films have been deposited from a ceramic target by RF MS. Structure, optical transmittance and electrical properties of the produced coatings have been analyzed as function of the target erosion grade. No noticeable differences have been found neither in optoelectronic properties nor in the structure of the coatings, indicating that the RF MS is a stable and consistent process through the whole life of the target.

Assessing Reliability of Cold Spray Sputter Targets in Photovoltaic Manufacturing

NASA Astrophysics Data System (ADS)

Hardikar, Kedar; Vlcek, Johannes; Bheemreddy, Venkata; Juliano, Daniel

2017-10-01

Cold spray has been used to manufacture more than 800 Cu-In-Ga (CIG) sputter targets for deposition of high-efficiency photovoltaic thin films. It is a preferred technique since it enables high deposit purity and transfer of non-equilibrium alloy states to the target material. In this work, an integrated approach to reliability assessment of such targets with deposit weight in excess of 50 lb. is undertaken, involving thermal-mechanical characterization of the material in as-deposited condition, characterization of the interface adhesion on cylindrical substrate in as-deposited condition, and developing means to assess target integrity under thermal-mechanical loads during the physical vapor deposition (PVD) sputtering process. Mechanical characterization of cold spray deposited CIG alloy is accomplished through the use of indentation testing and adaptation of Brazilian disk test. A custom lever test was developed to characterize adhesion along the cylindrical interface between the CIG deposit and cylindrical substrate, overcoming limitations of current standards. A cohesive zone model for crack initiation and propagation at the deposit interface is developed and validated using the lever test and later used to simulate the potential catastrophic target failure in the PVD process. It is shown that this approach enables reliability assessment of sputter targets and improves robustness.

Early Implementation of QbD in Biopharmaceutical Development: A Practical Example

PubMed Central

Zurdo, Jesús; Arnell, Andreas; Obrezanova, Olga; Smith, Noel; Gómez de la Cuesta, Ramón; Gallagher, Thomas R. A.; Michael, Rebecca; Stallwood, Yvette; Ekblad, Caroline; Abrahmsén, Lars; Höidén-Guthenberg, Ingmarie

2015-01-01

In drug development, the “onus” of the low R&D efficiency has been put traditionally onto the drug discovery process (i.e., finding the right target or “binding” functionality). Here, we show that manufacturing is not only a central component of product success, but also that, by integrating manufacturing and discovery activities in a “holistic” interpretation of QbD methodologies, we could expect to increase the efficiency of the drug discovery process as a whole. In this new context, early risk assessment, using developability methodologies and computational methods in particular, can assist in reducing risks during development in a cost-effective way. We define specific areas of risk and how they can impact product quality in a broad sense, including essential aspects such as product efficacy and patient safety. Emerging industry practices around developability are introduced, including some specific examples of applications to biotherapeutics. Furthermore, we suggest some potential workflows to illustrate how developability strategies can be introduced in practical terms during early drug development in order to mitigate risks, reduce drug attrition and ultimately increase the robustness of the biopharmaceutical supply chain. Finally, we also discuss how the implementation of such methodologies could accelerate the access of new therapeutic treatments to patients in the clinic. PMID:26075248

FDA's perspectives on cardiovascular devices.

PubMed

Chen, Eric A; Patel-Raman, Sonna M; O'Callaghan, Kathryn; Hillebrenner, Matthew G

2009-06-01

The Food and Drug Administration (FDA) decision process for approving or clearing medical devices is often determined by a review of robust clinical data and extensive preclinical testing of the device. The mission statement for the Center for Devices and Radiological Health (CDRH) is to review the information provided by manufacturers so that it can promote and protect the health of the public by ensuring the safety and effectiveness of medical devices deemed appropriate for human use (Food, Drug & Cosmetic Act, Section 903(b)(1, 2(C)), December 31, 2004; accessed December 17, 2008 http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm). For high-risk devices, such as ventricular assist devices (VADs), mechanical heart valves, stents, cardiac resynchronization therapy (CRT) devices, pacemakers, and defibrillators, the determination is based on FDA's review of extensive preclinical bench and animal testing followed by use of the device in a clinical trial in humans. These clinical trials allow the manufacturer to evaluate a device in the intended use population. FDA reviews the data from the clinical trial to determine if the device performed as predicted and the clinical benefits outweigh the risks. This article reviews the regulatory framework for different marketing applications related to cardiovascular devices and describes the process of obtaining approval to study a cardiovascular device in a U.S. clinical trial.

Improving the large scale purification of the HIV microbicide, griffithsin.

PubMed

Fuqua, Joshua L; Wanga, Valentine; Palmer, Kenneth E

2015-02-22

Griffithsin is a broad spectrum antiviral lectin that inhibits viral entry and maturation processes through binding clusters of oligomannose glycans on viral envelope glycoproteins. An efficient, scaleable manufacturing process for griffithsin active pharmaceutical ingredient (API) is essential for particularly cost-sensitive products such as griffithsin -based topical microbicides for HIV-1 prevention in resource poor settings. Our previously published purification method used ceramic filtration followed by two chromatography steps, resulting in a protein recovery of 30%. Our objective was to develop a scalable purification method for griffithsin expressed in Nicotiana benthamiana plants that would increase yield, reduce production costs, and simplify manufacturing techniques. Considering the future need to transfer griffithsin manufacturing technology to resource poor areas, we chose to focus modifying the purification process, paying particular attention to introducing simple, low-cost, and scalable procedures such as use of temperature, pH, ion concentration, and filtration to enhance product recovery. We achieved >99% pure griffithsin API by generating the initial green juice extract in pH 4 buffer, heating the extract to 55°C, incubating overnight with a bentonite MgCl2 mixture, and final purification with Capto™ multimodal chromatography. Griffithsin extracted with this protocol maintains activity comparable to griffithsin purified by the previously published method and we are able to recover a substantially higher yield: 88 ± 5% of griffithsin from the initial extract. The method was scaled to produce gram quantities of griffithsin with high yields, low endotoxin levels, and low purification costs maintained. The methodology developed to purify griffithsin introduces and develops multiple tools for purification of recombinant proteins from plants at an industrial scale. These tools allow for robust cost-effective production and purification of griffithsin. The methodology can be readily scaled to the bench top or industry and process components can be used for purification of additional proteins based on biophysical characteristics.

Improved HCP Reduction Using a New, All-Synthetic Depth Filtration Media Within an Antibody Purification Process.

PubMed

Nguyen, Hoang C; Langland, Amie L; Amara, John P; Dullen, Michael; Kahn, David S; Costanzo, Joseph A

2018-04-30

Biologic manufacturing processes typically employ clarification technologies like depth filtration to remove insoluble and soluble impurities. Conventional depth filtration media used in these processes contain naturally-derived components like diatomaceous earth and cellulose. These components may introduce performance variability and contribute extractable/leachable components like beta-glucans that could interfere with limulus amebocyte lysate endotoxin assays. Recently a novel, all-synthetic depth filtration media is developed (Millistak+ ® HC Pro X0SP) that may improve process consistency, efficiency, and drug substance product quality by reducing soluble process impurities. This new media is evaluated against commercially available benchmark filters containing naturally-derived components (Millistak+ ® HC X0HC and B1HC). Using model proteins, the synthetic media demonstrates increased binding capacity of positively charged proteins (72-126 mg g -1 media) compared to conventional media (0.3-8.6 mg g -1 media); and similar values for negatively charged species (1.3-5.6 mg g -1 media). Several CHO-derived monoclonal antibodies (mAbs) or mAb-like molecules are also evaluated. The X0SP filtration performance behaves similarly to benchmarks, and exhibits improved HCP reduction (at least 50% in 55% of cases tested). X0SP filtrates contained increased silicon extractables relative to benchmarks, but these were readily removed downstream. Finally, the X0SP devices demonstrates suitable lot-to-lot robustness when specific media components are altered intentionally to manufacturing specification limits. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cost effective solution using inverse lithography OPC for DRAM random contact layer

NASA Astrophysics Data System (ADS)

Jun, Jinhyuck; Hwang, Jaehee; Choi, Jaeseung; Oh, Seyoung; Park, Chanha; Yang, Hyunjo; Dam, Thuc; Do, Munhoe; Lee, Dong Chan; Xiao, Guangming; Choi, Jung-Hoe; Lucas, Kevin

2017-04-01

Many different advanced devices and design layers currently employ double patterning technology (DPT) as a means to overcome lithographic and OPC limitations at low k1 values. Certainly device layers with k1 value below 0.25 require DPT or other pitch splitting methodologies. DPT has also been used to improve patterning of certain device layers with k1 values slightly above 0.25, due to the difficulty of achieving sufficient pattern fidelity with only a single exposure. Unfortunately, this broad adoption of DPT also came with a significant increase in patterning process cost. In this paper, we discuss the development of a single patterning technology process using an integrated Inverse Lithography Technology (ILT) flow for mask synthesis. A single pattering technology flow will reduce the manufacturing cost for a k1 > 0.25 full chip random contact layer in a memory device by replacing the more expensive DPT process with ILT flow, while also maintaining good lithographic production quality and manufacturable OPC/RET production metrics. This new integrated flow consists of applying ILT to the difficult core region and traditional rule-based assist features (RBAFs) with OPC to the peripheral region of a DRAM contact layer. Comparisons of wafer results between the ILT process and the non-ILT process showed the lithographic benefits of ILT and its ability to enable a robust single patterning process for this low-k1 device layer. Advanced modeling with a negative tone develop (NTD) process achieved the accuracy levels needed for ILT to control feature shapes through dose and focus. Details of these afore mentioned results will be described in the paper.

15 CFR 400.33 - Restrictions on manufacturing and processing activity.

Code of Federal Regulations, 2010 CFR

2010-01-01

...-TRADE ZONES BOARD Manufacturing and Processing Activity-Reviews § 400.33 Restrictions on manufacturing and processing activity. (a) In general. In approving manufacturing or processing activity for a zone... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Restrictions on manufacturing and...

21 CFR 1005.25 - Service of process on manufacturers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Service of process on manufacturers. 1005.25....25 Service of process on manufacturers. (a) Every manufacturer of electronic products, prior to... United States as the manufacturer's agent upon whom service of all processes, notices, orders, decisions...

Quality management of manufacturing process based on manufacturing execution system

NASA Astrophysics Data System (ADS)

Zhang, Jian; Jiang, Yang; Jiang, Weizhuo

2017-04-01

Quality control elements in manufacturing process are elaborated. And the approach of quality management of manufacturing process based on manufacturing execution system (MES) is discussed. The functions of MES for a microcircuit production line are introduced conclusively.

Assessment of powder blend uniformity: Comparison of real-time NIR blend monitoring with stratified sampling in combination with HPLC and at-line NIR Chemical Imaging.

PubMed

Bakri, Barbara; Weimer, Marco; Hauck, Gerrit; Reich, Gabriele

2015-11-01

Scope of the study was (1) to develop a lean quantitative calibration for real-time near-infrared (NIR) blend monitoring, which meets the requirements in early development of pharmaceutical products and (2) to compare the prediction performance of this approach with the results obtained from stratified sampling using a sample thief in combination with off-line high pressure liquid chromatography (HPLC) and at-line near-infrared chemical imaging (NIRCI). Tablets were manufactured from powder blends and analyzed with NIRCI and HPLC to verify the real-time results. The model formulation contained 25% w/w naproxen as a cohesive active pharmaceutical ingredient (API), microcrystalline cellulose and croscarmellose sodium as cohesive excipients and free-flowing mannitol. Five in-line NIR calibration approaches, all using the spectra from the end of the blending process as reference for PLS modeling, were compared in terms of selectivity, precision, prediction accuracy and robustness. High selectivity could be achieved with a "reduced" approach i.e. API and time saving approach (35% reduction of API amount) based on six concentration levels of the API with three levels realized by three independent powder blends and the additional levels obtained by simply increasing the API concentration in these blends. Accuracy and robustness were further improved by combining this calibration set with a second independent data set comprising different excipient concentrations and reflecting different environmental conditions. The combined calibration model was used to monitor the blending process of independent batches. For this model formulation the target concentration of the API could be achieved within 3 min indicating a short blending time. The in-line NIR approach was verified by stratified sampling HPLC and NIRCI results. All three methods revealed comparable results regarding blend end point determination. Differences in both mean API concentration and RSD values could be attributed to differences in effective sample size and thief sampling errors. This conclusion was supported by HPLC and NIRCI analysis of tablets manufactured from powder blends after different blending times. In summary, the study clearly demonstrates the ability to develop efficient and robust quantitative calibrations for real-time NIR powder blend monitoring with a reduced set of powder blends while avoiding any bias caused by physical sampling. Copyright © 2015 Elsevier B.V. All rights reserved.

Imaging-based optical caliper for objects in hot manufacturing processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Howard

OG Technologies, Inc. (OGT), in conjunction with its industrial and academic partners, proposes to develop an Imaging-Based Optical Caliper (hereafter referred to as OC) for Objects in Hot Manufacturing Processes. The goal is to develop and demonstrate the OC with the synergy of OGT's current technological pool and other innovations to provide a light weight, robust, safe and accurate portable dimensional measurement device for hot objects with integrated wireless communication capacity to enable real time process control. The technical areas of interest in this project are the combination of advanced imaging, Sensor Fusion, and process control. OGT believes that themore » synergistic interactions between its current set of technologies and other innovations could deliver products that are viable and have high impact in the hot manufacture processes, such as steel making, steel rolling, open die forging, and glass industries, resulting in a new energy efficient control paradigm in the operations through improved yield, prolonged tool life and improved quality. In-line dimension measurement and control is of interest to the steel makers, yet current industry focus is on the final product dimension only instead of whole process due to the limit of man power, system cost and operator safety concerns. As sensor technologies advances, the industry started to see the need to enforce better dimensional control throughout the process, but lack the proper tools to do so. OGT along with its industrial partners represent the indigenous effort of technological development to serve the US steel industry. The immediate market that can use and get benefited from the proposed OC is the Steel Industry. The deployment of the OC has the potential to provide benefits in reduction of energy waste, CO2 emission, waste water amount, toxic waste, and so forth. The potential market after further expended function includes Hot Forging and Freight Industries. The OC prototypes were fabricated, and were progressively tested on-site in several steel mill and hot forging facilities for evaluation. Software refinements and new calibration procedures were also carried out to overcome the discovered glitches. Progress was presented to the hot manufacture facilities worldwide. Evidence showed a great interest and practical need for this product. OGT is in the pilot commercialization mode for this new development. The R&D team also successfully developed a 3D measurement function with no additional investment of hardware or equipment to measure low or room temperature object dimensions. Several tests were conducted in the reality environment to evaluate the measurement results. This new application will require additional development in product design.« less

Pressure activated interconnection of micro transfer printed components

NASA Astrophysics Data System (ADS)

Prevatte, Carl; Guven, Ibrahim; Ghosal, Kanchan; Gomez, David; Moore, Tanya; Bonafede, Salvatore; Raymond, Brook; Trindade, António Jose; Fecioru, Alin; Kneeburg, David; Meitl, Matthew A.; Bower, Christopher A.

2016-05-01

Micro transfer printing and other forms of micro assembly deterministically produce heterogeneously integrated systems of miniaturized components on non-native substrates. Most micro assembled systems include electrical interconnections to the miniaturized components, typically accomplished by metal wires formed on the non-native substrate after the assembly operation. An alternative scheme establishing interconnections during the assembly operation is a cost-effective manufacturing method for producing heterogeneous microsystems, and facilitates the repair of integrated microsystems, such as displays, by ex post facto addition of components to correct defects after system-level tests. This letter describes pressure-concentrating conductor structures formed on silicon (1 0 0) wafers to establish connections to preexisting conductive traces on glass and plastic substrates during micro transfer printing with an elastomer stamp. The pressure concentrators penetrate a polymer layer to form the connection, and reflow of the polymer layer bonds the components securely to the target substrate. The experimental yield of series-connected test systems with >1000 electrical connections demonstrates the suitability of the process for manufacturing, and robustness of the test systems against exposure to thermal shock, damp heat, and mechanical flexure shows reliability of the resulting bonds.

Analytical Method Development and Validation for the Quantification of Acetone and Isopropyl Alcohol in the Tartaric Acid Base Pellets of Dipyridamole Modified Release Capsules by Using Headspace Gas Chromatographic Technique

PubMed Central

2018-01-01

A simple, sensitive, accurate, robust headspace gas chromatographic method was developed for the quantitative determination of acetone and isopropyl alcohol in tartaric acid-based pellets of dipyridamole modified release capsules. The residual solvents acetone and isopropyl alcohol were used in the manufacturing process of the tartaric acid-based pellets of dipyridamole modified release capsules by considering the solubility of the dipyridamole and excipients in the different manufacturing stages. The method was developed and optimized by using fused silica DB-624 (30 m × 0.32 mm × 1.8 µm) column with the flame ionization detector. The method validation was carried out with regard to the guidelines for validation of analytical procedures Q2 demanded by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). All the validation characteristics were meeting the acceptance criteria. Hence, the developed and validated method can be applied for the intended routine analysis. PMID:29686931

Analytical Method Development and Validation for the Quantification of Acetone and Isopropyl Alcohol in the Tartaric Acid Base Pellets of Dipyridamole Modified Release Capsules by Using Headspace Gas Chromatographic Technique.

PubMed

Valavala, Sriram; Seelam, Nareshvarma; Tondepu, Subbaiah; Jagarlapudi, V Shanmukha Kumar; Sundarmurthy, Vivekanandan

2018-01-01

A simple, sensitive, accurate, robust headspace gas chromatographic method was developed for the quantitative determination of acetone and isopropyl alcohol in tartaric acid-based pellets of dipyridamole modified release capsules. The residual solvents acetone and isopropyl alcohol were used in the manufacturing process of the tartaric acid-based pellets of dipyridamole modified release capsules by considering the solubility of the dipyridamole and excipients in the different manufacturing stages. The method was developed and optimized by using fused silica DB-624 (30 m × 0.32 mm × 1.8  µ m) column with the flame ionization detector. The method validation was carried out with regard to the guidelines for validation of analytical procedures Q2 demanded by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). All the validation characteristics were meeting the acceptance criteria. Hence, the developed and validated method can be applied for the intended routine analysis.

GCD TechPort Data Sheets Thermal Protection System Materials (TPSM) Project

NASA Technical Reports Server (NTRS)

Chinnapongse, Ronald L.

2014-01-01

The Thermal Protection System Materials (TPSM) Project consists of three distinct project elements: the 3-Dimensional Multifunctional Ablative Thermal Protection System (3D MAT) project element; the Conformal Ablative Thermal Protection System (CA-TPS) project element; and the Heatshield for Extreme Entry Environment Technology (HEEET) project element. 3D MAT seeks to design, develop and deliver a game changing material solution based on 3-dimensional weaving and resin infusion approach for manufacturing a material that can function as a robust structure as well as a thermal protection system. CA-TPS seeks to develop and deliver a conformal ablative material designed to be efficient and capable of withstanding peak heat flux up to 500 W/ sq cm, peak pressure up to 0.4 atm, and shear up to 500 Pa. HEEET is developing a new ablative TPS that takes advantage of state-of-the-art 3D weaving technologies and traditional manufacturing processes to infuse woven preforms with a resin, machine them to shape, and assemble them as a tiled solution on the entry vehicle substructure or heatshield.

Factor analysis in optimization of formulation of high content uniformity tablets containing low dose active substance.

PubMed

Lukášová, Ivana; Muselík, Jan; Franc, Aleš; Goněc, Roman; Mika, Filip; Vetchý, David

2017-11-15

Warfarin is intensively discussed drug with narrow therapeutic range. There have been cases of bleeding attributed to varying content or altered quality of the active substance. Factor analysis is useful for finding suitable technological parameters leading to high content uniformity of tablets containing low amount of active substance. The composition of tabletting blend and technological procedure were set with respect to factor analysis of previously published results. The correctness of set parameters was checked by manufacturing and evaluation of tablets containing 1-10mg of warfarin sodium. The robustness of suggested technology was checked by using "worst case scenario" and statistical evaluation of European Pharmacopoeia (EP) content uniformity limits with respect to Bergum division and process capability index (Cpk). To evaluate the quality of active substance and tablets, dissolution method was developed (water; EP apparatus II; 25rpm), allowing for statistical comparison of dissolution profiles. Obtained results prove the suitability of factor analysis to optimize the composition with respect to batches manufactured previously and thus the use of metaanalysis under industrial conditions is feasible. Copyright © 2017 Elsevier B.V. All rights reserved.

An Overview of Cloud Implementation in the Manufacturing Process Life Cycle

NASA Astrophysics Data System (ADS)

Kassim, Noordiana; Yusof, Yusri; Hakim Mohamad, Mahmod Abd; Omar, Abdul Halim; Roslan, Rosfuzah; Aryanie Bahrudin, Ida; Ali, Mohd Hatta Mohamed

2017-08-01

The advancement of information and communication technology (ICT) has changed the structure and functions of various sectors and it has also started to play a significant role in modern manufacturing in terms of computerized machining and cloud manufacturing. It is important for industries to keep up with the current trend of ICT for them to be able survive and be competitive. Cloud manufacturing is an approach that wanted to realize a real-world manufacturing processes that will apply the basic concept from the field of Cloud computing to the manufacturing domain called Cloud-based manufacturing (CBM) or cloud manufacturing (CM). Cloud manufacturing has been recognized as a new paradigm for manufacturing businesses. In cloud manufacturing, manufacturing companies need to support flexible and scalable business processes in the shop floor as well as the software itself. This paper provides an insight or overview on the implementation of cloud manufacturing in the modern manufacturing processes and at the same times analyses the requirements needed regarding process enactment for Cloud manufacturing and at the same time proposing a STEP-NC concept that can function as a tool to support the cloud manufacturing concept.

Airborne Transducer Integrity under Operational Environment for Structural Health Monitoring

PubMed Central

Salmanpour, Mohammad Saleh; Sharif Khodaei, Zahra; Aliabadi, Mohammad Hossein

2016-01-01

This paper investigates the robustness of permanently mounted transducers used in airborne structural health monitoring systems, when exposed to the operational environment. Typical airliners operate in a range of conditions, hence, structural health monitoring (SHM) transducer robustness and integrity must be demonstrated for these environments. A set of extreme temperature, altitude and vibration environment test profiles are developed using the existing Radio Technical Commission for Aeronautics (RTCA)/DO-160 test methods. Commercially available transducers and manufactured versions bonded to carbon fibre reinforced polymer (CFRP) composite materials are tested. It was found that the DuraAct transducer is robust to environmental conditions tested, while the other transducer types degrade under the same conditions. PMID:27973450

Application of the network robustness index to identify critical links supporting Vermont's Bulk milk transportation.

DOT National Transportation Integrated Search

2011-08-18

The food supply chain is an interwoven network consisting of producers, processors, : manufacturers, distributors, retailers, and consumers. With the exception of direct : marketing or community-supported agriculture systems, some or all of these int...

Simple, robust storage of drops and fluids in a microfluidic device.

PubMed

Boukellal, Hakim; Selimović, Seila; Jia, Yanwei; Cristobal, Galder; Fraden, Seth

2009-01-21

We describe a single microfluidic device and two methods for the passive storage of aqueous drops in a continuous stream of oil without any external control but hydrodynamic flow. Advantages of this device are that it is simple to manufacture, robust under operation, and drops never come into contact with each other, making it unnecessary to stabilize drops against coalescence. In one method the device can be used to store drops that are created upstream from the storage zone. In the second method the same device can be used to simultaneously create and store drops from a single large continuous fluid stream without resorting to the usual flow focusing or T-junction drop generation processes. Additionally, this device stores all the fluid introduced, including the first amount, with zero waste. Transport of drops in this device depends, however, on whether or not the aqueous drops wet the device walls. Analysis of drop transport in these two cases is presented. Finally, a method for extraction of the drops from the device is also presented, which works best when drops do not wet the walls of the chip.

Evaluation of Cross-Protocol Stability of a Fully Automated Brain Multi-Atlas Parcellation Tool.

PubMed

Liang, Zifei; He, Xiaohai; Ceritoglu, Can; Tang, Xiaoying; Li, Yue; Kutten, Kwame S; Oishi, Kenichi; Miller, Michael I; Mori, Susumu; Faria, Andreia V

2015-01-01

Brain parcellation tools based on multiple-atlas algorithms have recently emerged as a promising method with which to accurately define brain structures. When dealing with data from various sources, it is crucial that these tools are robust for many different imaging protocols. In this study, we tested the robustness of a multiple-atlas, likelihood fusion algorithm using Alzheimer's Disease Neuroimaging Initiative (ADNI) data with six different protocols, comprising three manufacturers and two magnetic field strengths. The entire brain was parceled into five different levels of granularity. In each level, which defines a set of brain structures, ranging from eight to 286 regions, we evaluated the variability of brain volumes related to the protocol, age, and diagnosis (healthy or Alzheimer's disease). Our results indicated that, with proper pre-processing steps, the impact of different protocols is minor compared to biological effects, such as age and pathology. A precise knowledge of the sources of data variation enables sufficient statistical power and ensures the reliability of an anatomical analysis when using this automated brain parcellation tool on datasets from various imaging protocols, such as clinical databases.

Robust activation method for negative electron affinity photocathodes

DOEpatents

Mulhollan, Gregory A [Dripping Springs, TX; Bierman, John C [Austin, TX

2011-09-13

A method by which photocathodes(201), single crystal, amorphous, or otherwise ordered, can be surface modified to a robust state of lowered and in best cases negative, electron affinity has been discovered. Conventional methods employ the use of Cs(203) and an oxidizing agent(207), typically carried by diatomic oxygen or by more complex molecules, for example nitrogen trifluoride, to achieve a lowered electron affinity(404). In the improved activation method, a second alkali, other than Cs(205), is introduced onto the surface during the activation process, either by co-deposition, yo-yo, or sporadic or intermittent application. Best effect for GaAs photocathodes has been found through the use of Li(402) as the second alkali, though nearly the same effect can be found by employing Na(406). Suitable photocathodes are those which are grown, cut from boules, implanted, rolled, deposited or otherwise fabricated in a fashion and shape desired for test or manufacture independently supported or atop a support structure or within a framework or otherwise affixed or suspended in the place and position required for use.

Reduction of spiked porcine circovirus during the manufacture of a Vero cell-derived vaccine.

PubMed

Lackner, Cornelia; Leydold, Sandra M; Modrof, Jens; Farcet, Maria R; Grillberger, Leopold; Schäfer, Birgit; Anderle, Heinz; Kreil, Thomas R

2014-04-11

Porcine circovirus-1 (PCV1) was recently identified as a contaminant in live Rotavirus vaccines, which was likely caused by contaminated porcine trypsin. The event triggered the development of new regulatory guidance on the use of porcine trypsin which shall ensure that cell lines and porcine trypsin in use are free from PCV1. In addition, manufacturing processes of biologicals other than live vaccines include virus clearance steps that may prevent and mitigate any potential virus contamination of product. In this work, artificial spiking of down-scaled models for the manufacturing process of an inactivated pandemic influenza virus vaccine were used to investigate inactivation of PCV1 and the physico-chemically related porcine parvovirus (PPV) by formalin and ultraviolet-C (UV-C) treatment as well as removal by the purification step sucrose gradient ultracentrifugation. A PCV1 infectivity assay, using a real-time PCR infectivity readout was established. The formalin treatment (0.05% for 48h) showed substantial inactivation for both PCV1 and PPV with reduction factors of 3.0log10 and 6.8log10, respectively, whereas UV-C treatment resulted in complete PPV (≥5.9log10) inactivation already at a dose of 13mJ/cm but merely 1.7log10 at 24mJ/cm(2) for PCV1. The UV-C inactivation results with PPV were confirmed using minute virus of mice (MVM), indicating that parvoviruses are far more sensitive to UV-C than PCV1. The sucrose density gradient ultracentrifugation also contributed to PCV1 clearance with a reduction factor of 2log10. The low pH treatment during the production of procine trypsin was investigated and showed effective inactivation for both PCV1 (4.5log10) and PPV (6.4log10). In conclusion, PCV1 in general appears to be more resistant to virus inactivation than PPV. Still, the inactivated pandemic influenza vaccine manufacturing process provides for robust virus reduction, in addition to the already implemented testing for PCV1 to avoid any contaminations. Copyright © 2014 Elsevier Ltd. All rights reserved.

40 CFR 723.175 - Chemical substances used in or for the manufacture or processing of instant photographic and peel...

Code of Federal Regulations, 2010 CFR

2010-07-01

... manufacture and processing in the special production area. All manufacturing, processing, and use operations... shape or design during manufacture, (ii) which has end use function(s) dependent in whole or in part... production area, the ambient air concentration of the new chemical substance during manufacture, processing...

Integrated Dynamic Process Planning and Scheduling in Flexible Manufacturing Systems via Autonomous Agents

NASA Astrophysics Data System (ADS)

Nejad, Hossein Tehrani Nik; Sugimura, Nobuhiro; Iwamura, Koji; Tanimizu, Yoshitaka

Process planning and scheduling are important manufacturing planning activities which deal with resource utilization and time span of manufacturing operations. The process plans and the schedules generated in the planning phase shall be modified in the execution phase due to the disturbances in the manufacturing systems. This paper deals with a multi-agent architecture of an integrated and dynamic system for process planning and scheduling for multi jobs. A negotiation protocol is discussed, in this paper, to generate the process plans and the schedules of the manufacturing resources and the individual jobs, dynamically and incrementally, based on the alternative manufacturing processes. The alternative manufacturing processes are presented by the process plan networks discussed in the previous paper, and the suitable process plans and schedules are searched and generated to cope with both the dynamic status and the disturbances of the manufacturing systems. We initiatively combine the heuristic search algorithms of the process plan networks with the negotiation protocols, in order to generate suitable process plans and schedules in the dynamic manufacturing environment. A simulation software has been developed to carry out case studies, aimed at verifying the performance of the proposed multi-agent architecture.

A weak pattern random creation and scoring method for lithography process tuning

NASA Astrophysics Data System (ADS)

Zhang, Meili; Deng, Guogui; Wang, Mudan; Yu, Shirui; Hu, Xinyi; Du, Chunshan; Wan, Qijian; Liu, Zhengfang; Gao, Gensheng; Kabeel, Aliaa; Madkour, Kareem; ElManhawy, Wael; Kwan, Joe

2018-03-01

As the IC technology node moves forward, critical dimension becomes smaller and smaller, which brings huge challenge to IC manufacturing. Lithography is one of the most important steps during the whole manufacturing process and litho hotspots become a big source of yield detractors. Thus tuning lithographic recipes to cover a big range of litho hotspots is very essential to yield enhancing. During early technology developing stage, foundries only have limited customer layout data for recipe tuning. So collecting enough patterns is significant for process optimization. After accumulating enough patterns, a general way to treat them is not precise and applicable. Instead, an approach to scoring these patterns could provide a priority and reference to address different patterns more effectively. For example, the weakest group of patterns could be applied the most limited specs to ensure process robustness. This paper presents a new method of creation of real design alike patterns of multiple layers based on design rules using Layout Schema Generator (LSG) utility and a pattern scoring flow using Litho-friendly Design (LFD) and Pattern Matching. Through LSG, plenty of new unknown patterns could be created for further exploration. Then, litho simulation through LFD and topological matches by using Pattern Matching is applied on the output patterns of LSG. Finally, lithographical severity, printability properties and topological distribution of every pattern are collected. After a statistical analysis of pattern data, every pattern is given a relative score representing the pattern's yield detracting level. By sorting the output pattern score tables, weak patterns could be filtered out for further research and process tuning. This pattern generation and scoring flow is demonstrated on 28nm logic technology node. A weak pattern library is created and scored to help improve recipe coverage of litho hotspots and enhance the reliability of process.

Extending the process limits of laser polymer welding with high-brilliance beam sources (recent status and prospects of POLYBRIGHT)

NASA Astrophysics Data System (ADS)

Olowinsky, A.; Boglea, A.

2011-03-01

Plastics play an important role in almost every facet of our lives and constitute a wide variety of products, from everyday products such as food and beverage packaging, over furniture and building materials to high tech products in the automotive, electronics, aerospace, white goods, medical and other sectors [1]. The objective of PolyBright, the European Research project on laser polymer welding, is to provide high speed and flexible laser manufacturing technology and expand the limits of current plastic part assembly. New laser polymer joining processes for optimized thermal management in combination with adapted wavelengths will provide higher quality, high processing speed up to 1 m/s and robust manufacturing processes at lower costs. Key innovations of the PolyBright project are fibre lasers with high powers up to 500 W, high speed scanning and flexible beam manipulation systems for simultaneous welding and high-resolution welding, such as dynamic masks and multi kHz scanning heads. With this initial step, PolyBright will break new paths in processing of advanced plastic products overcoming the quality and speed limitations of conventional plastic part assembly. Completely new concepts for high speed processing, flexibility and quality need to be established in combination with high brilliance lasers and related equipment. PolyBright will thus open new markets for laser systems with a short term potential of over several 100 laser installations per year and a future much larger market share in the still growing plastic market. PolyBright will hence establish a comprehensive and sustainable development activity on new high brilliance lasers that will strengthen the laser system industry.

The performances of different overlay mark types at 65nm node on 300-mm wafers

NASA Astrophysics Data System (ADS)

Tseng, H. T.; Lin, Ling-Chieh; Huang, I. H.; Lin, Benjamin S.; Huang, Chin-Chou K.; Huang, Chien-Jen

2005-05-01

The integrated circuit (IC) manufacturing factories have measured overlay with conventional "box-in-box" (BiB) or "frame-in-frame" (FiF) structures for many years. Since UMC played as a roll of world class IC foundry service provider, tighter and tighter alignment accuracy specs need to be achieved from generation to generation to meet any kind of customers' requirement, especially according to International Technology Roadmap for Semiconductors (ITRS) 2003 METROLOGY section1. The process noises resulting from dishing, overlay mark damaging by chemical mechanism polishing (CMP), and the variation of film thickness during deposition are factors which can be very problematic in mark alignment. For example, the conventional "box-in-box" overlay marks could be damaged easily by CMP, because the less local pattern density and wide feature width of the box induce either dishing or asymmetric damages for the measurement targets, which will make the overlay measurement varied and difficult. After Advanced Imaging Metrology (AIM) overlay targets was introduced by KLA-Tencor, studies in the past shown AIM was more robust in overlay metrology than conventional FiF or BiB targets. In this study, the applications of AIM overlay marks under different process conditions will be discussed and compared with the conventional overlay targets. To evaluate the overlay mark performance against process variation on 65nm technology node in 300-mm wafer, three critical layers were chosen in this study. These three layers were Poly, Contact, and Cu-Metal. The overlay targets used for performance comparison were BiB and Non-Segmented AIM (NS AIM) marks. We compared the overlay mark performance on two main areas. The first one was total measurement uncertainty (TMU)3 related items that include Tool Induced Shift (TIS) variability, precision, and matching. The other area is the target robustness against process variations. Based on the present study AIM mark demonstrated an equal or better performance in the TMU related items under our process conditions. However, when non-optimized tungsten CMP was introduced in the tungsten contact process, due to the dense grating line structure design, we found that AIM mark was much more robust than BiB overlay target.

Post Processing Methods used to Improve Surface Finish of Products which are Manufactured by Additive Manufacturing Technologies: A Review

NASA Astrophysics Data System (ADS)

Kumbhar, N. N.; Mulay, A. V.

2016-08-01

The Additive Manufacturing (AM) processes open the possibility to go directly from Computer-Aided Design (CAD) to a physical prototype. These prototypes are used as test models before it is finalized as well as sometimes as a final product. Additive Manufacturing has many advantages over the traditional process used to develop a product such as allowing early customer involvement in product development, complex shape generation and also save time as well as money. Additive manufacturing also possess some special challenges that are usually worth overcoming such as Poor Surface quality, Physical Properties and use of specific raw material for manufacturing. To improve the surface quality several attempts had been made by controlling various process parameters of Additive manufacturing and also applying different post processing techniques on components manufactured by Additive manufacturing. The main objective of this work is to document an extensive literature review in the general area of post processing techniques which are used in Additive manufacturing.

In-line and Real-time Monitoring of Resonant Acoustic Mixing by Near-infrared Spectroscopy Combined with Chemometric Technology for Process Analytical Technology Applications in Pharmaceutical Powder Blending Systems.

PubMed

Tanaka, Ryoma; Takahashi, Naoyuki; Nakamura, Yasuaki; Hattori, Yusuke; Ashizawa, Kazuhide; Otsuka, Makoto

2017-01-01

Resonant acoustic ® mixing (RAM) technology is a system that performs high-speed mixing by vibration through the control of acceleration and frequency. In recent years, real-time process monitoring and prediction has become of increasing interest, and process analytical technology (PAT) systems will be increasingly introduced into actual manufacturing processes. This study examined the application of PAT with the combination of RAM, near-infrared spectroscopy, and chemometric technology as a set of PAT tools for introduction into actual pharmaceutical powder blending processes. Content uniformity was based on a robust partial least squares regression (PLSR) model constructed to manage the RAM configuration parameters and the changing concentration of the components. As a result, real-time monitoring may be possible and could be successfully demonstrated for in-line real-time prediction of active pharmaceutical ingredients and other additives using chemometric technology. This system is expected to be applicable to the RAM method for the risk management of quality.

Using process monitor wafers to understand directed self-assembly defects

NASA Astrophysics Data System (ADS)

Cao, Yi; Her, YoungJun; Delgadillo, Paulina R.; Vandenbroeck, Nadia; Gronheid, Roel; Chan, Boon Teik; Hashimoto, Yukio; Romo, Ainhoa; Somervell, Mark; Nafus, Kathleen; Nealey, Paul F.

2013-03-01

As directed self-assembly (DSA) has gained momentum over the past few years, questions about its application to high volume manufacturing have arisen. One of the major concerns is about the fundamental limits of defectivity that can be attained with the technology. If DSA applications demonstrate defectivity that rivals of traditional lithographic technologies, the pathway to the cost benefits of the technology creates a very compelling case for its large scale implementation. To address this critical question, our team at IMEC has established a process monitor flow to track the defectivity behaviors of an exemplary chemo-epitaxy application for printing line/space patterns. Through establishing this baseline, we have been able to understand both traditional lithographic defect sources in new materials as well as new classes of assembly defects associated with DSA technology. Moreover, we have explored new materials and processing to lower the level of the defectivity baseline. The robustness of the material sets and process is investigated as well. In this paper, we will report the understandings learned from the IMEC DSA process monitor flow.

Structurally Integrated, Damage-Tolerant, Thermal Spray Coatings

NASA Astrophysics Data System (ADS)

Vackel, Andrew; Dwivedi, Gopal; Sampath, Sanjay

2015-07-01

Thermal spray coatings are used extensively for the protection and life extension of engineering components exposed to harsh wear and/or corrosion during service in aerospace, energy, and heavy machinery sectors. Cermet coatings applied via high-velocity thermal spray are used in aggressive wear situations almost always coupled with corrosive environments. In several instances (e.g., landing gear), coatings are considered as part of the structure requiring system-level considerations. Despite their widespread use, the technology has lacked generalized scientific principles for robust coating design, manufacturing, and performance analysis. Advances in process and in situ diagnostics have provided significant insights into the process-structure-property-performance correlations providing a framework-enhanced design. In this overview, critical aspects of materials, process, parametrics, and performance are discussed through exemplary studies on relevant compositions. The underlying connective theme is understanding and controlling residual stresses generation, which not only addresses process dynamics but also provides linkage for process-property relationship for both the system (e.g., fatigue) and the surface (wear and corrosion). The anisotropic microstructure also invokes the need for damage-tolerant material design to meet future goals.

Fabrication of slender elastic shells by the coating of curved surfaces

NASA Astrophysics Data System (ADS)

Lee, A.; Brun, P.-T.; Marthelot, J.; Balestra, G.; Gallaire, F.; Reis, P. M.

2016-04-01

Various manufacturing techniques exist to produce double-curvature shells, including injection, rotational and blow molding, as well as dip coating. However, these industrial processes are typically geared for mass production and are not directly applicable to laboratory research settings, where adaptable, inexpensive and predictable prototyping tools are desirable. Here, we study the rapid fabrication of hemispherical elastic shells by coating a curved surface with a polymer solution that yields a nearly uniform shell, upon polymerization of the resulting thin film. We experimentally characterize how the curing of the polymer affects its drainage dynamics and eventually selects the shell thickness. The coating process is then rationalized through a theoretical analysis that predicts the final thickness, in quantitative agreement with experiments and numerical simulations of the lubrication flow field. This robust fabrication framework should be invaluable for future studies on the mechanics of thin elastic shells and their intrinsic geometric nonlinearities.

Advanced manufacturing—A transformative enabling capability for fusion

DOE PAGES

Nygren, Richard E.; Dehoff, Ryan R.; Youchison, Dennis L.; ...

2018-05-24

Additive Manufacturing (AM) can create novel and complex engineered material structures. Features such as controlled porosity, micro-fibers and/or nano-particles, transitions in materials and integral robust coatings can be important in developing solutions for fusion subcomponents. A realistic understanding of this capability would be particularly valuable in identifying development paths. Major concerns for using AM processes with lasers or electron beams that melt powder to make refractory parts are the power required and residual stresses arising in fabrication. A related issue is the required combination of lasers or e-beams to continue heating of deposited material (to reduce stresses) and to depositmore » new material at a reasonable built rate while providing adequate surface finish and resolution for meso-scale features. In conclusion, Some Direct Write processes that can make suitable preforms and be cured to an acceptable density may offer another approach for PFCs.« less

An Optical Interferometric Triaxial Displacement Sensor for Structural Health Monitoring: Characterization of Sliding and Debonding for a Delamination Process

PubMed Central

Chen, Yizheng; Zhuang, Yiyang; Du, Yang; Gerald, Rex E.; Tang, Yan

2017-01-01

This paper presents an extrinsic Fabry–Perot interferometer-based optical fiber sensor (EFPI) for measuring three-dimensional (3D) displacements, including interfacial sliding and debonding during delamination. The idea employs three spatially arranged EFPIs as the sensing elements. In our sensor, the three EFPIs are formed by three endfaces of three optical fibers and their corresponding inclined mirrors. Two coincident roof-like metallic structures are used to support the three fibers and the three mirrors, respectively. Our sensor was calibrated and then used to monitor interfacial sliding and debonding between a long square brick of mortar and its support structure (i.e., a steel base plate) during the drying/curing process. This robust and easy-to-manufacture triaxial EFPI-based 3D displacement sensor has great potential in structural health monitoring, the construction industry, oil well monitoring, and geotechnology. PMID:29165351

An Optical Interferometric Triaxial Displacement Sensor for Structural Health Monitoring: Characterization of Sliding and Debonding for a Delamination Process.

PubMed

Zhu, Chen; Chen, Yizheng; Zhuang, Yiyang; Du, Yang; Gerald, Rex E; Tang, Yan; Huang, Jie

2017-11-22

This paper presents an extrinsic Fabry-Perot interferometer-based optical fiber sensor (EFPI) for measuring three-dimensional (3D) displacements, including interfacial sliding and debonding during delamination. The idea employs three spatially arranged EFPIs as the sensing elements. In our sensor, the three EFPIs are formed by three endfaces of three optical fibers and their corresponding inclined mirrors. Two coincident roof-like metallic structures are used to support the three fibers and the three mirrors, respectively. Our sensor was calibrated and then used to monitor interfacial sliding and debonding between a long square brick of mortar and its support structure (i.e., a steel base plate) during the drying/curing process. This robust and easy-to-manufacture triaxial EFPI-based 3D displacement sensor has great potential in structural health monitoring, the construction industry, oil well monitoring, and geotechnology.

Analytic hierarchy process-based approach for selecting a Pareto-optimal solution of a multi-objective, multi-site supply-chain planning problem

NASA Astrophysics Data System (ADS)

Ayadi, Omar; Felfel, Houssem; Masmoudi, Faouzi

2017-07-01

The current manufacturing environment has changed from traditional single-plant to multi-site supply chain where multiple plants are serving customer demands. In this article, a tactical multi-objective, multi-period, multi-product, multi-site supply-chain planning problem is proposed. A corresponding optimization model aiming to simultaneously minimize the total cost, maximize product quality and maximize the customer satisfaction demand level is developed. The proposed solution approach yields to a front of Pareto-optimal solutions that represents the trade-offs among the different objectives. Subsequently, the analytic hierarchy process method is applied to select the best Pareto-optimal solution according to the preferences of the decision maker. The robustness of the solutions and the proposed approach are discussed based on a sensitivity analysis and an application to a real case from the textile and apparel industry.

Advanced manufacturing—A transformative enabling capability for fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nygren, Richard E.; Dehoff, Ryan R.; Youchison, Dennis L.

Additive Manufacturing (AM) can create novel and complex engineered material structures. Features such as controlled porosity, micro-fibers and/or nano-particles, transitions in materials and integral robust coatings can be important in developing solutions for fusion subcomponents. A realistic understanding of this capability would be particularly valuable in identifying development paths. Major concerns for using AM processes with lasers or electron beams that melt powder to make refractory parts are the power required and residual stresses arising in fabrication. A related issue is the required combination of lasers or e-beams to continue heating of deposited material (to reduce stresses) and to depositmore » new material at a reasonable built rate while providing adequate surface finish and resolution for meso-scale features. In conclusion, Some Direct Write processes that can make suitable preforms and be cured to an acceptable density may offer another approach for PFCs.« less

Large Scale Metal Additive Techniques Review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nycz, Andrzej; Adediran, Adeola I; Noakes, Mark W

2016-01-01

In recent years additive manufacturing made long strides toward becoming a main stream production technology. Particularly strong progress has been made in large-scale polymer deposition. However, large scale metal additive has not yet reached parity with large scale polymer. This paper is a review study of the metal additive techniques in the context of building large structures. Current commercial devices are capable of printing metal parts on the order of several cubic feet compared to hundreds of cubic feet for the polymer side. In order to follow the polymer progress path several factors are considered: potential to scale, economy, environmentmore » friendliness, material properties, feedstock availability, robustness of the process, quality and accuracy, potential for defects, and post processing as well as potential applications. This paper focuses on current state of art of large scale metal additive technology with a focus on expanding the geometric limits.« less

Instrumentation, metrology, and standards: key elements for the future of nanomanufacturing

NASA Astrophysics Data System (ADS)

Postek, Michael T.; Lyons, Kevin

2007-09-01

Nanomanufacturing is the essential bridge between the discoveries of nanoscience and real world nanotech products and is the vehicle by which the Nation and the World will realize the promise of major technological innovation across a spectrum of products that will affect virtually every industrial sector. For nanotech products to achieve the broad impacts envisioned, they must be manufactured in market-appropriate quantities in a reliable, repeatable, economical and commercially viable manner. In addition, they must be manufactured so that environmental and human health concerns are met, worker safety issues are appropriately assessed and handled, and liability issues are addressed. Critical to this realization of robust nanomanufacturing is the development of the necessary instrumentation, metrology, and standards. Integration of the instruments, their interoperability, and appropriate information management are also critical elements that must be considered for viable nanomanufacturing. Advanced instrumentation, metrology and standards will allow the physical dimensions, properties, functionality, and purity of the materials, processes, tools, systems, products, and emissions that will constitute nanomanufacturing to be measured and characterized. This will in turn enable production to be scaleable, controllable, predictable, and repeatable to meet market needs. If a nano-product cannot be measured it cannot be manufactured; additionally if that product cannot be made safely it should not be manufactured. This presentation introduces the Instrumentation, Metrology, and Standards for Nanomanufacturing Conference at the 2007 SPIE Optics and Photonics. This conference will become the leading forum for the exchange of foundational information and discussion of instrumentation, metrology and standards which are key elements for the success of nanomanufacturing.

Advanced optical manufacturing digital integrated system

NASA Astrophysics Data System (ADS)

Tao, Yizheng; Li, Xinglan; Li, Wei; Tang, Dingyong

2012-10-01

It is necessarily to adapt development of advanced optical manufacturing technology with modern science technology development. To solved these problems which low of ration, ratio of finished product, repetition, consistent in big size and high precision in advanced optical component manufacturing. Applied business driven and method of Rational Unified Process, this paper has researched advanced optical manufacturing process flow, requirement of Advanced Optical Manufacturing integrated System, and put forward architecture and key technology of it. Designed Optical component core and Manufacturing process driven of Advanced Optical Manufacturing Digital Integrated System. the result displayed effective well, realized dynamic planning Manufacturing process, information integration improved ratio of production manufactory.

Advanced Space Flight and Environmental Concerns

NASA Technical Reports Server (NTRS)

Whitaker, A.

2001-01-01

The aerospace industry has conquered numerous environmental challenges during the last decade. The aerospace industry of today has evolved due in part to the environmental challenges, becoming stronger, more robust, learning to push the limits of technology, materials and manufacturing, and performing cutting edge engineering.

Conformal ALON® and spinel windows

NASA Astrophysics Data System (ADS)

Goldman, Lee M.; Smith, Mark; Ramisetty, Mohan; Jha, Santosh; Sastri, Suri

2017-05-01

The requirements for modern aircraft based reconnaissance systems are driving the need for conformal windows for future sensor systems. However, limitations on optical systems and the ability to produce windows in complex geometries currently limit the geometry of existing windows and window assemblies to faceted assemblies of flat windows. ALON consists primarily of aluminum and oxygen, similar to that of alumina, with a small amount of nitrogen added to help stabilize the cubic gamma-AlON phase. ALON's chemical similarity to alumina, translates into a robust manufacturing process. This ease of processing has allowed Surmet to produce ALON windows and domes in a wide variety of geometries and sizes. Spinel (MgAl2O4) contains equal molar amounts of MgO and Al2O3, and is a cubic material, that transmits further into the Infrared than ALON. Spinel is produced via powder processing techniques similar to those used to produce ALON. Surmet is now applying the lessons learned with ALON to produce conformal spinel windows and domes as well.

Manufacturing Process Selection of Composite Bicycle’s Crank Arm using Analytical Hierarchy Process (AHP)

NASA Astrophysics Data System (ADS)

Luqman, M.; Rosli, M. U.; Khor, C. Y.; Zambree, Shayfull; Jahidi, H.

2018-03-01

Crank arm is one of the important parts in a bicycle that is an expensive product due to the high cost of material and production process. This research is aimed to investigate the potential type of manufacturing process to fabricate composite bicycle crank arm and to describe an approach based on analytical hierarchy process (AHP) that assists decision makers or manufacturing engineers in determining the most suitable process to be employed in manufacturing of composite bicycle crank arm at the early stage of the product development process to reduce the production cost. There are four types of processes were considered, namely resin transfer molding (RTM), compression molding (CM), vacuum bag molding and filament winding (FW). The analysis ranks these four types of process for its suitability in the manufacturing of bicycle crank arm based on five main selection factors and 10 sub factors. Determining the right manufacturing process was performed based on AHP process steps. Consistency test was performed to make sure the judgements are consistent during the comparison. The results indicated that the compression molding was the most appropriate manufacturing process because it has the highest value (33.6%) among the other manufacturing processes.

Designing Phononic Crystals with Wide and Robust Band Gaps

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, Zian; Chen, Yanyu; Yang, Haoxiang

Here, phononic crystals (PnCs) engineered to manipulate and control the propagation of mechanical waves have enabled the design of a range of novel devices, such as waveguides, frequency modulators, and acoustic cloaks, for which wide and robust phononic band gaps are highly preferable. While numerous PnCs have been designed in recent decades, to the best of our knowledge, PnCs that possess simultaneous wide and robust band gaps (to randomness and deformations) have not yet been reported. Here, we demonstrate that by combining the band-gap formation mechanisms of Bragg scattering and local resonances (the latter one is dominating), PnCs with widemore » and robust phononic band gaps can be established. The robustness of the phononic band gaps are then discussed from two aspects: robustness to geometric randomness (manufacture defects) and robustness to deformations (mechanical stimuli). Analytical formulations further predict the optimal design parameters, and an uncertainty analysis quantifies the randomness effect of each designing parameter. Moreover, we show that the deformation robustness originates from a local resonance-dominant mechanism together with the suppression of structural instability. Importantly, the proposed PnCs require only a small number of layers of elements (three unit cells) to obtain broad, robust, and strong attenuation bands, which offer great potential in designing flexible and deformable phononic devices.« less

Designing Phononic Crystals with Wide and Robust Band Gaps

DOE PAGES

Jia, Zian; Chen, Yanyu; Yang, Haoxiang; ...

2018-04-16

Here, phononic crystals (PnCs) engineered to manipulate and control the propagation of mechanical waves have enabled the design of a range of novel devices, such as waveguides, frequency modulators, and acoustic cloaks, for which wide and robust phononic band gaps are highly preferable. While numerous PnCs have been designed in recent decades, to the best of our knowledge, PnCs that possess simultaneous wide and robust band gaps (to randomness and deformations) have not yet been reported. Here, we demonstrate that by combining the band-gap formation mechanisms of Bragg scattering and local resonances (the latter one is dominating), PnCs with widemore » and robust phononic band gaps can be established. The robustness of the phononic band gaps are then discussed from two aspects: robustness to geometric randomness (manufacture defects) and robustness to deformations (mechanical stimuli). Analytical formulations further predict the optimal design parameters, and an uncertainty analysis quantifies the randomness effect of each designing parameter. Moreover, we show that the deformation robustness originates from a local resonance-dominant mechanism together with the suppression of structural instability. Importantly, the proposed PnCs require only a small number of layers of elements (three unit cells) to obtain broad, robust, and strong attenuation bands, which offer great potential in designing flexible and deformable phononic devices.« less

Designing Phononic Crystals with Wide and Robust Band Gaps

NASA Astrophysics Data System (ADS)

Jia, Zian; Chen, Yanyu; Yang, Haoxiang; Wang, Lifeng

2018-04-01

Phononic crystals (PnCs) engineered to manipulate and control the propagation of mechanical waves have enabled the design of a range of novel devices, such as waveguides, frequency modulators, and acoustic cloaks, for which wide and robust phononic band gaps are highly preferable. While numerous PnCs have been designed in recent decades, to the best of our knowledge, PnCs that possess simultaneous wide and robust band gaps (to randomness and deformations) have not yet been reported. Here, we demonstrate that by combining the band-gap formation mechanisms of Bragg scattering and local resonances (the latter one is dominating), PnCs with wide and robust phononic band gaps can be established. The robustness of the phononic band gaps are then discussed from two aspects: robustness to geometric randomness (manufacture defects) and robustness to deformations (mechanical stimuli). Analytical formulations further predict the optimal design parameters, and an uncertainty analysis quantifies the randomness effect of each designing parameter. Moreover, we show that the deformation robustness originates from a local resonance-dominant mechanism together with the suppression of structural instability. Importantly, the proposed PnCs require only a small number of layers of elements (three unit cells) to obtain broad, robust, and strong attenuation bands, which offer great potential in designing flexible and deformable phononic devices.

Enabling a Better Aft Heat Shield Solution for Future Mars Science Laboratory Class Vehicles

NASA Technical Reports Server (NTRS)

McGuire, Mary K.; Covington, Melmoth A.; Goldstein, Howard E.; Arnold, James O.; Beck, Robin

2013-01-01

System studies are described that compare masses and estimated manufacturing costs of options for the as-flown Mars Science Laboratory (MSL) aft body Thermal Light Weight Ablator (SLA) 561-V and its thickness was not optimized using the standard TPS Sizer Tool widely used for heat shield design. Use of the TPS sizing tool suggests that optimization of the SLA thickness could reduce the aft heat shield mass by 40 percent. Analysis of the predicted aft-shell aerothermodynamics suggests that the bulk of MSL class entry vehicle heat shields could incorporate Advanced Flexible Reusable Surface Insulation (AFRSI). AFRSI has a wellestablished record of relatively inexpensive manufacturing and flight certification based on its use on the lee side of the Space Shuttle. Runs with the TPS Sizer show that the AFRSI solution would be 60 percent lighter than the as-flown SLA. The issue of Reaction Control System (RCS) heating on the aft shell could be addressed by locally impregnating the AFRSI with silicone to enhance its robustness to short bursts ofheating. Stagnation point arcjet testing has shown that silicone impregnated AFRSI performs well at heat rates of 115 W/cm2 and 0.1 atmospheres for a duration of 40 seconds, far beyond conditions that are expected for MSL class vehicles. The paper concludes with a discussion of manufacturing processes for AFRSI, impregnation approaches and relative cost comparisons to the SLA solution.

Manufacturing of mushroom-shaped structures and its hydrophobic robustness analysis based on energy minimization approach

NASA Astrophysics Data System (ADS)

Wang, Li; Yang, Xiaonan; Wang, Quandai; Yang, Zhiqiang; Duan, Hui; Lu, Bingheng

2017-07-01

The construction of stable hydrophobic surfaces has increasingly gained attention owing to its wide range of potential applications. However, these surfaces may become wet and lose their slip effect owing to insufficient hydrophobic stability. Pillars with a mushroom-shaped tip are believed to enhance hydrophobicity stability. This work presents a facile method of manufacturing mushroom-shaped structures, where, compared with the previously used method, the modulation of the cap thickness, cap diameter, and stem height of the structures is more convenient. The effects of the development time on the cap diameter and overhanging angle are investigated and well-defined mushroom-shaped structures are demonstrated. The effect of the microstructure geometry on the contact state of a droplet is predicted by taking an energy minimization approach and is experimentally validated with nonvolatile ultraviolet-curable polymer with a low surface tension by inspecting the profiles of liquid-vapor interface deformation and tracking the trace of the receding contact line after exposure to ultraviolet light. Theoretical and experimental results show that, compared with regular pillar arrays having a vertical sidewall, the mushroom-like structures can effectively enhance hydrophobic stability. The proposed manufacturing method will be useful for fabricating robust hydrophobic surfaces in a cost-effective and convenient manner.

Contour scanning of textile preforms using a light-section sensor for the automated manufacturing of fibre-reinforced plastics

NASA Astrophysics Data System (ADS)

Schmitt, R.; Niggemann, C.; Mersmann, C.

2008-04-01

Fibre-reinforced plastics (FRP) are particularly suitable for components where light-weight structures with advanced mechanical properties are required, e.g. for aerospace parts. Nevertheless, many manufacturing processes for FRP include manual production steps without an integrated quality control. A vital step in the process chain is the lay-up of the textile preform, as it greatly affects the geometry and the mechanical performance of the final part. In order to automate the FRP production, an inline machine vision system is needed for a closed-loop control of the preform lay-up. This work describes the development of a novel laser light-section sensor for optical inspection of textile preforms and its integration and validation in a machine vision prototype. The proposed method aims at the determination of the contour position of each textile layer through edge scanning. The scanning route is automatically derived by using texture analysis algorithms in a preliminary step. As sensor output a distinct stage profile is computed from the acquired greyscale image. The contour position is determined with sub-pixel accuracy using a novel algorithm based on a non-linear least-square fitting to a sigmoid function. The whole contour position is generated through data fusion of the measured edge points. The proposed method provides robust process automation for the FRP production improving the process quality and reducing the scrap quota. Hence, the range of economically feasible FRP products can be increased and new market segments with cost sensitive products can be addressed.

Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets.

PubMed

Taipale-Kovalainen, Krista; Karttunen, Anssi-Pekka; Ketolainen, Jarkko; Korhonen, Ossi

2018-03-30

The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental design was used to generate a structured study plan which involved 19 runs. The formulation variables studied were the type of lubricant (magnesium stearate or stearic acid) and its concentration (0.5, 1.0 and 1.5%). Process variables were total production feed rate (5, 10.5 and 16kg/h), mixer speed rpm (500, 850 and 1200rpm), and mixer inlet port for lubricant (A or B). The continuous direct compression tableting line consisted of loss-in-weight feeders, a continuous mixer and a tablet press. The Quality Target Product Profile (QTPP) was defined for the final product, as the flowability of powder blends (2.5s), tablet strength (147N), dissolution in 2.5min (90%) and ejection force (425N). A design space was identified which fulfilled all the requirements of QTPP. The type and concentration of lubricant exerted the greatest influence on the design space. For example, stearic acid increased the tablet strength. Interestingly, the studied process parameters had only a very minor effect on the quality of the final product and the design space. It is concluded that the continuous direct compression tableting process itself is insensitive and can cope with changes in lubrication, whereas formulation parameters exert a major influence on the end product quality. Copyright © 2017 Elsevier B.V. All rights reserved.

The resources of Mars for human settlement.

PubMed

Meyer, T R; McKay, C P

1989-01-01

Spacecraft exploration of Mars has shown that the essential resources necessary for life support are present on the martian surface. The key life-support compounds O2, N2, and H2O are available on Mars. The soil could be used as radiation shielding and could provide many useful industrial and construction materials. Compounds with high chemical energy, such as rocket fuels, can be manufactured in-situ on Mars. Solar power, and possibly wind power, are available and practical on Mars. Preliminary engineering studies indicate that fairly autonomous processes can be designed to extract and stockpile Martian consumables. The ability to utilize these materials in support of a human exploration effort allows missions that are more robust and economical than would otherwise be possible.

On-chip copper-dielectric interference filters for manufacturing of ambient light and proximity CMOS sensors.

PubMed

Frey, Laurent; Masarotto, Lilian; D'Aillon, Patrick Gros; Pellé, Catherine; Armand, Marilyn; Marty, Michel; Jamin-Mornet, Clémence; Lhostis, Sandrine; Le Briz, Olivier

2014-07-10

Filter technologies implemented on CMOS image sensors for spectrally selective applications often use a combination of on-chip organic resists and an external substrate with multilayer dielectric coatings. The photopic-like and near-infrared bandpass filtering functions respectively required by ambient light sensing and user proximity detection through time-of-flight can be fully integrated on chip with multilayer metal-dielectric filters. Copper, silicon nitride, and silicon oxide are the materials selected for a technological proof-of-concept on functional wafers, due to their immediate availability in front-end semiconductor fabs. Filter optical designs are optimized with respect to specific performance criteria, and the robustness of the designs regarding process errors are evaluated for industrialization purposes.

Concentrating Solar Power Central Receiver Panel Component Fabrication and Testing FINAL REPORT

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDowell, Michael W; Miner, Kris

The objective of this project is to complete a design of an advanced concentrated solar panel and demonstrate the manufacturability of key components. Then confirm the operation of the key components under prototypic solar flux conditions. This work is an important step in reducing the levelized cost of energy (LCOE) from a central receiver solar power plant. The key technical risk to building larger power towers is building the larger receiver systems. Therefore, this proposed technology project includes the design of an advanced molten salt prototypic sub-scale receiver panel that can be utilized into a large receiver system. Then completemore » the fabrication and testing of key components of the receive design that will be used to validate the design. This project shall have a significant impact on solar thermal power plant design. Receiver panels of suitable size for utility scale plants are a key element to a solar power tower plant. Many subtle and complex manufacturing processes are involved in producing a reliable, robust receiver panel. Given the substantial size difference between receiver panels manufactured in the past and those needed for large plant designs, the manufacture and demonstration on prototype receiver panel components with representative features of a full-sized panel will be important to improving the build process for commercial success. Given the thermal flux limitations of the test facility, the panel components cannot be rendered full size. Significance changes occurred in the projects technical strategies from project initiation to the accomplishments described herein. The initial strategy was to define cost improvements for the receiver, design and build a scale prototype receiver and test, on sun, with a molten salt heat transport system. DOE had committed to constructing a molten salt heat transport loop to support receiver testing at the top of the NSTTF tower. Because of funding constraints this did not happen. A subsequent plan to test scale prototype receiver, off sun but at temperature, at a molten salt loop at ground level adjacent to the tower also had to be abandoned. Thus, no test facility existed for a molten salt receiver test. As a result, PWR completed the prototype receiver design and then fabricated key components for testing instead of fabricating the complete prototype receiver. A number of innovative design ideas have been developed. Key features of the receiver panel have been identified. This evaluation includes input from Solar 2, personal experience of people working on these programs and meetings with Sandia. Key components of the receiver design and key processes used to fabricate a receiver have been selected for further evaluation. The Test Plan, Concentrated Solar Power Receiver In Cooperation with the Department of Energy and Sandia National Laboratory was written to define the scope of the testing to be completed as well as to provide details related to the hardware, instrumentation, and data acquisition. The document contains a list of test objectives, a test matrix, and an associated test box showing the operating points to be tested. Test Objectives: 1. Demonstrate low-cost manufacturability 2. Demonstrate robustness of two different tube base materials 3. Collect temperature data during on sun operation 4. Demonstrate long term repeated daily operation of heat shields 5. Complete pinhole tube weld repairs 6. Anchor thermal models This report discusses the tests performed, the results, and implications for design improvements and LCOE reduction.« less

Characterization and Stability of Trypanosoma cruzi 24-C4 (Tc24-C4), a Candidate Antigen for a Therapeutic Vaccine Against Chagas Disease.

PubMed

Biter, Amadeo B; Weltje, Sarah; Hudspeth, Elissa M; Seid, Christopher A; McAtee, C Patrick; Chen, Wen-Hsiang; Pollet, Jeroen B; Strych, Ulrich; Hotez, Peter J; Bottazzi, Maria Elena

2018-05-01

Chagas disease due to chronic infection with Trypanosoma cruzi is a neglected cause of heart disease, affecting approximately 6-10 million individuals in Latin America and elsewhere. T. cruzi Tc24, a calcium-binding protein in the flagellar pocket of the parasite, is a candidate antigen for an injectable therapeutic vaccine as an alternative or a complement to chemotherapy. Previously, we reported that a genetically engineered construct from which all cysteine residues had been eliminated (Tc24-C4) yields a recombinant protein with reduced aggregation and improved analytical purity in comparison to the wild-type form, without compromising antigenicity and immunogenicity. We now report that the established process for producing Escherichia coli-expressed Tc24-C4 protein is robust and reproducibly yields protein lots with consistent analytical characteristics, freeze-thaw, accelerated, and long-term stability profiles. The data indicate that, like most proteins, Tc24-C4 should be stable at -80°C, but also at 4°C and room temperature for at least 30 days, and up to 7-15 days at 37°C. Thus, the production process for recombinant Tc24-C4 is suitable for Current Good Manufacturing Practice production and clinical testing, based on process robustness, analytical characteristics, and stability profile. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Depositing laser-generated nanoparticles on powders for additive manufacturing of oxide dispersed strengthened alloy parts via laser metal deposition

NASA Astrophysics Data System (ADS)

Streubel, René; Wilms, Markus B.; Doñate-Buendía, Carlos; Weisheit, Andreas; Barcikowski, Stephan; Henrich Schleifenbaum, Johannes; Gökce, Bilal

2018-04-01

We present a novel route for the adsorption of pulsed laser-dispersed nanoparticles onto metal powders in aqueous solution without using any binders or surfactants. By electrostatic interaction, we deposit Y2O3 nanoparticles onto iron-chromium based powders and obtain a high dispersion of nano-sized particles on the metallic powders. Within the additively manufactured component, we show that the particle spacing of the oxide inclusion can be adjusted by the initial mass fraction of the adsorbed Y2O3 particles on the micropowder. Thus, our procedure constitutes a robust route for additive manufacturing of oxide dispersion-strengthened alloys via oxide nanoparticles supported on steel micropowders.

Development of Integrated Programs for Aerospace-vehicle Design (IPAD): Product manufacture interactions with the design process

NASA Technical Reports Server (NTRS)

Crowell, H. A.

1979-01-01

The product manufacturing interactions with the design process and the IPAD requirements to support the interactions are described. The data requirements supplied to manufacturing by design are identified and quantified. Trends in computer-aided manufacturing are discussed and the manufacturing process of the 1980's is anticipated.

40 CFR 761.193 - Maintenance of monitoring records by persons who import, manufacture, process, distribute in...

Code of Federal Regulations, 2013 CFR

2013-07-01

... persons who import, manufacture, process, distribute in commerce, or use chemicals containing... records by persons who import, manufacture, process, distribute in commerce, or use chemicals containing inadvertently generated PCBs. (a) Persons who import, manufacture, process, distribute in commerce, or use...

40 CFR 761.193 - Maintenance of monitoring records by persons who import, manufacture, process, distribute in...

Code of Federal Regulations, 2011 CFR

2011-07-01

... persons who import, manufacture, process, distribute in commerce, or use chemicals containing... records by persons who import, manufacture, process, distribute in commerce, or use chemicals containing inadvertently generated PCBs. (a) Persons who import, manufacture, process, distribute in commerce, or use...

40 CFR 761.193 - Maintenance of monitoring records by persons who import, manufacture, process, distribute in...

Code of Federal Regulations, 2012 CFR

2012-07-01

... persons who import, manufacture, process, distribute in commerce, or use chemicals containing... records by persons who import, manufacture, process, distribute in commerce, or use chemicals containing inadvertently generated PCBs. (a) Persons who import, manufacture, process, distribute in commerce, or use...

40 CFR 761.193 - Maintenance of monitoring records by persons who import, manufacture, process, distribute in...

Code of Federal Regulations, 2014 CFR

2014-07-01

... persons who import, manufacture, process, distribute in commerce, or use chemicals containing... records by persons who import, manufacture, process, distribute in commerce, or use chemicals containing inadvertently generated PCBs. (a) Persons who import, manufacture, process, distribute in commerce, or use...

Supercritical fluid chromatography for GMP analysis in support of pharmaceutical development and manufacturing activities.

PubMed

Hicks, Michael B; Regalado, Erik L; Tan, Feng; Gong, Xiaoyi; Welch, Christopher J

2016-01-05

Supercritical fluid chromatography (SFC) has long been a preferred method for enantiopurity analysis in support of pharmaceutical discovery and development, but implementation of the technique in regulated GMP laboratories has been somewhat slow, owing to limitations in instrument sensitivity, reproducibility, accuracy and robustness. In recent years, commercialization of next generation analytical SFC instrumentation has addressed previous shortcomings, making the technique better suited for GMP analysis. In this study we investigate the use of modern SFC for enantiopurity analysis of several pharmaceutical intermediates and compare the results with the conventional HPLC approaches historically used for analysis in a GMP setting. The findings clearly illustrate that modern SFC now exhibits improved precision, reproducibility, accuracy and robustness; also providing superior resolution and peak capacity compared to HPLC. Based on these findings, the use of modern chiral SFC is recommended for GMP studies of stereochemistry in pharmaceutical development and manufacturing. Copyright © 2015 Elsevier B.V. All rights reserved.

The integration of quality function deployment and Kansei Engineering: An overview of application

NASA Astrophysics Data System (ADS)

Lokman, Anitawati Mohd; Awang, Ahmad Azran; Omar, Abdul Rahman; Abdullah, Nur Atiqah Sia

2016-02-01

As a result of today's globalized world and robust development of emerging markets, consumers are able to select from an endless number of products that are mostly similar in terms of design and properties, as well as equivalent in function and performance. The survival of businesses in a competitive ambience requires innovation, consumer loyalty, and products that are easily identifiable by consumers. Today's manufacturers have started to employ customer research instruments to survive in the highly industrialized world—for example, Conjoint Analysis, Design of Experiments and Semantic Design of Environment. However, this work only attempts to concentrate on Kansei Engineering and Quality Function Deployment. Kansei Engineering (KE) is deemed as the most appropriate method to link consumers' feelings, emotions or senses to the properties of a product because it translates people's impressions, interests, and feelings to the solutions of product design. Likewise, Quality Function Deployment (QFD) enables clearer interpretation of the needs of consumers, better concepts or products, and enhanced communication to internal operations that must then manufacture and deliver the product or services. The integration of both KE and QFD is believed possible, as many product manufacturers and businesses have started to utilize systematized methods to translate consumers' needs and wants into processes and products. Therefore, this work addresses areas of various integrations of KE and QFD processes in the industry, in an effort to assist an integration of KE and QFD. This work aims to provide evidence on the integration mechanism to enable successful incorporation of consumer's implicit feelings and demands into product quality improvement, and simultaneously providing an overview of both KE and QFD from the perspective of a novice.

Streamlined bioreactor-based production of human cartilage tissues.

PubMed

Tonnarelli, B; Santoro, R; Adelaide Asnaghi, M; Wendt, D

2016-05-27

Engineered tissue grafts have been manufactured using methods based predominantly on traditional labour-intensive manual benchtop techniques. These methods impart significant regulatory and economic challenges, hindering the successful translation of engineered tissue products to the clinic. Alternatively, bioreactor-based production systems have the potential to overcome such limitations. In this work, we present an innovative manufacturing approach to engineer cartilage tissue within a single bioreactor system, starting from freshly isolated human primary chondrocytes, through the generation of cartilaginous tissue grafts. The limited number of primary chondrocytes that can be isolated from a small clinically-sized cartilage biopsy could be seeded and extensively expanded directly within a 3D scaffold in our perfusion bioreactor (5.4 ± 0.9 doublings in 2 weeks), bypassing conventional 2D expansion in flasks. Chondrocytes expanded in 3D scaffolds better maintained a chondrogenic phenotype than chondrocytes expanded on plastic flasks (collagen type II mRNA, 18-fold; Sox-9, 11-fold). After this "3D expansion" phase, bioreactor culture conditions were changed to subsequently support chondrogenic differentiation for two weeks. Engineered tissues based on 3D-expanded chondrocytes were more cartilaginous than tissues generated from chondrocytes previously expanded in flasks. We then demonstrated that this streamlined bioreactor-based process could be adapted to effectively generate up-scaled cartilage grafts in a size with clinical relevance (50 mm diameter). Streamlined and robust tissue engineering processes, as the one described here, may be key for the future manufacturing of grafts for clinical applications, as they facilitate the establishment of compact and closed bioreactor-based production systems, with minimal automation requirements, lower operating costs, and increased compliance to regulatory guidelines.

Robust optical sensors for safety critical automotive applications

NASA Astrophysics Data System (ADS)

De Locht, Cliff; De Knibber, Sven; Maddalena, Sam

2008-02-01

Optical sensors for the automotive industry need to be robust, high performing and low cost. This paper focuses on the impact of automotive requirements on optical sensor design and packaging. Main strategies to lower optical sensor entry barriers in the automotive market include: Perform sensor calibration and tuning by the sensor manufacturer, sensor test modes on chip to guarantee functional integrity at operation, and package technology is key. As a conclusion, optical sensor applications are growing in automotive. Optical sensor robustness matured to the level of safety critical applications like Electrical Power Assisted Steering (EPAS) and Drive-by-Wire by optical linear arrays based systems and Automated Cruise Control (ACC), Lane Change Assist and Driver Classification/Smart Airbag Deployment by camera imagers based systems.

Robust design of (s, S) inventory policy parameters in supply chains with demand and lead time uncertainties

NASA Astrophysics Data System (ADS)

Karimi Movahed, Kamran; Zhang, Zhi-Hai

2015-09-01

Demand and lead time uncertainties have significant effects on supply chain behaviour. In this paper, we present a single-product three-level multi-period supply chain with uncertain demands and lead times by using robust techniques to study the managerial insights of the supply chain inventory system under uncertainty. We formulate this problem as a robust mixed-integer linear program with minimised expected cost and total cost variation to determine the optimal (s, S) values of the inventory parameters. Several numerical studies are performed to investigate the supply chain behaviour. Useful guidelines for the design of a robust supply chain are also provided. Results show that the order variance and the expected cost in a supply chain significantly increase when the manufacturer's review period is an integer ratio of the distributor's and the retailer's review periods.

Silicon Valley's Processing Needs versus San Jose State University's Manufacturing Systems Processing Component: Implications for Industrial Technology

ERIC Educational Resources Information Center

Obi, Samuel C.

2004-01-01

Manufacturing professionals within universities tend to view manufacturing systems from a global perspective. This perspective tends to assume that manufacturing processes are employed equally in every manufacturing enterprise, irrespective of the geography and the needs of the people in those diverse regions. But in reality local and societal…

Tuning and Robustness Analysis for the Orion Absolute Navigation System

NASA Technical Reports Server (NTRS)

Holt, Greg N.; Zanetti, Renato; D'Souza, Christopher

2013-01-01

The Orion Multi-Purpose Crew Vehicle (MPCV) is currently under development as NASA's next-generation spacecraft for exploration missions beyond Low Earth Orbit. The MPCV is set to perform an orbital test flight, termed Exploration Flight Test 1 (EFT-1), some time in late 2014. The navigation system for the Orion spacecraft is being designed in a Multi-Organizational Design Environment (MODE) team including contractor and NASA personnel. The system uses an Extended Kalman Filter to process measurements and determine the state. The design of the navigation system has undergone several iterations and modifications since its inception, and continues as a work-in-progress. This paper seeks to show the efforts made to-date in tuning the filter for the EFT-1 mission and instilling appropriate robustness into the system to meet the requirements of manned space ight. Filter performance is affected by many factors: data rates, sensor measurement errors, tuning, and others. This paper focuses mainly on the error characterization and tuning portion. Traditional efforts at tuning a navigation filter have centered around the observation/measurement noise and Gaussian process noise of the Extended Kalman Filter. While the Orion MODE team must certainly address those factors, the team is also looking at residual edit thresholds and measurement underweighting as tuning tools. Tuning analysis is presented with open loop Monte-Carlo simulation results showing statistical errors bounded by the 3-sigma filter uncertainty covariance. The Orion filter design uses 24 Exponentially Correlated Random Variable (ECRV) parameters to estimate the accel/gyro misalignment and nonorthogonality. By design, the time constant and noise terms of these ECRV parameters were set to manufacturer specifications and not used as tuning parameters. They are included in the filter as a more analytically correct method of modeling uncertainties than ad-hoc tuning of the process noise. Tuning is explored for the powered-flight ascent phase, where measurements are scarce and unmodelled vehicle accelerations dominate. On orbit, there are important trade-off cases between process and measurement noise. On entry, there are considerations about trading performance accuracy for robustness. Process Noise is divided into powered flight and coasting ight and can be adjusted for each phase and mode of the Orion EFT-1 mission. Measurement noise is used for the integrated velocity measurements during pad alignment. It is also used for Global Positioning System (GPS) pseudorange and delta- range measurements during the rest of the flight. The robustness effort has been focused on maintaining filter convergence and performance in the presence of unmodeled error sources. These include unmodeled forces on the vehicle and uncorrected errors on the sensor measurements. Orion uses a single-frequency, non-keyed GPS receiver, so the effects due to signal distortion in Earth's ionosphere and troposphere are present in the raw measurements. Results are presented showing the efforts to compensate for these errors as well as characterize the residual effect for measurement noise tuning. Another robustness tool in use is tuning the residual edit thresholds. The trade-off between noise tuning and edit thresholds is explored in the context of robustness to errors in dynamics models and sensor measurements. Measurement underweighting is also presented as a method of additional robustness when processing highly accurate measurements in the presence of large filter uncertainties.

21 CFR 201.122 - Drugs for processing, repacking, or manufacturing.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drugs for processing, repacking, or manufacturing... for processing, repacking, or manufacturing. A drug in a bulk package, except tablets, capsules, or... manufacturing, processing, or repacking”; and if in substantially all dosage forms in which it may be dispensed...

The presence of Enterococcus, coliforms and E. coli in a commercial yeast manufacturing process.

PubMed

O'Brien, S S; Lindsay, D; von Holy, A

2004-07-01

This study evaluated a typical commercial yeast manufacturing process for bacterial contamination. Product line samples of a commercial yeast manufacturing process and the corresponding seed yeast manufacturing process were obtained upstream from the final compressed and dry yeast products. All samples were analysed before (non-PI) and after preliminary incubation (PI) at 37 degrees C for 24 h. The PI procedure was incorporated for amplification of bacterial counts below the lower detection limit. Enterococcus, coliform and Escherichia coli counts were quantified by standard pour-plate techniques using selective media. Presence at all stages and progressive increases in counts of Enterococcus, coliforms and E. coli during processing in the commercial manufacturing operation suggested that the primary source of contamination of both compressed and dry yeast with these bacteria was the seed yeast manufacturing process and that contamination was amplified throughout the commercial yeast manufacturing process. This was confirmed by surveys of the seed yeast manufacturing process which indicated that contamination of the seed yeast with Enterococcus, coliforms and E. coli occurred during scale up of seed yeast biomass destined as inoculum for the commercial fermentation.

Quality by design approach for viral clearance by protein a chromatography

PubMed Central

Zhang, Min; Miesegaes, George R; Lee, Michael; Coleman, Daniel; Yang, Bin; Trexler-Schmidt, Melody; Norling, Lenore; Lester, Philip; Brorson, Kurt A; Chen, Qi

2014-01-01

Protein A chromatography is widely used as a capture step in monoclonal antibody (mAb) purification processes. Antibodies and Fc fusion proteins can be efficiently purified from the majority of other complex components in harvested cell culture fluid (HCCF). Protein A chromatography is also capable of removing modest levels of viruses and is often validated for viral clearance. Historical data mining of Genentech and FDA/CDER databases systematically evaluated the removal of model viruses by Protein A chromatography. First, we found that for each model virus, removal by Protein A chromatography varies significantly across mAbs, while remains consistent within a specific mAb product, even across the acceptable ranges of the process parameters. In addition, our analysis revealed a correlation between retrovirus and parvovirus removal, with retrovirus data generally possessing a greater clearance factor. Finally, we describe a multivariate approach used to evaluate process parameter impacts on viral clearance, based on the levels of retrovirus-like particles (RVLP) present among process characterization study samples. It was shown that RVLP removal by Protein A is robust, that is, parameter effects were not observed across the ranges tested. Robustness of RVLP removal by Protein A also correlates with that for other model viruses such as X-MuLV, MMV, and SV40. The data supports that evaluating RVLP removal using process characterization study samples can establish multivariate acceptable ranges for virus removal by the protein A step for QbD. By measuring RVLP instead of a model retrovirus, it may alleviate some of the technical and economic challenges associated with performing large, design-of-experiment (DoE)—type virus spiking studies. This approach could also serve to provide useful insight when designing strategies to ensure viral safety in the manufacturing of a biopharmaceutical product. PMID:23860745

Continuous direct compression as manufacturing platform for sustained release tablets.

PubMed

Van Snick, B; Holman, J; Cunningham, C; Kumar, A; Vercruysse, J; De Beer, T; Remon, J P; Vervaet, C

2017-03-15

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution. Copyright © 2017 Elsevier B.V. All rights reserved.

76 FR 8362 - Agency Information Collection Activities; Submission to OMB for Review and Approval; Comment...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-14

..., Glass Manufacturing and Secondary Nonferrous Metals Processing Area Sources (Renewal) AGENCY... for Clay Ceramics Manufacturing, Glass Manufacturing and Secondary Nonferrous Metals Processing Area..., glass manufacturing, and secondary nonferrous metals processing area sources. Estimated Number of...

Towards fast, reliable, and manufacturable DEAs: miniaturized motor and Rupert the rolling robot

NASA Astrophysics Data System (ADS)

Rosset, Samuel; Shea, Herbert

2015-04-01

Dielectric elastomer transducers (DETs) are known for their large strains, low mass and high compliance, making them very attractive for a broad range of applications, from soft robotics to tuneable optics, or energy harvesting. However, 15 years after the first major paper in the field, commercial applications of the technology are still scarce, owing to high driving voltages, short lifetimes, slow response speed, viscoelastic drift, and no optimal solution for the compliant electrodes. At the EPFL's Microsystems for Space Technologies laboratory, we have been working on the miniaturization and manufacturability of DETs for the past 10 years. In the frame of this talk, we present our fabrication processes for high quality thin-_lm silicone membranes, and for patterning compliant electrodes on the sub mm-scale. We use either implantation of gold nano-clusters through a mask, or pad-printing of conductive rubber to precisely shape the electrodes on the dielectric membrane. Our electrodes are compliant, time stable and present strong adhesion to the membrane. The combination of low mechanical- loss elastomers with robust and precisely-defined electrodes allows for the fabrication of very fast actuators that exhibit a long lifetime. We present different applications of our DET fabrication process, such as a soft tuneable lens with a settling time smaller than 175 microseconds, a motor spinning at 1500 rpm, and a self-commutating rolling robot.

In-situ calibration of nonuniformity in infrared staring and modulated systems

NASA Astrophysics Data System (ADS)

Black, Wiley T.

Infrared cameras can directly measure the apparent temperature of objects, providing thermal imaging. However, the raw output from most infrared cameras suffers from a strong, often limiting noise source called nonuniformity. Manufacturing imperfections in infrared focal planes lead to high pixel-to-pixel sensitivity to electronic bias, focal plane temperature, and other effects. The resulting imagery can only provide useful thermal imaging after a nonuniformity calibration has been performed. Traditionally, these calibrations are performed by momentarily blocking the field of view with a at temperature plate or blackbody cavity. However because the pattern is a coupling of manufactured sensitivities with operational variations, periodic recalibration is required, sometimes on the order of tens of seconds. A class of computational methods called Scene-Based Nonuniformity Correction (SBNUC) has been researched for over 20 years where the nonuniformity calibration is estimated in digital processing by analysis of the video stream in the presence of camera motion. The most sophisticated SBNUC methods can completely and robustly eliminate the high-spatial frequency component of nonuniformity with only an initial reference calibration or potentially no physical calibration. I will demonstrate a novel algorithm that advances these SBNUC techniques to support all spatial frequencies of nonuniformity correction. Long-wave infrared microgrid polarimeters are a class of camera that incorporate a microscale per-pixel wire-grid polarizer directly affixed to each pixel of the focal plane. These cameras have the capability of simultaneously measuring thermal imagery and polarization in a robust integrated package with no moving parts. I will describe the necessary adaptations of my SBNUC method to operate on this class of sensor as well as demonstrate SBNUC performance in LWIR polarimetry video collected on the UA mall.

Establishment and validation of analytical reference panels for the standardization of quantitative BCR-ABL1 measurements on the international scale.

PubMed

White, Helen E; Hedges, John; Bendit, Israel; Branford, Susan; Colomer, Dolors; Hochhaus, Andreas; Hughes, Timothy; Kamel-Reid, Suzanne; Kim, Dong-Wook; Modur, Vijay; Müller, Martin C; Pagnano, Katia B; Pane, Fabrizio; Radich, Jerry; Cross, Nicholas C P; Labourier, Emmanuel

2013-06-01

Current guidelines for managing Philadelphia-positive chronic myeloid leukemia include monitoring the expression of the BCR-ABL1 (breakpoint cluster region/c-abl oncogene 1, non-receptor tyrosine kinase) fusion gene by quantitative reverse-transcription PCR (RT-qPCR). Our goal was to establish and validate reference panels to mitigate the interlaboratory imprecision of quantitative BCR-ABL1 measurements and to facilitate global standardization on the international scale (IS). Four-level secondary reference panels were manufactured under controlled and validated processes with synthetic Armored RNA Quant molecules (Asuragen) calibrated to reference standards from the WHO and the NIST. Performance was evaluated in IS reference laboratories and with non-IS-standardized RT-qPCR methods. For most methods, percent ratios for BCR-ABL1 e13a2 and e14a2 relative to ABL1 or BCR were robust at 4 different levels and linear over 3 logarithms, from 10% to 0.01% on the IS. The intraassay and interassay imprecision was <2-fold overall. Performance was stable across 3 consecutive lots, in multiple laboratories, and over a period of 18 months to date. International field trials demonstrated the commutability of the reagents and their accurate alignment to the IS within the intra- and interlaboratory imprecision of IS-standardized methods. The synthetic calibrator panels are robust, reproducibly manufactured, analytically calibrated to the WHO primary standards, and compatible with most BCR-ABL1 RT-qPCR assay designs. The broad availability of secondary reference reagents will further facilitate interlaboratory comparative studies and independent quality assessment programs, which are of paramount importance for worldwide standardization of BCR-ABL1 monitoring results and the optimization of current and new therapeutic approaches for chronic myeloid leukemia. © 2013 American Association for Clinical Chemistry.

Astrium Technological Roadmaps for the Next Generation of Launchers Challenges

NASA Astrophysics Data System (ADS)

Larnac, Guy

2014-06-01

Main requirement on Ariane 6 are robustness, overall ownership cost and environmental impacts. To be able to meet these requirements it's mandatory to modify our usual way of working and to think the development and qualification of technologies differently. Airbus Defence and Space in the domain of materials, technologies and structures proposes a vision which address these points declined at different level:- Selection of key metallic and composite technologies to reduce drastically the cost of manufacturing,- Implementation of robust and economical way of assembly, promoting adhesive bonding and innovative technologies- Introducing virtual testing approach coupled with advanced methods and process simulation- Introduction of in-line monitoring to reduce cost of control- Implementation of the design for environment methodology with life cycle analysis to support the choice of technologies and materials- Development of EADS common materials to get benefice of aeronautic supply chain and communalitiesTo be efficient it seems evident and mandatory to develop all these approaches in an integrated and coordinated way. Advanced technologies and methodologies are supported by a strong network of collaboration enabling the integration of upstream ideas and concepts. This network is not only focused on low TRL level. Within EADS divisions intensive collaboration is deployed in order to get synergies. On the other side it's also mandatory for reliability and obsolescence issues to take care and master the supply chain.Additive layer manufacturing and thermoplastic based composite are directly concerned by this problematic. We present how, in the domain of materials and structures, aeronautic materials are considered first and how the mechanism of common qualification shared within EADS is now developed.This vision is being implemented within Airbus Defence and Space, described and reported through roadmaps. These roadmaps are the core of Airbus defence and Space strategies for the incoming years.

A Process Management System for Networked Manufacturing

NASA Astrophysics Data System (ADS)

Liu, Tingting; Wang, Huifen; Liu, Linyan

With the development of computer, communication and network, networked manufacturing has become one of the main manufacturing paradigms in the 21st century. Under the networked manufacturing environment, there exist a large number of cooperative tasks susceptible to alterations, conflicts caused by resources and problems of cost and quality. This increases the complexity of administration. Process management is a technology used to design, enact, control, and analyze networked manufacturing processes. It supports efficient execution, effective management, conflict resolution, cost containment and quality control. In this paper we propose an integrated process management system for networked manufacturing. Requirements of process management are analyzed and architecture of the system is presented. And a process model considering process cost and quality is developed. Finally a case study is provided to explain how the system runs efficiently.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weston, Brian T.

This dissertation focuses on the development of a fully-implicit, high-order compressible ow solver with phase change. The work is motivated by laser-induced phase change applications, particularly by the need to develop large-scale multi-physics simulations of the selective laser melting (SLM) process in metal additive manufacturing (3D printing). Simulations of the SLM process require precise tracking of multi-material solid-liquid-gas interfaces, due to laser-induced melting/ solidi cation and evaporation/condensation of metal powder in an ambient gas. These rapid density variations and phase change processes tightly couple the governing equations, requiring a fully compressible framework to robustly capture the rapid density variations ofmore » the ambient gas and the melting/evaporation of the metal powder. For non-isothermal phase change, the velocity is gradually suppressed through the mushy region by a variable viscosity and Darcy source term model. The governing equations are discretized up to 4th-order accuracy with our reconstructed Discontinuous Galerkin spatial discretization scheme and up to 5th-order accuracy with L-stable fully implicit time discretization schemes (BDF2 and ESDIRK3-5). The resulting set of non-linear equations is solved using a robust Newton-Krylov method, with the Jacobian-free version of the GMRES solver for linear iterations. Due to the sti nes associated with the acoustic waves and thermal and viscous/material strength e ects, preconditioning the GMRES solver is essential. A robust and scalable approximate block factorization preconditioner was developed, which utilizes the velocity-pressure (vP) and velocity-temperature (vT) Schur complement systems. This multigrid block reduction preconditioning technique converges for high CFL/Fourier numbers and exhibits excellent parallel and algorithmic scalability on classic benchmark problems in uid dynamics (lid-driven cavity ow and natural convection heat transfer) as well as for laser-induced phase change problems in 2D and 3D.« less

Robust production of virus-like particles and monoclonal antibodies with geminiviral replicon vectors in lettuce

PubMed Central

Lai, Huafang; He, Junyun; Engle, Michael; Diamond, Michael S.; Chen, Qiang

2011-01-01

Summary Pharmaceutical protein production in plants has been greatly promoted by the development of viral-based vectors and transient expression systems. Tobacco and related Nicotiana species are currently the most common host plants for generation of plant-made pharmaceutical proteins (PMPs). Downstream processing of target PMPs from these plants, however, is hindered by potential technical and regulatory difficulties due to the presence of high levels of phenolics and toxic alkaloids. Here, we explored the use of lettuce, which grows quickly yet produces low levels of secondary metabolites, and viral vector-based transient expression systems to develop a robust PMP production platform. Our results showed that a geminiviral replicon system based on the bean yellow dwarf virus permits high-level expression in lettuce of virus-like particles (VLP) derived from the Norwalk virus capsid protein and therapeutic monoclonal antibodies (mAbs) against Ebola and West Nile viruses. These vaccine and therapeutic candidates can be readily purified from lettuce leaves with scalable processing methods while fully retaining functional activity. Furthermore, this study also demonstrated the feasibility of using commercially produced lettuce for high-level PMP production. This allows our production system to have access to unlimited quantities of inexpensive plant material for large-scale production. These results establish a new production platform for biological pharmaceutical agents that is effective, safe, low-cost, and amenable to large-scale manufacturing. PMID:21883868

Achieving continuous manufacturing for final dosage formation: challenges and how to meet them. May 20-21, 2014 Continuous Manufacturing Symposium.

PubMed

Byrn, Stephen; Futran, Maricio; Thomas, Hayden; Jayjock, Eric; Maron, Nicola; Meyer, Robert F; Myerson, Allan S; Thien, Michael P; Trout, Bernhardt L

2015-03-01

We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to continuous manufacturing. We also give the key motivations for moving to continuous manufacturing, some of the exciting new technologies, and the barriers to implementation of continuous manufacturing. Continuous processing of heterogeneous blends is the natural first step in converting existing batch processes to continuous. In heterogeneous processing, there are discrete particles that can segregate, versus in homogeneous processing, components are blended and homogenized such that they do not segregate. Heterogeneous processing can incorporate technologies that are closer to existing technologies, where homogeneous processing necessitates the development and incorporation of new technologies. Homogeneous processing has the greatest potential for reaping the full rewards of continuous manufacturing, but it takes long-term vision and a more significant change in process development than heterogeneous processing. Heterogeneous processing has the detriment that, as the technologies are adopted rather than developed, there is a strong tendency to incorporate correction steps, what we call below "The Rube Goldberg Problem." Thus, although heterogeneous processing will likely play a major role in the near-term transformation of heterogeneous to continuous processing, it is expected that homogeneous processing is the next step that will follow. Specific action items for industry leaders are: Form precompetitive partnerships, including industry (pharmaceutical companies and equipment manufacturers), government, and universities. These precompetitive partnerships would develop case studies of continuous manufacturing and ideally perform joint-technology development, including development of small-scale equipment and processes. Develop ways to invest internally in continuous manufacturing. How best to do this will depend on the specifics of a given organization, in particular the current development projects. Upper managers will need to energize their process developers to incorporate continuous manufacturing in at least part of their processes to gain experience and demonstrate directly the benefits. Training of continuous manufacturing technologies, organizational approaches, and regulatory approaches is a key area that industrial leaders should pursue together. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Harnessing the Potential of Additive Manufacturing

DTIC Science & Technology

2016-12-01

manufacturing age, which is dominated by standards for materials, processes and process control. Conventional manufacturing is based upon a design that is...documented either in a drawing or a computer-aided design (CAD) file. The manufacturing team then develops a docu- mented public or private process for...31 Defense AT&L: November-December 2016 Harnessing the Potential of Additive Manufacturing Bill Decker Decker is director of Technology

The Relationship of Skilled Aerospace Manufacturing Workforce Performance to Training

ERIC Educational Resources Information Center

Malsberry, Suzanne

2014-01-01

A major economic driver, the aerospace industry contributes to exports and higher wage jobs, which the United States requires to maintain robust economic health. Despite the investment in vocational educational training programs, insufficient workers have been available to aerospace companies. The purpose of this study was to investigate the…

76 FR 43983 - Request for Information on How To Structure Proposed New Program: Advanced Manufacturing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-22

... agenda most likely to achieve high rates of technological innovation. The goals of AMTech include...; Collapsing the time scale of technological innovation; Fostering a robust U.S. innovation system through... key players across the entire innovation lifecycle, AMTech consortia will work toward eliminating...

76 FR 40052 - Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-07

... Current Good Manufacturing 0910-AG10 Practice in Manufacturing, Processing, Packing or Holding Animal Food... in Manufacturing, Processing, Packing or Holding Animal Food Legal Authority: 21 U.S.C. 342; 21 U.S.C... constitute on farm manufacturing or processing of food that is not grown, raised, or consumed on a farm or...

Metabolic Control in Mammalian Fed-Batch Cell Cultures for Reduced Lactic Acid Accumulation and Improved Process Robustness

PubMed Central

Konakovsky, Viktor; Clemens, Christoph; Müller, Markus Michael; Bechmann, Jan; Berger, Martina; Schlatter, Stefan; Herwig, Christoph

2016-01-01

Biomass and cell-specific metabolic rates usually change dynamically over time, making the “feed according to need” strategy difficult to realize in a commercial fed-batch process. We here demonstrate a novel feeding strategy which is designed to hold a particular metabolic state in a fed-batch process by adaptive feeding in real time. The feed rate is calculated with a transferable biomass model based on capacitance, which changes the nutrient flow stoichiometrically in real time. A limited glucose environment was used to confine the cell in a particular metabolic state. In order to cope with uncertainty, two strategies were tested to change the adaptive feed rate and prevent starvation while in limitation: (i) inline pH and online glucose concentration measurement or (ii) inline pH alone, which was shown to be sufficient for the problem statement. In this contribution, we achieved metabolic control within a defined target range. The direct benefit was two-fold: the lactic acid profile was improved and pH could be kept stable. Multivariate Data Analysis (MVDA) has shown that pH influenced lactic acid production or consumption in historical data sets. We demonstrate that a low pH (around 6.8) is not required for our strategy, as glucose availability is already limiting the flux. On the contrary, we boosted glycolytic flux in glucose limitation by setting the pH to 7.4. This new approach led to a yield of lactic acid/glucose (Y L/G) around zero for the whole process time and high titers in our labs. We hypothesize that a higher carbon flux, resulting from a higher pH, may lead to more cells which produce more product. The relevance of this work aims at feeding mammalian cell cultures safely in limitation with a desired metabolic flux range. This resulted in extremely stable, low glucose levels, very robust pH profiles without acid/base interventions and a metabolic state in which lactic acid was consumed instead of being produced from day 1. With this contribution, we wish to extend the basic repertoire of available process control strategies, which will open up new avenues in automation technology and radically improve process robustness in both process development and manufacturing. PMID:28952567

Manufacturing Process Simulation of Large-Scale Cryotanks

NASA Technical Reports Server (NTRS)

Babai, Majid; Phillips, Steven; Griffin, Brian; Munafo, Paul M. (Technical Monitor)

2002-01-01

NASA's Space Launch Initiative (SLI) is an effort to research and develop the technologies needed to build a second-generation reusable launch vehicle. It is required that this new launch vehicle be 100 times safer and 10 times cheaper to operate than current launch vehicles. Part of the SLI includes the development of reusable composite and metallic cryotanks. The size of these reusable tanks is far greater than anything ever developed and exceeds the design limits of current manufacturing tools. Several design and manufacturing approaches have been formulated, but many factors must be weighed during the selection process. Among these factors are tooling reachability, cycle times, feasibility, and facility impacts. The manufacturing process simulation capabilities available at NASA's Marshall Space Flight Center have played a key role in down selecting between the various manufacturing approaches. By creating 3-D manufacturing process simulations, the varying approaches can be analyzed in a virtual world before any hardware or infrastructure is built. This analysis can detect and eliminate costly flaws in the various manufacturing approaches. The simulations check for collisions between devices, verify that design limits on joints are not exceeded, and provide cycle times which aid in the development of an optimized process flow. In addition, new ideas and concerns are often raised after seeing the visual representation of a manufacturing process flow. The output of the manufacturing process simulations allows for cost and safety comparisons to be performed between the various manufacturing approaches. This output helps determine which manufacturing process options reach the safety and cost goals of the SLI.

3D Printing, Additive Manufacturing, and Solid Freeform Fabrication: The Technologies of the Past, Present and Future

NASA Astrophysics Data System (ADS)

Beaman, Joseph

2015-03-01

Starting in the late 1980's, several new technologies were created that have the potential to revolutionize manufacturing. These technologies are, for the most part, additive processes that build up parts layer by layer. In addition, the processes that are being touted for hard-core manufacturing are primarily laser or e-beam based processes. This presentation gives a brief history of Additive Manufacturing and gives an assessment for these technologies. These technologies initially grew out of a commercial need for rapid prototyping. This market has a different requirement for process and quality control than traditional manufacturing. The relatively poor process control of the existing commercial Additive Manufacturing equipment is a vestige of this history. This presentation discusses this history and improvements in quality over time. The emphasis will be on Additive Manufacturing processes that are being considered for direct manufacturing, which is a different market than the 3D Printing ``Makerbot'' market. Topics discussed include past and present machine sensors, materials, and operational methods that were used in the past and those that are used today to create manufactured parts. Finally, a discussion of new methods and future directions of AM is presented.

Femtosecond Laser Fabrication of Cavity Microball Lens (CMBL) inside a PMMA Substrate for Super-Wide Angle Imaging.

PubMed

Zheng, Chong; Hu, Anming; Kihm, Kenneth D; Ma, Qian; Li, Ruozhou; Chen, Tao; Duley, W W

2015-07-01

Since microlenses have to date been fabricated primarily by surface manufacturing, they are highly susceptible to surface damage, and their microscale size makes it cumbersome to handle. Thus, cavity lenses are preferred, as they alleviate these difficulties associated with the surface-manufactured microlenses. Here, it is shown that a high repetition femtosecond laser can effectively fabricate cavity microball lenses (CMBLs) inside a polymethyl methacrylate slice. Optimal CMBL fabrication conditions are determined by examining the pertinent parameters, including the laser processing time, the average irradiation power, and the pulse repetition rates. In addition, a heat diffusion modeling is developed to better understand the formation of the spherical cavity and the slightly compressed affected zone surrounding the cavity. A micro-telescope consisting of a microscope objective and a CMBL demonstrates a super-wide field-of-view imaging capability. Finally, detailed optical characterizations of CMBLs are elaborated to account for the refractive index variations of the affected zone. The results presented in the current study demonstrate that a femtosecond laser-fabricated CMBL can be used for robust and super-wide viewing micro imaging applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evolutionary Technologies: Fundamentals and Applications to Information/Communication Systems and Manufacturing/Logistics Systems

NASA Astrophysics Data System (ADS)

Gen, Mitsuo; Kawakami, Hiroshi; Tsujimura, Yasuhiro; Handa, Hisashi; Lin, Lin; Okamoto, Azuma

As efficient utilization of computational resources is increasing, evolutionary technology based on the Genetic Algorithm (GA), Genetic Programming (GP), Evolution Strategy (ES) and other Evolutionary Computations (ECs) is making rapid progress, and its social recognition and the need as applied technology are increasing. This is explained by the facts that EC offers higher robustness for knowledge information processing systems, intelligent production and logistics systems, most advanced production scheduling and other various real-world problems compared to the approaches based on conventional theories, and EC ensures flexible applicability and usefulness for any unknown system environment even in a case where accurate mathematical modeling fails in the formulation. In this paper, we provide a comprehensive survey of the current state-of-the-art in the fundamentals and applications of evolutionary technologies.

Automation of extrusion of porous cable products based on a digital controller

NASA Astrophysics Data System (ADS)

Chostkovskii, B. K.; Mitroshin, V. N.

2017-07-01

This paper presents a new approach to designing an automated system for monitoring and controlling the process of applying porous insulation material on a conductive cable core, which is based on using structurally and parametrically optimized digital controllers of an arbitrary order instead of calculating typical PID controllers using known methods. The digital controller is clocked by signals from the clock length sensor of a measuring wheel, instead of a timer signal, and this provides the robust properties of the system with respect to the changing insulation speed. Digital controller parameters are tuned to provide the operating parameters of the manufactured cable using a simulation model of stochastic extrusion and are minimized by moving a regular simplex in the parameter space of the tuned controller.

40 CFR 63.149 - Control requirements for certain liquid streams in open systems within a chemical manufacturing...

Code of Federal Regulations, 2010 CFR

2010-07-01

... streams in open systems within a chemical manufacturing process unit. 63.149 Section 63.149 Protection of... open systems within a chemical manufacturing process unit. (a) The owner or operator shall comply with... Air Pollutants From the Synthetic Organic Chemical Manufacturing Industry for Process Vents, Storage...

19 CFR Appendix A to Part 191 - General Manufacturing Drawback Rulings

Code of Federal Regulations, 2014 CFR

2014-04-01

... drawback; and 9. Description of the manufacturing or production process, unless specifically described in...) and 55207(1) (see § 191.9 of this part). D. Process Of Manufacture Or Production The imported... it is first separated in the manufacturing process. 2. Appearing-in method The appearing in basis may...

19 CFR Appendix A to Part 191 - General Manufacturing Drawback Rulings

Code of Federal Regulations, 2013 CFR

2013-04-01

... drawback; and 9. Description of the manufacturing or production process, unless specifically described in...) and 55207(1) (see § 191.9 of this part). D. Process Of Manufacture Or Production The imported... it is first separated in the manufacturing process. 2. Appearing-in method The appearing in basis may...

19 CFR Appendix A to Part 191 - General Manufacturing Drawback Rulings

Code of Federal Regulations, 2011 CFR

2011-04-01

... drawback; and 9. Description of the manufacturing or production process, unless specifically described in...) and 55207(1) (see § 191.9 of this part). D. Process Of Manufacture Or Production The imported... it is first separated in the manufacturing process. 2. Appearing-in method The appearing in basis may...

19 CFR Appendix A to Part 191 - General Manufacturing Drawback Rulings

Code of Federal Regulations, 2012 CFR

2012-04-01

... drawback; and 9. Description of the manufacturing or production process, unless specifically described in...) and 55207(1) (see § 191.9 of this part). D. Process Of Manufacture Or Production The imported... it is first separated in the manufacturing process. 2. Appearing-in method The appearing in basis may...

Boosting Manufacturing through Modular Chemical Process Intensification

ScienceCinema

None

2018-06-12

Manufacturing USA's Rapid Advancement in Process Intensification Deployment Institute will focus on developing breakthrough technologies to boost domestic energy productivity and energy efficiency by 20 percent in five years through manufacturing processes.

Boosting Manufacturing through Modular Chemical Process Intensification

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2016-12-09

Manufacturing USA's Rapid Advancement in Process Intensification Deployment Institute will focus on developing breakthrough technologies to boost domestic energy productivity and energy efficiency by 20 percent in five years through manufacturing processes.

A novel rapid analysis using mass spectrometry to evaluate downstream refolding of recombinant human insulin-like growth factor-1 (mecasermin).

PubMed

Furuki, Kenichiro; Toyo'oka, Toshimasa; Yamaguchi, Hideto

2017-08-15

Mecasermin is used to treat elevated blood sugar as well as growth-hormone-resistant Laron-type dwarfism. Mecasermin isolated from inclusion bodies in extracts of E. coli must be refolded to acquire sufficient activity. However, there is no rapid analytical method for monitoring refolding during the purification process. We prepared mecasermin drug product, in-process samples during the oxidation of mecasermin, forced-reduced mecasermin, and aerially oxidized mecasermin after forced reduction. Desalted mecasermin samples were analyzed using MALDI-ISD. The peak intensity ratio of product to precursor ion was determined. The charge-state distribution (CSD) of mecasermin ions was evaluated using ESI-MS coupled with SEC-mode HPLC. The drift time and collision cross-sectional area (CCS) of mecasermin ions were evaluated using ESI-IMS-MS coupled with SEC-mode HPLC. MALDI-ISD data, CSD values determined using ESI-MS, and the CCS acquired using ESI-IMS-MS revealed the relationship between the folded and unfolded proteoforms of forced-reduced mecasermin and aerially oxidized mecasermin with the free-SH:protein ratio of mecasermin drug product. The CCS area, which is determined using ESI-IMS-MS, provided proteoform information through rapid monitoring (<2 min) of in-process samples during the manufacture of mecasermin. ESI-IMS-MS coupled with SEC-mode HPLC is a rapid and robust method for analyzing the free-SH:protein ratio of mecasermin that allows proteoform changes to be evaluated and monitored during the oxidation of mecasermin. ESI-IMS-MS is applicable as a process analytical technology tool for identifying the "critical quality attributes" and implementing "quality by design" for manufacturing mecasermin. Copyright © 2017 John Wiley & Sons, Ltd.

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing.

PubMed

Burcham, Christopher L; Florence, Alastair J; Johnson, Martin D

2018-06-07

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.

Potential of Continuous Manufacturing for Liposomal Drug Products.

PubMed

Worsham, Robert D; Thomas, Vaughan; Farid, Suzanne S

2018-05-21

Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits (e.g. improved economics, more consistent quality) that come with continuous processing. If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This paper reviews the current state of continuous manufacturing technology applicable to liposomal drug product manufacturing and an assessment of the challenges and potential of this application. This article is protected by copyright. All rights reserved.

21 CFR 801.122 - Medical devices for processing, repacking, or manufacturing.

Code of Federal Regulations, 2010 CFR

2010-04-01

....122 Medical devices for processing, repacking, or manufacturing. A device intended for processing... act if its label bears the statement “Caution: For manufacturing, processing, or repacking”. ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Medical devices for processing, repacking, or...

Advanced Material Strategies for Next-Generation Additive Manufacturing

PubMed Central

Chang, Jinke; He, Jiankang; Zhou, Wenxing; Lei, Qi; Li, Xiao; Li, Dichen

2018-01-01

Additive manufacturing (AM) has drawn tremendous attention in various fields. In recent years, great efforts have been made to develop novel additive manufacturing processes such as micro-/nano-scale 3D printing, bioprinting, and 4D printing for the fabrication of complex 3D structures with high resolution, living components, and multimaterials. The development of advanced functional materials is important for the implementation of these novel additive manufacturing processes. Here, a state-of-the-art review on advanced material strategies for novel additive manufacturing processes is provided, mainly including conductive materials, biomaterials, and smart materials. The advantages, limitations, and future perspectives of these materials for additive manufacturing are discussed. It is believed that the innovations of material strategies in parallel with the evolution of additive manufacturing processes will provide numerous possibilities for the fabrication of complex smart constructs with multiple functions, which will significantly widen the application fields of next-generation additive manufacturing. PMID:29361754

Advanced Material Strategies for Next-Generation Additive Manufacturing.

PubMed

Chang, Jinke; He, Jiankang; Mao, Mao; Zhou, Wenxing; Lei, Qi; Li, Xiao; Li, Dichen; Chua, Chee-Kai; Zhao, Xin

2018-01-22

Additive manufacturing (AM) has drawn tremendous attention in various fields. In recent years, great efforts have been made to develop novel additive manufacturing processes such as micro-/nano-scale 3D printing, bioprinting, and 4D printing for the fabrication of complex 3D structures with high resolution, living components, and multimaterials. The development of advanced functional materials is important for the implementation of these novel additive manufacturing processes. Here, a state-of-the-art review on advanced material strategies for novel additive manufacturing processes is provided, mainly including conductive materials, biomaterials, and smart materials. The advantages, limitations, and future perspectives of these materials for additive manufacturing are discussed. It is believed that the innovations of material strategies in parallel with the evolution of additive manufacturing processes will provide numerous possibilities for the fabrication of complex smart constructs with multiple functions, which will significantly widen the application fields of next-generation additive manufacturing.

The use of Tecnomatix software to simulate the manufacturing flows in an industrial enterprise producing hydrostatic components

NASA Astrophysics Data System (ADS)

Petrila, S.; Brabie, G.; Chirita, B.

2016-08-01

The analysis performed on manufacturing flows within industrial enterprises producing hydrostatic components twos made on a number of factors that influence smooth running of production such: distance between pieces, waiting time from one surgery to another; time achievement of setups on CNC machines; tool changing in case of a large number of operators and manufacturing complexity of large files [2]. To optimize the manufacturing flow it was used the software Tecnomatix. This software represents a complete portfolio of manufacturing solutions digital manufactured by Siemens. It provides innovation by linking all production methods of a product from process design, process simulation, validation and ending the manufacturing process. Among its many capabilities to create a wide range of simulations, the program offers various demonstrations regarding the behavior manufacturing cycles. This program allows the simulation and optimization of production systems and processes in several areas such as: car suppliers, production of industrial equipment; electronics manufacturing, design and production of aerospace and defense parts.

19 CFR Appendix B to Part 191 - Sample Formats for Applications for Specific Manufacturing Drawback Rulings

Code of Federal Regulations, 2010 CFR

2010-04-01

... (see § 191.8(a)).) LOCATION OF FACTORY (Give the address of the factory(s) where the process of... article described under the PROCESS OF MANUFACTURE OR PRODUCTION section below and each article listed... manufacture or production by giving a thorough description of the manufacturing process. This description...

Research on manufacturing service behavior modeling based on block chain theory

NASA Astrophysics Data System (ADS)

Zhao, Gang; Zhang, Guangli; Liu, Ming; Yu, Shuqin; Liu, Yali; Zhang, Xu

2018-04-01

According to the attribute characteristics of processing craft, the manufacturing service behavior is divided into service attribute, basic attribute, process attribute, resource attribute. The attribute information model of manufacturing service is established. The manufacturing service behavior information is successfully divided into public and private domain. Additionally, the block chain technology is introduced, and the information model of manufacturing service based on block chain principle is established, which solves the problem of sharing and secreting information of processing behavior, and ensures that data is not tampered with. Based on the key pairing verification relationship, the selective publishing mechanism for manufacturing information is established, achieving the traceability of product data, guarantying the quality of processing quality.

Alternatives for the intermediate recovery of plasmid DNA: performance, economic viability and environmental impact.

PubMed

Freitas, Sindelia; Canário, Sónia; Santos, José A L; Prazeres, Duarte M F

2009-02-01

Robust cGMP manufacturing is required to produce high-quality plasmid DNA (pDNA). Three established techniques, isopropanol and ammonium sulfate (AS) precipitation (PP), tangential flow filtration (TFF) and aqueous two-phase systems (ATPS) with PEG600/AS, were tested as alternatives to recover pDNA from alkaline lysates. Yield and purity data were used to evaluate the economic and environmental impact of each option. Although pDNA yields > or = 90% were always obtained, ATPS delivered the highest HPLC purity (59%), followed by PP (48%) and TFF (18%). However, the ability of ATPS to concentrate pDNA was very poor when compared with PP or TFF. Processes were also implemented by coupling TFF with ATPS or AS-PP. Process simulations indicate that all options require large amounts of water (100-200 tons/kg pDNA) and that the ATPS process uses large amounts of mass separating agents (65 tons/kg pDNA). Estimates indicate that operating costs of the ATPS process are 2.5-fold larger when compared with the PP and TFF processes. The most significant contributions to the costs in the PP, TFF and ATPS processes came from operators (59%), consumables (75%) and raw materials (84%), respectively. The ATPS process presented the highest environmental impact, whereas the impact of the TFF process was negligible.

27 CFR 40.525 - Discontinuance of operations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... operations. 40.525 Section 40.525 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... AND TUBES, AND PROCESSED TOBACCO Manufacture of Processed Tobacco Operations by Manufacturers of Processed Tobacco § 40.525 Discontinuance of operations. Every manufacturer of processed tobacco who desires...

Key technologies for manufacturing and processing sheet materials: A global perspective

NASA Astrophysics Data System (ADS)

Demeri, Mahmoud Y.

2001-02-01

Modern industrial technologies continue to seek new materials and processes to produce products that meet design and functional requirements. Sheet materials made from ferrous and non-ferrous metals, laminates, composites, and reinforced plastics constitute a large percentage of today’s products, components, and systems. Major manufacturers of sheet products include automotive, aerospace, appliance, and food-packaging industries. The Second Global Symposium on Innovations in Materials Processing & Manufacturing: Sheet Materials is organized to provide a forum for presenting advances in sheet processing and manufacturing by worldwide researchers and engineers from industrial, research, and academic centers. The symposium, sponsored by the TMS Materials Processing & Manufacturing Division (MPMD), was planned for the 2001 TMS Annual Meeting, New Orleans, Louisiana, February 11 15, 2001. This article is a review of key papers submitted for publication in the concurrent volume. The selected papers present significant developments in the rapidly expanding areas of advanced sheet materials, innovative forming methods, industrial applications, primary and secondary processing, composite processing, and numerical modeling of manufacturing processes.

Optimization evaluation of cutting technology based on mechanical parts

NASA Astrophysics Data System (ADS)

Wang, Yu

2018-04-01

The relationship between the mechanical manufacturing process and the carbon emission is studied on the basis of the process of the mechanical manufacturing process. The formula of carbon emission calculation suitable for mechanical manufacturing process is derived. Based on this, a green evaluation method for cold machining process of mechanical parts is proposed. The application verification and data analysis of the proposed evaluation method are carried out by an example. The results show that there is a great relationship between the mechanical manufacturing process data and carbon emissions.

Current manufacturing processes of drug-eluting sutures.

PubMed

Champeau, Mathilde; Thomassin, Jean-Michel; Tassaing, Thierry; Jérôme, Christine

2017-11-01

Drug-eluting sutures represent the next generation of surgical sutures since they fulfill their mechanical functions but also deliver the drug in their vicinity after implantation. These implants are produced by a variety of manufacturing processes. Drug-eluting sutures represent the next generation of surgical sutures since they fulfill their mechanical functions but also deliver the drug in their vicinity after implantation. These implants are produced by a variety of manufacturing processes. Two general approaches can be followed: (i) the ones that add the API into the material during the manufacturing process of the suture and (ii) the ones that load the API to an already manufactured suture. Areas covered: This review provides an overview of the current manufacturing processes for drug-eluting suture production and discusses their benefits and drawbacks depending on the type of drugs. The mechanical properties and the drug delivery profile of drug-eluting sutures are highlighted since these implants must fulfill both criteria. Expert opinion: For limited drug contents, melt extrusion and electrospinning are the emerging processes since the drug is added during the suture manufacture process. Advantageously, the drug release profile can be tuned by controlling the processing parameters specific to each process and the composition of the drug-containing polymer. If high drug content is targeted, the coating or grafting of a drug layer on a pre-manufactured suture allows for preservation of the tensile strength requirements of the suture.

Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey.

PubMed

Fortunak, Joseph M; de Souza, Rodrigo O M A; Kulkarni, Amol A; King, Christopher L; Ellison, Tiffany; Miranda, Leandro S M

2014-01-01

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President's Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent.

Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey

PubMed Central

Fortunak, Joseph M; de Souza, Rodrigo OMA; Kulkarni, Amol A; King, Christopher L; Ellison, Tiffany; Miranda, Leandro SM

2015-01-01

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President’s Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent. PMID:25310430

25 CFR 547.7 - What are the minimum technical hardware standards applicable to Class II gaming systems?

Code of Federal Regulations, 2013 CFR

2013-04-01

... or integrity of the game, and are specially manufactured or proprietary and not off-the-shelf, must... the potential to affect the outcome or integrity of any game, progressive award, financial instrument... of a robust construction designed to resist determined illegal entry. All protuberances and...

25 CFR 547.7 - What are the minimum technical hardware standards applicable to Class II gaming systems?

Code of Federal Regulations, 2014 CFR

2014-04-01

... or integrity of the game, and are specially manufactured or proprietary and not off-the-shelf, must... the potential to affect the outcome or integrity of any game, progressive award, financial instrument... of a robust construction designed to resist determined illegal entry. All protuberances and...

Orbiter lessons learned: A guide to future vehicle development

NASA Technical Reports Server (NTRS)

Greenberg, Harry Stan

1993-01-01

Topics addressed are: (1) wind persistence loads methodology; (2) emphasize supportability in design of reusable vehicles; (3) design for robustness; (4) improved aerodynamic environment prediction methods for complex vehicles; (5) automated integration of aerothermal, manufacturing, and structures analysis; (6) continued electronic documentation of structural design and analysis; and (7) landing gear rollout load simulations.

10 CFR Appendix A to Subpart C of... - Procedures, Interpretations and Policies for Consideration of New or Revised Energy Conservation...

Code of Federal Regulations, 2013 CFR

2013-01-01

... robust analytical methods. The Department seeks to use qualitative and quantitative analytical methods... uncertainties will be carried forward in subsequent analyses. The use of quantitative models will be... manufacturers and other interested parties. The use of quantitative models will be supplemented by qualitative...

10 CFR Appendix A to Subpart C of... - Procedures, Interpretations and Policies for Consideration of New or Revised Energy Conservation...

Code of Federal Regulations, 2012 CFR

2012-01-01

... robust analytical methods. The Department seeks to use qualitative and quantitative analytical methods... uncertainties will be carried forward in subsequent analyses. The use of quantitative models will be... manufacturers and other interested parties. The use of quantitative models will be supplemented by qualitative...

10 CFR Appendix A to Subpart C of... - Procedures, Interpretations and Policies for Consideration of New or Revised Energy Conservation...

Code of Federal Regulations, 2014 CFR

2014-01-01

... robust analytical methods. The Department seeks to use qualitative and quantitative analytical methods... uncertainties will be carried forward in subsequent analyses. The use of quantitative models will be... manufacturers and other interested parties. The use of quantitative models will be supplemented by qualitative...

75 FR 74773 - Mandatory Reporting of Greenhouse Gases: Additional Sources of Fluorinated GHGs

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-01

..., Methods for Estimating Air Emissions from Chemical Manufacturing Facilities; Protocol for Equipment Leak... chemical vapor deposition process (CVD) or other manufacturing processes use N 2 O. Production processes.... N 2 O emissions from chemical vapor deposition and other electronics manufacturing processes...

27 CFR 40.523 - Inventories.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Inventories. 40.523... PROCESSED TOBACCO Manufacture of Processed Tobacco Operations by Manufacturers of Processed Tobacco § 40.523 Inventories. Every manufacturer of processed tobacco must provide a true and accurate inventory on TTB F 5210...

Manufacturing Process Simulation of Large-Scale Cryotanks

NASA Technical Reports Server (NTRS)

Babai, Majid; Phillips, Steven; Griffin, Brian

2003-01-01

NASA's Space Launch Initiative (SLI) is an effort to research and develop the technologies needed to build a second-generation reusable launch vehicle. It is required that this new launch vehicle be 100 times safer and 10 times cheaper to operate than current launch vehicles. Part of the SLI includes the development of reusable composite and metallic cryotanks. The size of these reusable tanks is far greater than anything ever developed and exceeds the design limits of current manufacturing tools. Several design and manufacturing approaches have been formulated, but many factors must be weighed during the selection process. Among these factors are tooling reachability, cycle times, feasibility, and facility impacts. The manufacturing process simulation capabilities available at NASA.s Marshall Space Flight Center have played a key role in down selecting between the various manufacturing approaches. By creating 3-D manufacturing process simulations, the varying approaches can be analyzed in a virtual world before any hardware or infrastructure is built. This analysis can detect and eliminate costly flaws in the various manufacturing approaches. The simulations check for collisions between devices, verify that design limits on joints are not exceeded, and provide cycle times which aide in the development of an optimized process flow. In addition, new ideas and concerns are often raised after seeing the visual representation of a manufacturing process flow. The output of the manufacturing process simulations allows for cost and safety comparisons to be performed between the various manufacturing approaches. This output helps determine which manufacturing process options reach the safety and cost goals of the SLI. As part of the SLI, The Boeing Company was awarded a basic period contract to research and propose options for both a metallic and a composite cryotank. Boeing then entered into a task agreement with the Marshall Space Flight Center to provide manufacturing simulation support. This paper highlights the accomplishments of this task agreement, while also introducing the capabilities of simulation software.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wiebenga, J. H.; Atzema, E. H.; Boogaard, A. H. van den

Robust design of forming processes using numerical simulations is gaining attention throughout the industry. In this work, it is demonstrated how robust optimization can assist in further stretching the limits of metal forming processes. A deterministic and a robust optimization study are performed, considering a stretch-drawing process of a hemispherical cup product. For the robust optimization study, both the effect of material and process scatter are taken into account. For quantifying the material scatter, samples of 41 coils of a drawing quality forming steel have been collected. The stochastic material behavior is obtained by a hybrid approach, combining mechanical testingmore » and texture analysis, and efficiently implemented in a metamodel based optimization strategy. The deterministic and robust optimization results are subsequently presented and compared, demonstrating an increased process robustness and decreased number of product rejects by application of the robust optimization approach.« less

40 CFR 63.101 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... chemical that is produced coincidentally during the production of another chemical. Chemical manufacturing... manufacture an intended product. A chemical manufacturing process unit consists of more than one unit... ethylene process does not include the manufacture of SOCMI chemicals such as the production of butadiene...

Microstructure characterisation of Ti-6Al-4V from different additive manufacturing processes

NASA Astrophysics Data System (ADS)

Neikter, M.; Åkerfeldt, P.; Pederson, R.; Antti, M.-L.

2017-10-01

The focus of this work has been microstructure characterisation of Ti-6Al-4V manufactured by five different additive manufacturing (AM) processes. The microstructure features being characterised are the prior β size, grain boundary α and α lath thickness. It was found that material manufactured with powder bed fusion processes has smaller prior β grains than the material from directed energy deposition processes. The AM processes with fast cooling rate render in thinner α laths and also thinner, and in some cases discontinuous, grain boundary α. Furthermore, it has been observed that material manufactured with the directed energy deposition processes has parallel bands, except for one condition when the parameters were changed, while the powder bed fusion processes do not have any parallel bands.

Automated and inexpensive method to manufacture solid- state nanopores and micropores in robust silicon wafers

NASA Astrophysics Data System (ADS)

Vega, M.; Granell, P.; Lasorsa, C.; Lerner, B.; Perez, M.

2016-02-01

In this work an easy, reproducible and inexpensive technique for the production of solid state nanopores and micropores using silicon wafer substrate is proposed. The technique is based on control of pore formation, by neutralization etchant (KOH) with a strong acid (HCl). Thus, a local neutralization is produced around the nanopore, which stops the silicon etching. The etching process was performed with 7M KOH at 80°C, where 1.23µm/min etching speed was obtained, similar to those published in literature. The control of the pore formation with the braking acid method was done using 12M HCl and different extreme conditions: i) at 25°C, ii) at 80°C and iii) at 80°C applying an electric potential. In these studies, it was found that nanopores and micropores can be obtained automatically and at a low cost. Additionally, the process was optimized to obtain clean silicon wafers after the pore fabrication process. This method opens the possibility for an efficient scale-up from laboratory production.

An RFID-Based Manufacturing Control Framework for Loosely Coupled Distributed Manufacturing System Supporting Mass Customization

NASA Astrophysics Data System (ADS)

Chen, Ruey-Shun; Tsai, Yung-Shun; Tu, Arthur

In this study we propose a manufacturing control framework based on radio-frequency identification (RFID) technology and a distributed information system to construct a mass-customization production process in a loosely coupled shop-floor control environment. On the basis of this framework, we developed RFID middleware and an integrated information system for tracking and controlling the manufacturing process flow. A bicycle manufacturer was used to demonstrate the prototype system. The findings of this study were that the proposed framework can improve the visibility and traceability of the manufacturing process as well as enhance process quality control and real-time production pedigree access. Using this framework, an enterprise can easily integrate an RFID-based system into its manufacturing environment to facilitate mass customization and a just-in-time production model.

Clinical-Grade Manufacturing of Therapeutic Human Mesenchymal Stem/Stromal Cells in Microcarrier-Based Culture Systems.

PubMed

Fernandes-Platzgummer, Ana; Carmelo, Joana G; da Silva, Cláudia Lobato; Cabral, Joaquim M S

2016-01-01

The therapeutic potential of mesenchymal stem/stromal cells (MSC) has triggered the need for high cell doses in a vast number of clinical applications. This demand requires the development of good manufacturing practices (GMP)-compliant ex vivo expansion protocols that should be effective to deliver a robust and reproducible supply of clinical-grade cells in a safe and cost-effective manner. Controlled stirred-tank bioreactor systems under xenogeneic (xeno)-free culture conditions offer ideal settings to develop and optimize cell manufacturing to meet the standards and needs of human MSC for cellular therapies. Herein we describe two microcarrier-based stirred culture systems using spinner flasks and controlled stirred-tank bioreactors under xeno-free conditions for the efficient ex vivo expansion of human bone marrow and adipose tissue-derived MSC.

Multiobjective robust design of the double wishbone suspension system based on particle swarm optimization.

PubMed

Cheng, Xianfu; Lin, Yuqun

2014-01-01

The performance of the suspension system is one of the most important factors in the vehicle design. For the double wishbone suspension system, the conventional deterministic optimization does not consider any deviations of design parameters, so design sensitivity analysis and robust optimization design are proposed. In this study, the design parameters of the robust optimization are the positions of the key points, and the random factors are the uncertainties in manufacturing. A simplified model of the double wishbone suspension is established by software ADAMS. The sensitivity analysis is utilized to determine main design variables. Then, the simulation experiment is arranged and the Latin hypercube design is adopted to find the initial points. The Kriging model is employed for fitting the mean and variance of the quality characteristics according to the simulation results. Further, a particle swarm optimization method based on simple PSO is applied and the tradeoff between the mean and deviation of performance is made to solve the robust optimization problem of the double wishbone suspension system.

Impact of mechanism vibration characteristics by joint clearance and optimization design of its multi-objective robustness

NASA Astrophysics Data System (ADS)

Zeng, Baoping; Wang, Chao; Zhang, Yu; Gong, Yajun; Hu, Sanbao

2017-12-01

Joint clearances and friction characteristics significantly influence the mechanism vibration characteristics; for example: as for joint clearances, the shaft and bearing of its clearance joint collide to bring about the dynamic normal contact force and tangential coulomb friction force while the mechanism works; thus, the whole system may vibrate; moreover, the mechanism is under contact-impact with impact force constraint from free movement under action of the above dynamic forces; in addition, the mechanism topology structure also changes. The constraint relationship between joints may be established by a repeated complex nonlinear dynamic process (idle stroke - contact-impact - elastic compression - rebound - impact relief - idle stroke movement - contact-impact). Analysis of vibration characteristics of joint parts is still a challenging open task by far. The dynamic equations for any mechanism with clearance is often a set of strong coupling, high-dimensional and complex time-varying nonlinear differential equations which are solved very difficultly. Moreover, complicated chaotic motions very sensitive to initial values in impact and vibration due to clearance let high-precision simulation and prediction of their dynamic behaviors be more difficult; on the other hand, their subsequent wearing necessarily leads to some certain fluctuation of structure clearance parameters, which acts as one primary factor for vibration of the mechanical system. A dynamic model was established to the device for opening the deepwater robot cabin door with joint clearance by utilizing the finite element method and analysis was carried out to its vibration characteristics in this study. Moreover, its response model was carried out by utilizing the DOE method and then the robust optimization design was performed to sizes of the joint clearance and the friction coefficient change range so that the optimization design results may be regarded as reference data for selecting bearings and controlling manufacturing process parameters for the opening mechanism. Several optimization objectives such as x/y/z accelerations for various measuring points and dynamic reaction forces of mounting brackets, and a few constraints including manufacturing process were taken into account in the optimization models, which were solved by utilizing the multi-objective genetic algorithm (NSGA-II). The vibration characteristics of the optimized opening mechanism are superior to those of the original design. In addition, the numerical forecast results are in good agreement with the test results of the prototype.

Characterization of Machine Variability and Progressive Heat Treatment in Selective Laser Melting of Inconel 718

NASA Technical Reports Server (NTRS)

Prater, T.; Tilson, W.; Jones, Z.

2015-01-01

The absence of an economy of scale in spaceflight hardware makes additive manufacturing an immensely attractive option for propulsion components. As additive manufacturing techniques are increasingly adopted by government and industry to produce propulsion hardware in human-rated systems, significant development efforts are needed to establish these methods as reliable alternatives to conventional subtractive manufacturing. One of the critical challenges facing powder bed fusion techniques in this application is variability between machines used to perform builds. Even with implementation of robust process controls, it is possible for two machines operating at identical parameters with equivalent base materials to produce specimens with slightly different material properties. The machine variability study presented here evaluates 60 specimens of identical geometry built using the same parameters. 30 samples were produced on machine 1 (M1) and the other 30 samples were built on machine 2 (M2). Each of the 30-sample sets were further subdivided into three subsets (with 10 specimens in each subset) to assess the effect of progressive heat treatment on machine variability. The three categories for post-processing were: stress relief, stress relief followed by hot isostatic press (HIP), and stress relief followed by HIP followed by heat treatment per AMS 5664. Each specimen (a round, smooth tensile) was mechanically tested per ASTM E8. Two formal statistical techniques, hypothesis testing for equivalency of means and one-way analysis of variance (ANOVA), were applied to characterize the impact of machine variability and heat treatment on six material properties: tensile stress, yield stress, modulus of elasticity, fracture elongation, and reduction of area. This work represents the type of development effort that is critical as NASA, academia, and the industrial base work collaboratively to establish a path to certification for additively manufactured parts. For future flight programs, NASA and its commercial partners will procure parts from vendors who will use a diverse range of machines to produce parts and, as such, it is essential that the AM community develop a sound understanding of the degree to which machine variability impacts material properties.

Lessons from pandemic influenza A(H1N1): the research-based vaccine industry's perspective.

PubMed

Abelin, Atika; Colegate, Tony; Gardner, Stephen; Hehme, Norbert; Palache, Abraham

2011-02-01

As A(H1N1) influenza enters the post-pandemic phase, health authorities around the world are reviewing the response to the pandemic. To ensure this process enhances future preparations, it is essential that perspectives are included from all relevant stakeholders, including vaccine manufacturers. This paper outlines the contribution of R&D-based influenza vaccine producers to the pandemic response, and explores lessons that can be learned to improve future preparedness. The emergence of 2009 A(H1N1) influenza led to unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade. During this period, manufacturers greatly increased influenza vaccine production capacity, and estimates suggest a further doubling of capacity by 2014. Producers also introduced cell-culture technology, while adjuvant and whole virion technologies significantly reduced pandemic vaccine antigen content. This substantially increased pandemic vaccine production capacity, which in July 2009 WHO estimated reached 4.9 billion doses per annum. Manufacturers also worked with health authorities to establish risk management plans for robust vaccine surveillance during the pandemic. Individual producers pledged significant donations of vaccine doses and tiered-pricing approaches for developing country supply. Based on the pandemic experience, a number of improvements would strengthen future preparedness. Technical improvements to rapidly select optimal vaccine viruses, and processes to speed up vaccine standardization, could accelerate and extend vaccine availability. Establishing vaccine supply agreements beforehand would avoid the need for complex discussions during a period of intense time pressure. Enhancing international regulatory co-operation and mutual recognition of approvals could accelerate vaccine supply, while maintaining safety standards. Strengthening communications with the public and healthcare workers using new approaches and new channels could help improve vaccine uptake. Finally, increasing seasonal vaccine coverage will be particularly important to extend and sustain pandemic vaccine production capacity. Copyright © 2010 Elsevier Ltd. All rights reserved.

Direct Immersion Annealing of Thin Block Copolymer Films.

PubMed

Modi, Arvind; Bhaway, Sarang M; Vogt, Bryan D; Douglas, Jack F; Al-Enizi, Abdullah; Elzatahry, Ahmed; Sharma, Ashutosh; Karim, Alamgir

2015-10-07

We demonstrate ordering of thin block copolymer (BCP) films via direct immersion annealing (DIA) at enhanced rate leading to stable morphologies. The BCP films are immersed in carefully selected mixtures of good and marginal solvents that can impart enhanced polymer mobility, while inhibiting film dissolution. DIA is compatible with roll-to-roll assembly manufacturing and has distinct advantages over conventional thermal annealing and batch processing solvent-vapor annealing methods. We identify three solvent composition-dependent BCP film ordering regimes in DIA for the weakly interacting polystyrene-poly(methyl methacrylate) (PS-PMMA) system: rapid short-range order, optimal long-range order, and a film instability regime. Kinetic studies in the "optimal long-range order" processing regime as a function of temperature indicate a significant reduction of activation energy for BCP grain growth compared to oven annealing at conventional temperatures. An attractive feature of DIA is its robustness to ordering other BCP (e.g. PS-P2VP) and PS-PMMA systems exhibiting spherical, lamellar and cylindrical ordering.

The reliability and stability of multijunction amorphous silicon PV modules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carlson, D.E.

1995-11-01

Solarex is developing a manufacturing process for the commercial production of 8 ft{sup 2} multijunction amorphous silicon (a-Si) PV modules starting in 1996. The device structure used in these multijunction modules is: glass/textured tin oxide/p-i-n/p-i-n/ZnO/Al/EVA/Tedlar where the back junction of the tandem structure contains an amorphous silicon germanium alloy. As an interim step, 4 ft{sup 2} multijunction modules have been fabricated in a pilot production mode over the last several months. The distribution of initial conversion efficiencies for an engineering run of 67 modules (4 ft{sup 2}) is shown. Measurements recently performed at NREL indicate that the actual efficiencies aremore » about 5% higher than those shown, and thus exhibit an average initial conversion efficiency of about 9.5%. The data indicates that the process is relatively robust since there were no modules with initial efficiencies less than 7.5%.« less

Direct Immersion Annealing of Thin Block Copolymer Films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Modi, Arvind; Bhaway, Sarang M.; Vogt, Bryan D.

2015-09-09

We demonstrate ordering of thin block copolymer (BCP) films via direct immersion annealing (DIA) at enhanced rate leading to stable morphologies. The BCP films are immersed in carefully selected mixtures of good and marginal solvents that can impart enhanced polymer mobility, while inhibiting film dissolution. DIA is compatible with roll-to-roll assembly manufacturing and has distinct advantages over conventional thermal annealing and batch processing solvent-vapor annealing methods. We identify three solvent composition-dependent BCP film ordering regimes in DIA for the weakly interacting polystyrene–poly(methyl methacrylate) (PS–PMMA) system: rapid short-range order, optimal long-range order, and a film instability regime. Kinetic studies in themore » “optimal long-range order” processing regime as a function of temperature indicate a significant reduction of activation energy for BCP grain growth compared to oven annealing at conventional temperatures. An attractive feature of DIA is its robustness to ordering other BCP (e.g. PS-P2VP) and PS-PMMA systems exhibiting spherical, lamellar and cylindrical ordering.« less

Machine vision 1992-1996: technology program to promote research and its utilization in industry

NASA Astrophysics Data System (ADS)

Soini, Antti J.

1994-10-01

Machine vision technology has got a strong interest in Finnish research organizations, which is resulting in many innovative products to industry. Despite this end users were very skeptical towards machine vision and its robustness for harsh industrial environments. Therefore Technology Development Centre, TEKES, who funds technology related research and development projects in universities and individual companies, decided to start a national technology program, Machine Vision 1992 - 1996. Led by industry the program boosts research in machine vision technology and seeks to put the research results to work in practical industrial applications. The emphasis is in nationally important, demanding applications. The program will create new industry and business for machine vision producers and encourage the process and manufacturing industry to take advantage of this new technology. So far 60 companies and all major universities and research centers are working on our forty different projects. The key themes that we have are process control, robot vision and quality control.

Manufacturing of GLARE Parts and Structures

NASA Astrophysics Data System (ADS)

Sinke, J.

2003-07-01

GLARE is a hybrid material consisting of alternating layers of metal sheets and composite layers, requiring special attention when manufacturing of parts and structures is concerned. On one hand the applicable manufacturing processes for GLARE are limited, on the other hand, due to the constituents and composition of the laminate, it offers new opportunities for production. One of the opportunities is the manufacture of very large skin panels by lay-up techniques. Lay-up techniques are common for full composites, but uncommon for metallic structures. Nevertheless, large GLARE skin panels are made by lay-up processes. In addition, the sequences of forming and laminating processes, that can be selected, offer manufacturing options that are not applicable to metals or full composites. With respect to conventional manufacturing processes, the possibilities for Fibre Metal Laminates in general, are limited. The limits are partly due to the different failure modes, partly due to the properties of the constituents in the laminate. For machining processes: the wear of the cutting tools during machining operations of GLARE stems from the abrasive nature of the glass fibres. For the forming processes: the limited formability, expressed by a small failure strain, is related to the glass fibres. However, although these manufacturing issues may restrict the use of manufacturing processes for FMLs, application of these laminates in aircraft is not hindered.

Numerical simulation of complex part manufactured by selective laser melting process

NASA Astrophysics Data System (ADS)

Van Belle, Laurent

2017-10-01

Selective Laser Melting (SLM) process belonging to the family of the Additive Manufacturing (AM) technologies, enable to build parts layer by layer, from metallic powder and a CAD model. Physical phenomena that occur in the process have the same issues as conventional welding. Thermal gradients generate significant residual stresses and distortions in the parts. Moreover, the large and complex parts to manufacturing, accentuate the undesirable effects. Therefore, it is essential for manufacturers to offer a better understanding of the process and to ensure production reliability of parts with high added value. This paper focuses on the simulation of manufacturing turbine by SLM process in order to calculate residual stresses and distortions. Numerical results will be presented.

Free-world microelectronic manufacturing equipment

NASA Astrophysics Data System (ADS)

Kilby, J. S.; Arnold, W. H.; Booth, W. T.; Cunningham, J. A.; Hutcheson, J. D.; Owen, R. W.; Runyan, W. R.; McKenney, Barbara L.; McGrain, Moira; Taub, Renee G.

1988-12-01

Equipment is examined and evaluated for the manufacture of microelectronic integrated circuit devices and sources for that equipment within the Free World. Equipment suitable for the following are examined: single-crystal silicon slice manufacturing and processing; required lithographic processes; wafer processing; device packaging; and test of digital integrated circuits. Availability of the equipment is also discussed, now and in the near future. Very adequate equipment for most stages of the integrated circuit manufacturing process is available from several sources, in different countries, although the best and most widely used versions of most manufacturing equipment are made in the United States or Japan. There is also an active market in used equipment, suitable for manufacture of capable integrated circuits with performance somewhat short of the present state of the art.

77 FR 48992 - Tobacco Product Manufacturing Facility Visits

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-15

... manufacturing operations--from the receipt of raw materials to the distribution of finished products, and Learn... Manufacturing facilities for materials used for further processing in finished tobacco products (including, but..., parts, accessories, and Manufacturers of materials used for further processing in finished tobacco...

At-line process analytical technology (PAT) for more efficient scale up of biopharmaceutical microfiltration unit operations.

PubMed

Watson, Douglas S; Kerchner, Kristi R; Gant, Sean S; Pedersen, Joseph W; Hamburger, James B; Ortigosa, Allison D; Potgieter, Thomas I

2016-01-01

Tangential flow microfiltration (MF) is a cost-effective and robust bioprocess separation technique, but successful full scale implementation is hindered by the empirical, trial-and-error nature of scale-up. We present an integrated approach leveraging at-line process analytical technology (PAT) and mass balance based modeling to de-risk MF scale-up. Chromatography-based PAT was employed to improve the consistency of an MF step that had been a bottleneck in the process used to manufacture a therapeutic protein. A 10-min reverse phase ultra high performance liquid chromatography (RP-UPLC) assay was developed to provide at-line monitoring of protein concentration. The method was successfully validated and method performance was comparable to previously validated methods. The PAT tool revealed areas of divergence from a mass balance-based model, highlighting specific opportunities for process improvement. Adjustment of appropriate process controls led to improved operability and significantly increased yield, providing a successful example of PAT deployment in the downstream purification of a therapeutic protein. The general approach presented here should be broadly applicable to reduce risk during scale-up of filtration processes and should be suitable for feed-forward and feed-back process control. © 2015 American Institute of Chemical Engineers.

Essential Aspects in Assessing the Safety Impact of Interactions between a Drug Product and Its Associated Manufacturing System.

PubMed

Jenke, Dennis

2012-01-01

An emerging trend in the biotechnology industry is the utilization of plastic components in manufacturing systems for the production of an active pharmaceutical ingredient (API) or a finished drug product (FDP). If the API, the FDP, or any solution used to generate them (for example, process streams such as media, buffers, and the like) come in contact with a plastic at any time during the manufacturing process, there is the potential that substances leached from the plastic may accumulate in the API or FDP, affecting safety and/or efficacy. In this article the author develops a terminology that addresses process streams associated with the manufacturing process. Additionally, the article outlines the safety assessment process for manufacturing systems, specifically addressing the topics of risk management and the role of compendial testing. Finally, the proper use of vendor-supplied extractables information is considered. Manufacturing suites used to produce biopharmaceuticals can include components that are made out of plastics. Thus it is possible that substances could leach out of the plastics and into manufacturing solutions, and it is further possible that such leachables could accumulate in the pharmaceutical product. In this article, the author develops a terminology that addresses process streams associated with the manufacturing process. Additionally, the author proposes a process by which the impact on product safety of such leached substances can be assessed.

Agile manufacturing: The factory of the future

NASA Technical Reports Server (NTRS)

Loibl, Joseph M.; Bossieux, Terry A.

1994-01-01

The factory of the future will require an operating methodology which effectively utilizes all of the elements of product design, manufacturing and delivery. The process must respond rapidly to changes in product demand, product mix, design changes or changes in the raw materials. To achieve agility in a manufacturing operation, the design and development of the manufacturing processes must focus on customer satisfaction. Achieving greatest results requires that the manufacturing process be considered from product concept through sales. This provides the best opportunity to build a quality product for the customer at a reasonable rate. The primary elements of a manufacturing system include people, equipment, materials, methods and the environment. The most significant and most agile element in any process is the human resource. Only with a highly trained, knowledgeable work force can the proper methods be applied to efficiently process materials with machinery which is predictable, reliable and flexible. This paper discusses the affect of each element on the development of agile manufacturing systems.

21 CFR 110.80 - Processes and controls.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HUMAN CONSUMPTION CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PACKING, OR HOLDING HUMAN FOOD Production and Process Controls § 110.80 Processes and controls. All operations in the receiving, inspecting, transporting, segregating, preparing, manufacturing, packaging, and storing of food shall be conducted in...

Automotive Manufacturing Processes. Volume II - Manufacturing Processes for Passive Restraint Systems

DOT National Transportation Integrated Search

1981-02-01

Extensive material substitution and resizing of the domestic automotive fleet, as well as the introduction of new technologies, will require major changes in the techniques and equipment used in the various manufacturing processes employed in the pro...

The use of 'Omics technology to rationally improve industrial mammalian cell line performance.

PubMed

Lewis, Amanda M; Abu-Absi, Nicholas R; Borys, Michael C; Li, Zheng Jian

2016-01-01

Biologics represent an increasingly important class of therapeutics, with 7 of the 10 top selling drugs from 2013 being in this class. Furthermore, health authority approval of biologics in the immuno-oncology space is expected to transform treatment of patients with debilitating and deadly diseases. The growing importance of biologics in the healthcare field has also resulted in the recent approvals of several biosimilars. These recent developments, combined with pressure to provide treatments at lower costs to payers, are resulting in increasing need for the industry to quickly and efficiently develop high yielding, robust processes for the manufacture of biologics with the ability to control quality attributes within narrow distributions. Achieving this level of manufacturing efficiency and the ability to design processes capable of regulating growth, death and other cellular pathways through manipulation of media, feeding strategies, and other process parameters will undoubtedly be facilitated through systems biology tools generated in academic and public research communities. Here we discuss the intersection of systems biology, 'Omics technologies, and mammalian bioprocess sciences. Specifically, we address how these methods in conjunction with traditional monitoring techniques represent a unique opportunity to better characterize and understand host cell culture state, shift from an empirical to rational approach to process development and optimization of bioreactor cultivation processes. We summarize the following six key areas: (i) research applied to parental, non-recombinant cell lines; (ii) systems level datasets generated with recombinant cell lines; (iii) datasets linking phenotypic traits to relevant biomarkers; (iv) data depositories and bioinformatics tools; (v) in silico model development, and (vi) examples where these approaches have been used to rationally improve cellular processes. We critically assess relevant and state of the art research being conducted in academic, government and industrial laboratories. Furthermore, we apply our expertise in bioprocess to define a potential model for integration of these systems biology approaches into biologics development. © 2015 Wiley Periodicals, Inc.

40 CFR 98.70 - Definition of source category.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.70 Definition of source category. The ammonia manufacturing source category comprises the process units listed in paragraphs (a) and (b) of this section. (a) Ammonia manufacturing processes in which ammonia is manufactured from a fossil...

40 CFR 98.70 - Definition of source category.

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.70 Definition of source category. The ammonia manufacturing source category comprises the process units listed in paragraphs (a) and (b) of this section. (a) Ammonia manufacturing processes in which ammonia is manufactured from a fossil...

40 CFR 98.70 - Definition of source category.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.70 Definition of source category. The ammonia manufacturing source category comprises the process units listed in paragraphs (a) and (b) of this section. (a) Ammonia manufacturing processes in which ammonia is manufactured from a fossil...

40 CFR 98.70 - Definition of source category.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.70 Definition of source category. The ammonia manufacturing source category comprises the process units listed in paragraphs (a) and (b) of this section. (a) Ammonia manufacturing processes in which ammonia is manufactured from a fossil...

40 CFR 98.70 - Definition of source category.

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.70 Definition of source category. The ammonia manufacturing source category comprises the process units listed in paragraphs (a) and (b) of this section. (a) Ammonia manufacturing processes in which ammonia is manufactured from a fossil...

Assessment of low-cost manufacturing process sequences. [photovoltaic solar arrays

NASA Technical Reports Server (NTRS)

Chamberlain, R. G.

1979-01-01

An extensive research and development activity to reduce the cost of manufacturing photovoltaic solar arrays by a factor of approximately one hundred is discussed. Proposed and actual manufacturing process descriptions were compared to manufacturing costs. An overview of this methodology is presented.

Final Air Toxics Standards for Clay Ceramics Manufacturing, Glass Manufacturing, and Secondary Nonferrous Metals Processing Area Sources Fact Sheet

EPA Pesticide Factsheets

This page contains a December 2007 fact sheet with information regarding the National Emissions Standards for Hazardous Air Pollutants (NESHAP) for Clay Ceramics Manufacturing, Glass Manufacturing, and Secondary Nonferrous Metals Processing Area Sources

Space Manufacturing: The Next Great Challenge

NASA Technical Reports Server (NTRS)

Whitaker, Ann F.; Curreri, Peter; Sharpe, Jonathan B.; Colberg, Wendell R.; Vickers, John H.

1998-01-01

Space manufacturing encompasses the research, development and manufacture necessary for the production of any product to be used in near zero gravity, and the production of spacecraft required for transporting research or production devices to space. Manufacturing for space, and manufacturing in space will require significant breakthroughs in materials and manufacturing technology, as well as in equipment designs. This report reviews some of the current initiatives in achieving space manufacturing. The first initiative deals with materials processing in space, e.g., processing non-terrestrial and terrestrial materials, especially metals. Some of the ramifications of the United States Microgravity Payloads fourth (USMP-4) mission are discussed. Some problems in non-terrestrial materials processing are mentioned. The second initiative is structures processing in space. In order to accomplish this, the International Space Welding Experiment was designed to demonstrate welding technology in near-zero gravity. The third initiative is advancements in earth-based manufacturing technologies necessary to achieve low cost access to space. The advancements discussed include development of lightweight material having high specific strength, and automated fabrication and manufacturing methods for these materials.

A risk-based auditing process for pharmaceutical manufacturers.

PubMed

Vargo, Susan; Dana, Bob; Rangavajhula, Vijaya; Rönninger, Stephan

2014-01-01

The purpose of this article is to share ideas on developing a risk-based model for the scheduling of audits (both internal and external). Audits are a key element of a manufacturer's quality system and provide an independent means of evaluating the manufacturer's or the supplier/vendor's compliance status. Suggestions for risk-based scheduling approaches are discussed in the article. Pharmaceutical manufacturers are required to establish and implement a quality system. The quality system is an organizational structure defining responsibilities, procedures, processes, and resources that the manufacturer has established to ensure quality throughout the manufacturing process. Audits are a component of the manufacturer's quality system and provide a systematic and an independent means of evaluating the manufacturer's overall quality system and compliance status. Audits are performed at defined intervals for a specified duration. The intention of the audit process is to focus on key areas within the quality system and may not cover all relevant areas during each audit. In this article, the authors provide suggestions for risk-based scheduling approaches to aid pharmaceutical manufacturers in identifying the key focus areas for an audit.

Affordable Design: A Methodolgy to Implement Process-Based Manufacturing Cost into the Traditional Performance-Focused Multidisciplinary Design Optimization

NASA Technical Reports Server (NTRS)

Bao, Han P.; Samareh, J. A.

2000-01-01

The primary objective of this paper is to demonstrate the use of process-based manufacturing and assembly cost models in a traditional performance-focused multidisciplinary design and optimization process. The use of automated cost-performance analysis is an enabling technology that could bring realistic processbased manufacturing and assembly cost into multidisciplinary design and optimization. In this paper, we present a new methodology for incorporating process costing into a standard multidisciplinary design optimization process. Material, manufacturing processes, and assembly processes costs then could be used as the objective function for the optimization method. A case study involving forty-six different configurations of a simple wing is presented, indicating that a design based on performance criteria alone may not necessarily be the most affordable as far as manufacturing and assembly cost is concerned.

Cleaning and Cleanliness Measurement of Additive Manufactured Parts

NASA Technical Reports Server (NTRS)

Mitchell, Mark A.; Edwards, Kevin; Fox, Eric; Boothe, Richard

2017-01-01

Additive Manufacturing processes allow for the manufacture of complex three dimensional components that otherwise could not be manufactured. Post treatment processes require the removal of any remnant bulk powder that may become entrapped within small cavities and channels within a component. This project focuses on several gross cleaning methods and the verification metrics associated with additive manufactured parts for oxygen propulsion usage.

Photoreversible Covalent Hydrogels for Soft-Matter Additive Manufacturing.

PubMed

Kabb, Christopher P; O'Bryan, Christopher S; Deng, Christopher C; Angelini, Thomas E; Sumerlin, Brent S

2018-05-16

Reversible covalent chemistry provides access to robust materials with the ability to be degraded and reformed upon exposure to an appropriate stimulus. Photoresponsive units are attractive for this purpose, as the spatial and temporal application of light is easily controlled. Coumarin derivatives undergo a [2 + 2] cycloaddition upon exposure to long-wave UV irradiation (365 nm), and this process can be reversed using short-wave UV light (254 nm). Therefore, polymers cross-linked by coumarin groups are excellent candidates as reversible covalent gels. In this work, copolymerization of coumarin-containing monomers with the hydrophilic comonomer N, N-dimethylacrylamide yielded water-soluble, linear polymers that could be cured with long-wave UV light into free-standing hydrogels, even in the absence of a photoinitiator. Importantly, the gels were reverted back to soluble copolymers upon short-wave UV irradiation. This process could be cycled, allowing for recycling and remolding of the hydrogel into additional shapes. Further, this hydrogel can be imprinted with patterns through a mask-based, post-gelation photoetching method. Traditional limitations of this technique, such as the requirement for uniform etching in one direction, have been overcome by combining these materials with a soft-matter additive manufacturing methodology. In a representative application of this approach, we printed solid structures in which the interior coumarin-cross-linked gel is surrounded by a nondegradable gel. Upon exposure to short-wave UV irradiation, the coumarin-cross-linked gel was reverted to soluble prepolymers that were washed away to yield hollow hydrogel objects.

Developing a performance data suite to facilitate lean improvement in a chemotherapy day unit.

PubMed

Lingaratnam, Senthil; Murray, Danielle; Carle, Amber; Kirsa, Sue W; Paterson, Rebecca; Rischin, Danny

2013-07-01

A multidisciplinary team from the Peter MacCallum Cancer Centre in Melbourne, Australia, developed a performance data suite to support a service improvement project based on lean manufacturing principles in its 19-chair chemotherapy day unit (CDU) and cytosuite chemotherapy production facility. The aims of the project were to reduce patient wait time and improve equity of access to the CDU. A project team consisting of a pharmacist and CDU nurse supported the management team for 10 months in engaging staff and customers to identify waste in processes, analyze root causes, eliminate non-value-adding steps, reduce variation, and level workloads to improve quality and flow. Process mapping, staff and patient tracking and opinion surveys, medical record audits, and interrogation of electronic treatment records were undertaken. This project delivered a 38% reduction in median wait time on the day (from 32 to 20 minutes; P < .01), 7-day reduction in time to commencement of treatment for patients receiving combined chemoradiotherapy regimens (from 25 to 18 days; P < .01), and 22% reduction in wastage associated with expired drug and pharmacy rework (from 29% to 7%; P < .01). Improvements in efficiency enabled the cytosuite to increase the percentage of product manufactured within 10 minutes of appointment times by 29% (from 47% to 76%; P < .01). A lean improvement methodology provided a robust framework for improved understanding and management of complex system constraints within a CDU, resulting in improved access to treatment and reduced waiting times on the day.

Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them May 20-21 2014 Continuous Manufacturing Symposium.

PubMed

Byrn, Stephen; Futran, Maricio; Thomas, Hayden; Jayjock, Eric; Maron, Nicola; Meyer, Robert F; Myerson, Allan S; Thien, Michael P; Trout, Bernhardt L

2015-03-01

We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to continuous manufacturing. We also give the key motivations for moving to continuous manufacturing, some of the exciting new technologies, and the barriers to implementation of continuous manufacturing. Continuous processing of heterogeneous blends is the natural first step in converting existing batch processes to continuous. In heterogeneous processing, there are discrete particles that can segregate, versus in homogeneous processing, components are blended and homogenized such that they do not segregate. Heterogeneous processing can incorporate technologies that are closer to existing technologies, where homogeneous processing necessitates the development and incorporation of new technologies. Homogeneous processing has the greatest potential for reaping the full rewards of continuous manufacturing, but it takes long-term vision and a more significant change in process development than heterogeneous processing. Heterogeneous processing has the detriment that, as the technologies are adopted rather than developed, there is a strong tendency to incorporate correction steps, what we call below "The Rube Goldberg Problem." Thus, although heterogeneous processing will likely play a major role in the near-term transformation of heterogeneous to continuous processing, it is expected that homogeneous processing is the next step that will follow. Specific action items for industry leaders are. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

27 CFR 40.1 - Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco.

Code of Federal Regulations, 2012 CFR

2012-04-01

... products, cigarette papers and tubes, and processed tobacco. 40.1 Section 40.1 Alcohol, Tobacco Products... MANUFACTURE OF TOBACCO PRODUCTS, CIGARETTE PAPERS AND TUBES, AND PROCESSED TOBACCO Scope of Regulations § 40.1 Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco. This part contains...

Printing Processes Used to Manufacture Photovoltaic Solar Cells

ERIC Educational Resources Information Center

Rardin, Tina E.; Xu, Renmei

2011-01-01

There is a growing need for renewable energy sources, and solar power is a good option in many instances. Photovoltaic solar panels are now being manufactured via various methods, and different printing processes are being incorporated into the manufacturing process. Screen printing has been used most prevalently in the printing process to make…

27 CFR 40.1 - Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco.

Code of Federal Regulations, 2013 CFR

2013-04-01

... products, cigarette papers and tubes, and processed tobacco. 40.1 Section 40.1 Alcohol, Tobacco Products... MANUFACTURE OF TOBACCO PRODUCTS, CIGARETTE PAPERS AND TUBES, AND PROCESSED TOBACCO Scope of Regulations § 40.1 Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco. This part contains...

27 CFR 40.1 - Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco.

Code of Federal Regulations, 2011 CFR

2011-04-01

... products, cigarette papers and tubes, and processed tobacco. 40.1 Section 40.1 Alcohol, Tobacco Products... MANUFACTURE OF TOBACCO PRODUCTS, CIGARETTE PAPERS AND TUBES, AND PROCESSED TOBACCO Scope of Regulations § 40.1 Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco. This part contains...

27 CFR 40.1 - Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco.

Code of Federal Regulations, 2010 CFR

2010-04-01

... products, cigarette papers and tubes, and processed tobacco. 40.1 Section 40.1 Alcohol, Tobacco Products... MANUFACTURE OF TOBACCO PRODUCTS, CIGARETTE PAPERS AND TUBES, AND PROCESSED TOBACCO Scope of Regulations § 40.1 Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco. This part contains...

27 CFR 40.1 - Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco.

Code of Federal Regulations, 2014 CFR

2014-04-01

... products, cigarette papers and tubes, and processed tobacco. 40.1 Section 40.1 Alcohol, Tobacco Products... MANUFACTURE OF TOBACCO PRODUCTS, CIGARETTE PAPERS AND TUBES, AND PROCESSED TOBACCO Scope of Regulations § 40.1 Manufacture of tobacco products, cigarette papers and tubes, and processed tobacco. This part contains...

Intelligent Processing Equipment Developments Within the Navy's Manufacturing Technology Centers of Excellence

NASA Technical Reports Server (NTRS)

Nanzetta, Philip

1992-01-01

The U.S. Navy has had an active Manufacturing Technology (MANTECH) Program aimed at developing advanced production processes and equipment since the late-1960's. During the past decade, however, the resources of the MANTECH program were concentrated in Centers of Excellence. Today, the Navy sponsors four manufacturing technology Centers of Excellence: the Automated Manufacturing Research Facility (AMRF); the Electronics Manufacturing Productivity Facility (EMPF); the National Center for Excellence in Metalworking Technology (NCEMT); and the Center of Excellence for Composites Manufacturing Technology (CECMT). This paper briefly describes each of the centers and summarizes typical Intelligent Equipment Processing (IEP) projects that were undertaken.

75 FR 17645 - Polychlorinated Biphenyls (PCBs); Reassessment of Use Authorizations

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-07

... reassessing the definitions of ``excluded manufacturing process,'' ``quantifiable level/level of detection... reassessing the definitions of ``excluded manufacturing process,'' ``quantifiable level/level of detection... to authorize by rule the manufacturing, processing, distribution in commerce, and use of PCBs in a...

Vehicle logo recognition using multi-level fusion model

NASA Astrophysics Data System (ADS)

Ming, Wei; Xiao, Jianli

2018-04-01

Vehicle logo recognition plays an important role in manufacturer identification and vehicle recognition. This paper proposes a new vehicle logo recognition algorithm. It has a hierarchical framework, which consists of two fusion levels. At the first level, a feature fusion model is employed to map the original features to a higher dimension feature space. In this space, the vehicle logos become more recognizable. At the second level, a weighted voting strategy is proposed to promote the accuracy and the robustness of the recognition results. To evaluate the performance of the proposed algorithm, extensive experiments are performed, which demonstrate that the proposed algorithm can achieve high recognition accuracy and work robustly.

[Chinese medicine industry 4.0：advancing digital pharmaceutical manufacture toward intelligent pharmaceutical manufacture].

PubMed

Cheng, Yi-Yu; Qu, Hai-Bin; Zhang, Bo-Li

2016-01-01

A perspective analysis on the technological innovation in pharmaceutical engineering of Chinese medicine unveils a vision on "Future Factory" of Chinese medicine industry in mind. The strategy as well as the technical roadmap of "Chinese medicine industry 4.0" is proposed, with the projection of related core technology system. It is clarified that the technical development path of Chinese medicine industry from digital manufacture to intelligent manufacture. On the basis of precisely defining technical terms such as process control, on-line detection and process quality monitoring for Chinese medicine manufacture, the technical concepts and characteristics of intelligent pharmaceutical manufacture as well as digital pharmaceutical manufacture are elaborated. Promoting wide applications of digital manufacturing technology of Chinese medicine is strongly recommended. Through completely informationized manufacturing processes and multi-discipline cluster innovation, intelligent manufacturing technology of Chinese medicine should be developed, which would provide a new driving force for Chinese medicine industry in technology upgrade, product quality enhancement and efficiency improvement. Copyright© by the Chinese Pharmaceutical Association.

Study of process variables associated with manufacturing hermetically-sealed nickel-cadmium cells

NASA Technical Reports Server (NTRS)

Miller, L.

1974-01-01

A two year study of the major process variables associated with the manufacturing process for sealed, nickel-cadmium, areospace cells is summarized. Effort was directed toward identifying the major process variables associated with a manufacturing process, experimentally assessing each variable's effect, and imposing the necessary changes (optimization) and controls for the critical process variables to improve results and uniformity. A critical process variable associated with the sintered nickel plaque manufacturing process was identified as the manual forming operation. Critical process variables identified with the positive electrode impregnation/polarization process were impregnation solution temperature, free acid content, vacuum impregnation, and sintered plaque strength. Positive and negative electrodes were identified as a major source of carbonate contamination in sealed cells.

77 FR 58112 - Notice of Intent To Prepare an Environmental Assessment (EA) for the Proposed Conveyance of Land...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-19

..., including warehousing and distribution; research and development; technology manufacturing; food processing... warehousing and distribution; research and development; technology manufacturing; food processing and... defense manufacturing, sensor manufacturing, or medical devices; (iv) Food/Agriculture--such as wine, food...

76 FR 21652 - Oil Pollution Prevention; Spill Prevention, Control, and Countermeasure (SPCC) Rule-Amendments...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-18

... of Agriculture (USDA) Recommended Requirements for Milk for Manufacturing Purposes and its Production and Processing (Milk for Manufacturing Purposes and Its Production and Processing; Requirements... for Manufacturing Purposes and its Production and Processing, or equivalent State dairy regulatory...

Simulation of a Start-Up Manufacturing Facility for Nanopore Arrays

ERIC Educational Resources Information Center

Field, Dennis W.

2009-01-01

Simulation is a powerful tool in developing and troubleshooting manufacturing processes, particularly when considering process flows for manufacturing systems that do not yet exist. Simulation can bridge the gap in terms of setting up full-scale manufacturing for nanotechnology products if limited production experience is an issue. An effective…

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Joshua, E-mail: joshuk7@uci.edu; Park, Sun-Jun; Nguyen, Thao

With the growing prominence of wearable electronic technology, there is a need to improve the mechanical reliability of electronics for more demanding applications. Conductive wires represent a vital component present in all electronics. Unlike traditional planar and rigid electronics, these new wearable electrical components must conform to curvilinear surfaces, stretch with the body, and remain unobtrusive and low profile. In this paper, the piezoresistive response of shrink induced wrinkled gold thin films under strain demonstrates robust conductive performance in excess of 200% strain. Importantly, the wrinkled metallic thin films displayed negligible change in resistance of up to 100% strain. Themore » wrinkled metallic wires exhibited consistent performance after repetitive strain. Importantly, these wrinkled thin films are inexpensive to fabricate and are compatible with roll to roll manufacturing processes. We propose that these wrinkled metal thin film wires are an attractive alternative to conventional wires for wearable applications.« less

Wireless physiological monitoring system for psychiatric patients.

PubMed

Rademeyer, A J; Blanckenberg, M M; Scheffer, C

2009-01-01

Patients in psychiatric hospitals that are sedated or secluded are at risk of death or injury if they are not continuously monitored. Some psychiatric patients are restless and aggressive, and hence the monitoring device should be robust and must transmit the data wirelessly. Two devices, a glove that measures oxygen saturation and a dorsally-mounted device that measures heart rate, skin temperature and respiratory rate were designed and tested. Both devices connect to one central monitoring station using two separate Bluetooth connections, ensuring a completely wireless setup. A Matlab graphical user interface (GUI) was developed for signal processing and monitoring of the vital signs of the psychiatric patient. Detection algorithms were implemented to detect ECG arrhythmias such as premature ventricular contraction and atrial fibrillation. The prototypes were manufactured and tested in a laboratory setting on healthy volunteers.

Concise Review: Process Development Considerations for Cell Therapy

PubMed Central

Brieva, Thomas; Raviv, Lior; Rowley, Jon; Niss, Knut; Brandwein, Harvey; Oh, Steve; Karnieli, Ohad

2015-01-01

The development of robust and well-characterized methods of production of cell therapies has become increasingly important as therapies advance through clinical trials toward approval. A successful cell therapy will be a consistent, safe, and effective cell product, regardless of the cell type or application. Process development strategies can be developed to gain efficiency while maintaining or improving safety and quality profiles. This review presents an introduction to the process development challenges of cell therapies and describes some of the tools available to address production issues. This article will provide a summary of what should be considered to efficiently advance a cellular therapy from the research stage through clinical trials and finally toward commercialization. The identification of the basic questions that affect process development is summarized in the target product profile, and considerations for process optimization are discussed. The goal is to identify potential manufacturing concerns early in the process so they may be addressed effectively and thus increase the probability that a therapy will be successful. Significance The present study contributes to the field of cell therapy by providing a resource for those transitioning a potential therapy from the research stage to clinical and commercial applications. It provides the necessary steps that, when followed, can result in successful therapies from both a clinical and commercial perspective. PMID:26315572

Mechanical characterisation of agarose-based chromatography resins for biopharmaceutical manufacture.

PubMed

Nweke, Mauryn C; McCartney, R Graham; Bracewell, Daniel G

2017-12-29

Mechanical characterisation of agarose-based resins is an important factor in ensuring robust chromatographic performance in the manufacture of biopharmaceuticals. Pressure-flow profiles are most commonly used to characterise these properties. There are a number of drawbacks with this method, including the potential need for several re-packs to achieve the desired packing quality, the impact of wall effects on experimental set up and the quantities of chromatography media and buffers required. To address these issues, we have developed a dynamic mechanical analysis (DMA) technique that characterises the mechanical properties of resins based on the viscoelasticity of a 1ml sample of slurry. This technique was conducted on seven resins with varying degrees of mechanical robustness and the results were compared to pressure-flow test results on the same resins. Results show a strong correlation between the two techniques. The most mechanically robust resin (Capto Q) had a critical velocity 3.3 times higher than the weakest (Sepharose CL-4B), whilst the DMA technique showed Capto Q to have a slurry deformation rate 8.3 times lower than Sepharose CL-4B. To ascertain whether polymer structure is indicative of mechanical strength, scanning electron microscopy images were also used to study the structural properties of each resin. Results indicate that DMA can be used as a small volume, complementary technique for the mechanical characterisation of chromatography media. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

40 CFR 98.73 - Calculating GHG emissions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.73 Calculating GHG emissions. You must calculate and report the annual process CO2 emissions from each ammonia manufacturing process unit... ammonia manufacturing unit, the CO2 process emissions from gaseous feedstock according to Equation G-1 of...

40 CFR 98.73 - Calculating GHG emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.73 Calculating GHG emissions. You must calculate and report the annual process CO2 emissions from each ammonia manufacturing process unit... ammonia manufacturing unit, the CO2 process emissions from gaseous feedstock according to Equation G-1 of...

40 CFR 98.73 - Calculating GHG emissions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.73 Calculating GHG emissions. You must calculate and report the annual process CO2 emissions from each ammonia manufacturing process unit... ammonia manufacturing unit, the CO2 process emissions from gaseous feedstock according to Equation G-1 of...

40 CFR 98.73 - Calculating GHG emissions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.73 Calculating GHG emissions. You must calculate and report the annual process CO2 emissions from each ammonia manufacturing process unit... ammonia manufacturing unit, the CO2 process emissions from gaseous feedstock according to Equation G-1 of...

40 CFR 98.73 - Calculating GHG emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.73 Calculating GHG emissions. You must calculate and report the annual process CO2 emissions from each ammonia manufacturing process unit... ammonia manufacturing unit, the CO2 process emissions from gaseous feedstock according to Equation G-1 of...

77 FR 24722 - Draft Guidance for Industry: Assessing the Effects of Significant Manufacturing Process Changes...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-25

...] Draft Guidance for Industry: Assessing the Effects of Significant Manufacturing Process Changes... Substances, Including Food Ingredients That Are Color Additives; Availability AGENCY: Food and Drug... Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food...

Automotive Manufacturing Processes. Volume V - Manufacturing Processes and Equipment for the Mass Production and Assembly of Motor Vehicles

DOT National Transportation Integrated Search

1981-02-01

Extensive material substitution and resizing of the domestic automotive fleet, as well as the introduction of new technologies, will require major changes in the techniques and equipment used in the various manufacturing processes employed in the pro...

31 CFR 500.412 - Process vs. manufacture.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Process vs. manufacture. 500.412... OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN ASSETS CONTROL REGULATIONS Interpretations § 500.412 Process vs. manufacture. A commodity subject to § 500.204 remains subject howsoever it...

Analysis and evaluation in the production process and equipment area of the low-cost solar array project

NASA Technical Reports Server (NTRS)

Goldman, H.; Wolf, M.

1979-01-01

The energy consumed in manufacturing silicon solar cell modules was calculated for the current process, as well as for 1982 and 1986 projected processes. In addition, energy payback times for the above three sequences are shown. The module manufacturing energy was partitioned two ways. In one way, the silicon reduction, silicon purification, sheet formation, cell fabrication, and encapsulation energies were found. In addition, the facility, equipment, processing material and direct material lost-in-process energies were appropriated in junction formation processes and full module manufacturing sequences. A brief methodology accounting for the energy of silicon wafers lost-in-processing during cell manufacturing is described.

Low Cost Manufacturing of Composite Cryotanks

NASA Technical Reports Server (NTRS)

Meredith, Brent; Palm, Tod; Deo, Ravi; Munafo, Paul M. (Technical Monitor)

2002-01-01

This viewgraph presentation reviews research and development of cryotank manufacturing conducted by Northrup Grumman. The objectives of the research and development included the development and validation of manufacturing processes and technology for fabrication of large scale cryogenic tanks, the establishment of a scale-up and facilitization plan for full scale cryotanks, the development of non-autoclave composite manufacturing processes, the fabrication of subscale tank joints for element tests, the performance of manufacturing risk reduction trials for the subscale tank, and the development of full-scale tank manufacturing concepts.

Additive Manufacturing of Functional Elements on Sheet Metal

NASA Astrophysics Data System (ADS)

Schaub, Adam; Ahuja, Bhrigu; Butzhammer, Lorenz; Osterziel, Johannes; Schmidt, Michael; Merklein, Marion

Laser Beam Melting (LBM) process with its advantages of high design flexibility and free form manufacturing methodology is often applied limitedly due to its low productivity and unsuitability for mass production compared to conventional manufacturing processes. In order to overcome these limitations, a hybrid manufacturing methodology is developed combining the additive manufacturing process of laser beam melting with sheet forming processes. With an interest towards aerospace and medical industry, the material in focus is Ti-6Al-4V. Although Ti-6Al-4V is a commercially established material and its application for LBM process has been extensively investigated, the combination of LBM of Ti-6Al-4V with sheet metal still needs to be researched. Process dynamics such as high temperature gradients and thermally induced stresses lead to complex stress states at the interaction zone between the sheet and LBM structure. Within the presented paper mechanical characterization of hybrid parts will be performed by shear testing. The association of shear strength with process parameters is further investigated by analyzing the internal structure of the hybrid geometry at varying energy inputs during the LBM process. In order to compare the hybrid manufacturing methodology with conventional fabrication, the conventional methodologies subtractive machining and state of the art Laser Beam Melting is evaluated within this work. These processes will be analyzed for their mechanical characteristics and productivity by determining the build time and raw material consumption for each case. The paper is concluded by presenting the characteristics of the hybrid manufacturing methodology compared to alternative manufacturing technologies.

UOE Pipe Manufacturing Process Simulation: Equipment Designing and Construction

NASA Astrophysics Data System (ADS)

Delistoian, Dmitri; Chirchor, Mihael

2017-12-01

UOE pipe manufacturing process influence directly on pipeline resilience and operation capacity. At present most spreaded pipe manufacturing method is UOE. This method is based on cold forming. After each technological step appears a certain stress and strain level. For pipe stress strain study is designed and constructed special equipment that simulate entire technological process.UOE pipe equipment is dedicated for manufacturing of longitudinally submerged arc welded DN 400 (16 inch) steel pipe.

Managing dual warehouses with an incentive policy for deteriorating items

NASA Astrophysics Data System (ADS)

Yu, Jonas C. P.; Wang, Kung-Jeng; Lin, Yu-Siang

2016-02-01

Distributors in a supply chain usually limit their own warehouse in finite capacity for cost reduction and excess stock is held in a rent warehouse. In this study, we examine inventory control for deteriorating items in a two-warehouse setting. Assuming that there is an incentive offered by a rent warehouse that allows the rental fee to decrease over time, the objective of this study is to maximise the joint profit of the manufacturer and the distributor. An optimisation procedure is developed to derive the optimal joint economic lot size policy. Several criteria are identified to select the most appropriate warehouse configuration and inventory policy on the basis of storage duration of materials in a rent warehouse. Sensitivity analysis is done to examine the results of model robustness. The proposed model enables a manufacturer with a channel distributor to coordinate the use of alternative warehouses, and to maximise the joint profit of the manufacturer and the distributor.

Verification of low-Mach number combustion codes using the method of manufactured solutions

NASA Astrophysics Data System (ADS)

Shunn, Lee; Ham, Frank; Knupp, Patrick; Moin, Parviz

2007-11-01

Many computational combustion models rely on tabulated constitutive relations to close the system of equations. As these reactive state-equations are typically multi-dimensional and highly non-linear, their implications on the convergence and accuracy of simulation codes are not well understood. In this presentation, the effects of tabulated state-relationships on the computational performance of low-Mach number combustion codes are explored using the method of manufactured solutions (MMS). Several MMS examples are developed and applied, progressing from simple one-dimensional configurations to problems involving higher dimensionality and solution-complexity. The manufactured solutions are implemented in two multi-physics hydrodynamics codes: CDP developed at Stanford University and FUEGO developed at Sandia National Laboratories. In addition to verifying the order-of-accuracy of the codes, the MMS problems help highlight certain robustness issues in existing variable-density flow-solvers. Strategies to overcome these issues are briefly discussed.

OPERATOR BURDEN IN METAL ADDITIVE MANUFACTURING

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elliott, Amy M; Love, Lonnie J

2016-01-01

Additive manufacturing (AM) is an emerging manufacturing process that creates usable machine parts via layer-by-layer joining of a stock material. With this layer-wise approach, high-performance geometries can be created which are impossible with traditional manufacturing methods. Metal AM technology has the potential to significantly reduce the manufacturing burden of developing custom hardware; however, a major consideration in choosing a metal AM system is the required amount of operator involvement (i.e., operator burden) in the manufacturing process. The operator burden not only determines the amount of operator training and specialization required but also the usability of the system in a facility.more » As operators of several metal AM processes, the Manufacturing Demonstration Facility (MDF) at Oak Ridge National Labs is uniquely poised to provide insight into requirements for operator involvement in each of the three major metal AM processes. The paper covers an overview of each of the three metal AM technologies, focusing on the burden on the operator to complete the build cycle, process the part for final use, and reset the AM equipment for future builds.« less

Additive Manufacturing in Production: A Study Case Applying Technical Requirements

NASA Astrophysics Data System (ADS)

Ituarte, Iñigo Flores; Coatanea, Eric; Salmi, Mika; Tuomi, Jukka; Partanen, Jouni

Additive manufacturing (AM) is expanding the manufacturing capabilities. However, quality of AM produced parts is dependent on a number of machine, geometry and process parameters. The variability of these parameters affects the manufacturing drastically and therefore standardized processes and harmonized methodologies need to be developed to characterize the technology for end use applications and enable the technology for manufacturing. This research proposes a composite methodology integrating Taguchi Design of Experiments, multi-objective optimization and statistical process control, to optimize the manufacturing process and fulfil multiple requirements imposed to an arbitrary geometry. The proposed methodology aims to characterize AM technology depending upon manufacturing process variables as well as to perform a comparative assessment of three AM technologies (Selective Laser Sintering, Laser Stereolithography and Polyjet). Results indicate that only one machine, laser-based Stereolithography, was feasible to fulfil simultaneously macro and micro level geometrical requirements but mechanical properties were not at required level. Future research will study a single AM system at the time to characterize AM machine technical capabilities and stimulate pre-normative initiatives of the technology for end use applications.

Additive Manufacturing Infrared Inspection

NASA Technical Reports Server (NTRS)

Gaddy, Darrell; Nettles, Mindy

2015-01-01

The Additive Manufacturing Infrared Inspection Task started the development of a real-time dimensional inspection technique and digital quality record for the additive manufacturing process using infrared camera imaging and processing techniques. This project will benefit additive manufacturing by providing real-time inspection of internal geometry that is not currently possible and reduce the time and cost of additive manufactured parts with automated real-time dimensional inspections which deletes post-production inspections.

An Introduction to Intelligent Processing Programs Developed by the Air Force Manufacturing Technology Directorate

NASA Technical Reports Server (NTRS)

Sampson, Paul G.; Sny, Linda C.

1992-01-01

The Air Force has numerous on-going manufacturing and integration development programs (machine tools, composites, metals, assembly, and electronics) which are instrumental in improving productivity in the aerospace industry, but more importantly, have identified strategies and technologies required for the integration of advanced processing equipment. An introduction to four current Air Force Manufacturing Technology Directorate (ManTech) manufacturing areas is provided. Research is being carried out in the following areas: (1) machining initiatives for aerospace subcontractors which provide for advanced technology and innovative manufacturing strategies to increase the capabilities of small shops; (2) innovative approaches to advance machine tool products and manufacturing processes; (3) innovative approaches to advance sensors for process control in machine tools; and (4) efforts currently underway to develop, with the support of industry, the Next Generation Workstation/Machine Controller (Low-End Controller Task).

40 CFR 98.72 - GHGs to report.

Code of Federal Regulations, 2011 CFR

2011-07-01

... GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.72 GHGs to report. You must report: (a) CO2 process..., reported for each ammonia manufacturing process unit following the requirements of this subpart (CO2... production, and therefore is not released to the ambient air from the ammonia manufacturing process unit). (b...

40 CFR 98.72 - GHGs to report.

Code of Federal Regulations, 2014 CFR

2014-07-01

... GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.72 GHGs to report. You must report: (a) CO2 process..., reported for each ammonia manufacturing process unit following the requirements of this subpart (CO2... production, and therefore is not released to the ambient air from the ammonia manufacturing process unit). (b...

40 CFR 98.72 - GHGs to report.

Code of Federal Regulations, 2013 CFR

2013-07-01

... GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.72 GHGs to report. You must report: (a) CO2 process..., reported for each ammonia manufacturing process unit following the requirements of this subpart (CO2... production, and therefore is not released to the ambient air from the ammonia manufacturing process unit). (b...

40 CFR 98.72 - GHGs to report.

Code of Federal Regulations, 2012 CFR

2012-07-01

... GREENHOUSE GAS REPORTING Ammonia Manufacturing § 98.72 GHGs to report. You must report: (a) CO2 process..., reported for each ammonia manufacturing process unit following the requirements of this subpart (CO2... production, and therefore is not released to the ambient air from the ammonia manufacturing process unit). (b...

75 FR 28335 - Testing and Labeling Pertaining to Product Certification

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-20

... material change in the product's design or manufacturing process, including the sourcing of component parts... ``material change'' in a product's design or manufacturing process? Are there criteria by which one might... production begins. Some comments stated that neither the same materials nor the same manufacturing processes...

40 CFR 63.100 - Applicability and designation of source.

Code of Federal Regulations, 2010 CFR

2010-07-01

... manufacturing process unit has two or more products that have the same maximum annual design capacity on a mass... subject to this subpart. (3) For chemical manufacturing process units that are designed and operated as... chemical manufacturing process units that are designed and operated as flexible operation units shall be...

40 CFR 761.193 - Maintenance of monitoring records by persons who import, manufacture, process, distribute in...

Code of Federal Regulations, 2010 CFR

2010-07-01

... persons who import, manufacture, process, distribute in commerce, or use chemicals containing..., DISTRIBUTION IN COMMERCE, AND USE PROHIBITIONS General Records and Reports § 761.193 Maintenance of monitoring records by persons who import, manufacture, process, distribute in commerce, or use chemicals containing...

Encapsulation Processing and Manufacturing Yield Analysis

NASA Technical Reports Server (NTRS)

Willis, P. B.

1984-01-01

The development of encapsulation processing and a manufacturing productivity analysis for photovoltaic cells are discussed. The goals were: (1) to understand the relationships between both formulation variables and process variables; (2) to define conditions required for optimum performance; (3) to predict manufacturing yield; and (4) to provide documentation to industry.

Encapsulation processing and manufacturing yield analysis

NASA Astrophysics Data System (ADS)

Willis, P. B.

1984-10-01

The development of encapsulation processing and a manufacturing productivity analysis for photovoltaic cells are discussed. The goals were: (1) to understand the relationships between both formulation variables and process variables; (2) to define conditions required for optimum performance; (3) to predict manufacturing yield; and (4) to provide documentation to industry.

27 CFR 40.522 - Reports.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 27 Alcohol, Tobacco Products and Firearms 2 2012-04-01 2011-04-01 true Reports. 40.522 Section 40... TOBACCO Manufacture of Processed Tobacco Operations by Manufacturers of Processed Tobacco § 40.522 Reports. (a) General. Every manufacturer of processed tobacco must prepare a monthly report on TTB F 5250.1 in...

27 CFR 40.522 - Reports.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 2 2011-04-01 2011-04-01 false Reports. 40.522 Section 40... TOBACCO Manufacture of Processed Tobacco Operations by Manufacturers of Processed Tobacco § 40.522 Reports. (a) General. Every manufacturer of processed tobacco must prepare a monthly report on TTB F 5250.1 in...

27 CFR 40.522 - Reports.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 27 Alcohol, Tobacco Products and Firearms 2 2013-04-01 2013-04-01 false Reports. 40.522 Section 40... TOBACCO Manufacture of Processed Tobacco Operations by Manufacturers of Processed Tobacco § 40.522 Reports. (a) General. Every manufacturer of processed tobacco must prepare a monthly report on TTB F 5250.1 in...

78 FR 18234 - Service of Process on Manufacturers; Manufacturers Importing Electronic Products Into the United...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-26

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 1005 [Docket No. FDA-2007-N-0091; (formerly 2007N-0104)] Service of Process on Manufacturers; Manufacturers Importing Electronic Products Into the United States; Agent Designation; Change of Address AGENCY: Food and Drug...

Rapid prototyping of multi-scale biomedical microdevices by combining additive manufacturing technologies.

PubMed

Hengsbach, Stefan; Lantada, Andrés Díaz

2014-08-01

The possibility of designing and manufacturing biomedical microdevices with multiple length-scale geometries can help to promote special interactions both with their environment and with surrounding biological systems. These interactions aim to enhance biocompatibility and overall performance by using biomimetic approaches. In this paper, we present a design and manufacturing procedure for obtaining multi-scale biomedical microsystems based on the combination of two additive manufacturing processes: a conventional laser writer to manufacture the overall device structure, and a direct-laser writer based on two-photon polymerization to yield finer details. The process excels for its versatility, accuracy and manufacturing speed and allows for the manufacture of microsystems and implants with overall sizes up to several millimeters and with details down to sub-micrometric structures. As an application example we have focused on manufacturing a biomedical microsystem to analyze the impact of microtextured surfaces on cell motility. This process yielded a relevant increase in precision and manufacturing speed when compared with more conventional rapid prototyping procedures.

Manufacturing with the Sun

NASA Astrophysics Data System (ADS)

Murphy, L. M.; Hauser, S. G.; Clyne, R. J.

1992-05-01

Concentrated solar radiation is now a viable alternative energy source for many advanced manufacturing processes. Researchers at the National Renewable Energy Laboratory (NREL) have demonstrated the feasibility of processes such as solar-induced surface transformation of materials (SISTM), solar-based manufacturing, and solar-pumped lasers. Researchers are also using sunlight to decontaminate water and soils polluted with organic compounds; these techniques could provide manufacturers with innovative alternatives to traditional methods of waste management. The solar technology that is now being integrated into today's manufacturing processes offers even greater potential for tomorrow, especially as applied to the radiation-abundant environment available in space and on the lunar surface.

Manufacturing with the Sun

NASA Astrophysics Data System (ADS)

Murphy, Lawrence M.; Hauser, Steven G.; Clyne, Richard J.

1991-12-01

Concentrated solar radiation is now a viable alternative source for many advanced manufacturing processes. Researchers at the National Renewable Energy Laboratory (NREL) have demonstrated the feasibility of processes such as solar induced surface transformation of materials (SISTM), solar based manufacturing, and solar pumped lasers. Researchers are also using sunlight to decontaminate water and soils polluted with organic compounds; these techniques could provide manufacturers with innovative alternatives to traditional methods of waste management. The solar technology that is now being integrated into today's manufacturing processes offer greater potential for tomorrow, especially as applied to the radiation abundant environment available in space and on the lunar surface.

Manufacturing with the Sun

NASA Technical Reports Server (NTRS)

Murphy, Lawrence M.; Hauser, Steven G.; Clyne, Richard J.

1991-01-01

Concentrated solar radiation is now a viable alternative source for many advanced manufacturing processes. Researchers at the National Renewable Energy Laboratory (NREL) have demonstrated the feasibility of processes such as solar induced surface transformation of materials (SISTM), solar based manufacturing, and solar pumped lasers. Researchers are also using sunlight to decontaminate water and soils polluted with organic compounds; these techniques could provide manufacturers with innovative alternatives to traditional methods of waste management. The solar technology that is now being integrated into today's manufacturing processes offer greater potential for tomorrow, especially as applied to the radiation abundant environment available in space and on the lunar surface.

Technological Improvements for Digital Fire Control Systems

DTIC Science & Technology

2017-09-30

Final Technical Status Report For DOTC-12-01-INIT061 Technological Improvements for Digital Fire Control Systems Reporting Period: 30 Sep...Initiative Information Develop and fabricate next generation designs using advanced materials and processes. This will include but is not limited to...4.2 Develop manufacturing processes 100% 4.3 Develop manufacturing processes 100% 4.4 Develop manufacturing processes 100% 5 Design Tooling

Energetic additive manufacturing process with feed wire

DOEpatents

Harwell, Lane D.; Griffith, Michelle L.; Greene, Donald L.; Pressly, Gary A.

2000-11-07

A process for additive manufacture by energetic wire deposition is described. A source wire is fed into a energy beam generated melt-pool on a growth surface as the melt-pool moves over the growth surface. This process enables the rapid prototyping and manufacture of fully dense, near-net shape components, as well as cladding and welding processes. Alloys, graded materials, and other inhomogeneous materials can be grown using this process.

Efficient Robust Optimization of Metal Forming Processes using a Sequential Metamodel Based Strategy

NASA Astrophysics Data System (ADS)

Wiebenga, J. H.; Klaseboer, G.; van den Boogaard, A. H.

2011-08-01

The coupling of Finite Element (FE) simulations to mathematical optimization techniques has contributed significantly to product improvements and cost reductions in the metal forming industries. The next challenge is to bridge the gap between deterministic optimization techniques and the industrial need for robustness. This paper introduces a new and generally applicable structured methodology for modeling and solving robust optimization problems. Stochastic design variables or noise variables are taken into account explicitly in the optimization procedure. The metamodel-based strategy is combined with a sequential improvement algorithm to efficiently increase the accuracy of the objective function prediction. This is only done at regions of interest containing the optimal robust design. Application of the methodology to an industrial V-bending process resulted in valuable process insights and an improved robust process design. Moreover, a significant improvement of the robustness (>2σ) was obtained by minimizing the deteriorating effects of several noise variables. The robust optimization results demonstrate the general applicability of the robust optimization strategy and underline the importance of including uncertainty and robustness explicitly in the numerical optimization procedure.

Roll-to-Roll Manufacturing of Robust Superhydrophobic Coating on Metallic Engineering Materials.

PubMed

Dong, Shuliang; Wang, Zhenlong; Wang, Yukui; Bai, Xuelin; Fu, Yong Qing; Guo, Bin; Tan, Chaoliang; Zhang, Jia; Hu, PingAn

2018-01-17

Creating a robust superhydrophobic surface on the conventional engineering materials at mass production is of great importance for a self-cleaning, anti-icing, nonwetting surface and low flow resistance in industrial applications. Herein, we report a roll-to-roll strategy to create durable and robust superhydrophobic surfaces with designed micro-/nanoscale hierarchical structures on many conventional engineering materials by combining electrical discharge machining and coating of carbon nanoparticles, followed by oil penetration and drying. The treated surface shows good superhydrophobic properties with a static water contact angle of 170 ± 2° and slide angle of 3 ± 1°. The treated surface also exhibits good resilience and maintains the performance after being tested in various harsh conditions, including water flushing for several days, sand abrasion, scratching with sandpapers, and corrosive solution. Significantly, the superhydrophobic surfaces also show a high efficiency of self-cleaning properties even after oil contamination during applications.

Creating a Holistic Extractables and Leachables (E&L) Program for Biotechnology Products.

PubMed

Li, Kim; Rogers, Gary; Nashed-Samuel, Yasser; Lee, Hans; Mire-Sluis, Anthony; Cherney, Barry; Forster, Ronald; Yeh, Ping; Markovic, Ingrid

2015-01-01

The risk mitigation of extractables and leachables presents significant challenges to regulators and drug manufacturers with respect to the development, as well as the lifecycle management, of drug products. A holistic program is proposed, using a science- and risk-based strategy for testing extractables and leachables from primary containers, drug delivery devices, and single-use systems for the manufacture of biotechnology products. The strategy adopts the principles and concepts from ICH Q9 and ICH Q8(R2). The strategy is phase-appropriate, progressing from extractables testing for material screening/selection/qualification through leachables testing of final products. The strategy is designed primarily to ensure patient safety and product quality of biotechnology products. The holistic program requires robust extraction studies using model solvents, with careful consideration of solvation effect, pH, ionic strength, temperature, and product-contact surface and duration. From a wide variety of process- and product-contact materials, such extraction studies have identified and quantified over 200 organic extractable compounds. The most commonly observed compounds were siloxanes, fatty acid amides, and methacrylates. Toxicology assessments were conducted on these compounds using risk-based decision analysis. Parenteral permitted daily exposure limits were derived, as appropriate, for the majority of these compounds. Analysis of the derived parenteral permitted daily exposure limits helped to establish action thresholds to target high-risk leachables in drug products on stability until expiry. Action thresholds serve to trigger quality investigations to determine potential product impact. The holistic program also evaluates the potential risk for immunogenicity. This approach for primary drug containers and delivery devices is also applicable to single-use systems when justified with a historical knowledge base and understanding of the manufacturing processes of biotechnology products. In the development of a drug product, careful consideration is given to impurities that may originate from manufacturing equipment, process components, and packaging materials. The majority of such impurities are common chemical additives used to improve the physicochemical properties of a wide range of plastic materials. Suppliers and drug manufacturers conduct studies to extract chemical additives from the plastic materials in order to screen and predict those that may leach into a drug product. In this context, the term extractables refers to a profile of extracted compounds observed in studies under harsh conditions. In contrast, the term leachables refers to those impurities that leach from the materials under real-use conditions and may be present in final drug products. The purpose of this article is to present a holistic approach that effectively minimizes the risk of leachables to patient safety and product quality. © PDA, Inc. 2015.

Overview of the production of sintered SiC optics and optical sub-assemblies

NASA Astrophysics Data System (ADS)

Williams, S.; Deny, P.

2005-08-01

The following is an overview on sintered silicon carbide (SSiC) material properties and processing requirements for the manufacturing of components for advanced technology optical systems. The overview will compare SSiC material properties to typical materials used for optics and optical structures. In addition, it will review manufacturing processes required to produce optical components in detail by process step. The process overview will illustrate current manufacturing process and concepts to expand the process size capability. The overview will include information on the substantial capital equipment employed in the manufacturing of SSIC. This paper will also review common in-process inspection methodology and design rules. The design rules are used to improve production yield, minimize cost, and maximize the inherent benefits of SSiC for optical systems. Optimizing optical system designs for a SSiC manufacturing process will allow systems designers to utilize SSiC as a low risk, cost competitive, and fast cycle time technology for next generation optical systems.

Advanced Manufacturing Processes in the Motor Vehicle Industry

DOT National Transportation Integrated Search

1983-05-01

Advanced manufacturing processes, which include a range of automation and management techniques, are aiding U.S. motor vehicle manufacturers to reduce vehicle costs. This report discusses these techniques in general and their specific applications in...

The Development of Model for Measuring Railway Wheels Manufacturing Readiness Level

NASA Astrophysics Data System (ADS)

Inrawan Wiratmadja, Iwan; Mufid, Anas

2016-02-01

In an effort to grow the railway wheel industry in Indonesia and reduce the dependence on imports, Metal Industries Development Center (MIDC) makes the implementation of the railway wheel manufacturing technology in Indonesia. MIDC is an institution based on research and development having a task to research the production of railway wheels prototype and acts as a supervisor to the industry in Indonesia, for implementing the railway wheel manufacturing technology. The process of implementing manufacturing technology requires a lot of resources. Therefore it is necessary to measure the manufacturing readiness process. Measurement of railway wheels manufacturing readiness was in this study done using the manufacturing readiness level (MRL) model from the United States Department of Defense. MRL consists of 10 manufacturing readiness levels described by 90 criteria and 184 sub-criteria. To get a manufacturing readiness measurement instrument that is good and accurate, the development process involved experts through expert judgment method and validated with a content validity ratio (CVR). Measurement instrument developed in this study consist of 448 indicators. The measurement results show that MIDC's railway wheels manufacturing readiness is at the level 4. This shows that there is a gap between the current level of manufacturing readiness owned by MIDC and manufacturing readiness levels required to achieve the program objectives, which is level 5. To achieve the program objectives at level 5, a number of actions were required to be done by MIDC. Indicators that must be improved to be able to achieve level 5 are indicators related to the cost and financing, process capability and control, quality management, workers, and manufacturing management criteria.

Scalable manufacturing of biomimetic moldable hydrogels for industrial applications.

PubMed

Yu, Anthony C; Chen, Haoxuan; Chan, Doreen; Agmon, Gillie; Stapleton, Lyndsay M; Sevit, Alex M; Tibbitt, Mark W; Acosta, Jesse D; Zhang, Tony; Franzia, Paul W; Langer, Robert; Appel, Eric A

2016-12-13

Hydrogels are a class of soft material that is exploited in many, often completely disparate, industrial applications, on account of their unique and tunable properties. Advances in soft material design are yielding next-generation moldable hydrogels that address engineering criteria in several industrial settings such as complex viscosity modifiers, hydraulic or injection fluids, and sprayable carriers. Industrial implementation of these viscoelastic materials requires extreme volumes of material, upwards of several hundred million gallons per year. Here, we demonstrate a paradigm for the scalable fabrication of self-assembled moldable hydrogels using rationally engineered, biomimetic polymer-nanoparticle interactions. Cellulose derivatives are linked together by selective adsorption to silica nanoparticles via dynamic and multivalent interactions. We show that the self-assembly process for gel formation is easily scaled in a linear fashion from 0.5 mL to over 15 L without alteration of the mechanical properties of the resultant materials. The facile and scalable preparation of these materials leveraging self-assembly of inexpensive, renewable, and environmentally benign starting materials, coupled with the tunability of their properties, make them amenable to a range of industrial applications. In particular, we demonstrate their utility as injectable materials for pipeline maintenance and product recovery in industrial food manufacturing as well as their use as sprayable carriers for robust application of fire retardants in preventing wildland fires.

Scalable manufacturing of biomimetic moldable hydrogels for industrial applications

NASA Astrophysics Data System (ADS)

Yu, Anthony C.; Chen, Haoxuan; Chan, Doreen; Agmon, Gillie; Stapleton, Lyndsay M.; Sevit, Alex M.; Tibbitt, Mark W.; Acosta, Jesse D.; Zhang, Tony; Franzia, Paul W.; Langer, Robert; Appel, Eric A.

2016-12-01

Hydrogels are a class of soft material that is exploited in many, often completely disparate, industrial applications, on account of their unique and tunable properties. Advances in soft material design are yielding next-generation moldable hydrogels that address engineering criteria in several industrial settings such as complex viscosity modifiers, hydraulic or injection fluids, and sprayable carriers. Industrial implementation of these viscoelastic materials requires extreme volumes of material, upwards of several hundred million gallons per year. Here, we demonstrate a paradigm for the scalable fabrication of self-assembled moldable hydrogels using rationally engineered, biomimetic polymer-nanoparticle interactions. Cellulose derivatives are linked together by selective adsorption to silica nanoparticles via dynamic and multivalent interactions. We show that the self-assembly process for gel formation is easily scaled in a linear fashion from 0.5 mL to over 15 L without alteration of the mechanical properties of the resultant materials. The facile and scalable preparation of these materials leveraging self-assembly of inexpensive, renewable, and environmentally benign starting materials, coupled with the tunability of their properties, make them amenable to a range of industrial applications. In particular, we demonstrate their utility as injectable materials for pipeline maintenance and product recovery in industrial food manufacturing as well as their use as sprayable carriers for robust application of fire retardants in preventing wildland fires.