Single Batch Production Research Articles

Two‐Stage Hybrid Optimization Algorithm for Silicon Single Crystal Batch Scheduling Problem under Fuzzy Processing Time

Considering the widely existing processing time uncertainty in the real‐world production process, this paper constructs a fuzzy mathematical model for the silicon single crystal production batch scheduling problem to minimize the maximum completion time. In this paper, a two‐stage hybrid optimization algorithm (TSHOA) is proposed for solving the scheduling model. Firstly, the improved differential evolution algorithm (IDE) is used to solve the order quantity allocation problem of silicon single crystal with different sizes to obtain the quantity of silicon single crystal rods with different sizes produced by different types of single crystal furnaces. Secondly, the variable neighborhood search (VNS) algorithm is adopted to optimize the order quantity sequencingof batch production processes. Finally, simulations and comparisons demonstrate the feasibility of the model and the effectiveness of TSHOA.

Investigation on validation of scale-up manufacture technologies of overcoating particles for HTR fuel elements

A set of overcoating equipment with a single batch output of 80–100 kg overcoated particles was developed. The experimental results obtained by using the optimized process validated that the equipment and process can not only maintain a high yield within a wide range of process parameters, but also be suitable for producing in a wide range of batch size. By studying the particle size distributions (PSDs) of different batches of overcoated particles and the transformations of PSDs and sphericity during a single batch production, combined with the movement law of particles in the overcoating drum, the reasons for the transformation of PSDs from near normal to positive skewness to negative skewness during the overcoating process was revealed. The origin of the formation of abnormal particles with different shapes was explained by analyzing the details of the defects of odd-shaped particles. The technology in this study can effectively improve the productivity, production efficiency and quality of overcoated particles, which can meet the demand of mass manufacture of fuel elements for HTR.

Optimised GMP-compliant production of [18F]DPA-714 on the Trasis AllinOne module

BackgroundThe translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [18F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [18F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity.Results[18F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [18F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100∘C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [18F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [18F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies.ConclusionTo the best of our knowledge, the process presented herein is the most efficient [18F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.

Which is the best 9Be carrier for 10Be/9Be accelerator mass spectrometry?

Commercial 9Be solutions used for chemical preparation of samples for accelerator mass spectrometry contain the cosmogenic long-lived radionuclide 10Be at elevated but different 10Be/9Be levels. Within a systematic study of recently produced solutions, comparison to published data and new data on customised solutions from minerals, we recommend - if no customised solution is available - the 9Be solutions from Australian Chemical Reagents (ACR) or from LGC. They contain 10Be/9Be at the 3.4 × 10−15 level, which is still suitable for the majority of Earth science applications, compared to customised solutions at the 10−16 level for lowest-level studies. Commercial solutions from Scharlab having different lot numbers, i.e. an identification number assigned to a particular lot of material from a single manufacturer, vary in 10Be/9Be by up to a factor of nine. Hence, it seems an advisable strategy to buy a bigger quantity of a single production batch (such as 10 × 100 ml bottles of 9Be at 1 g l−1) and have them tested once at any AMS facility before first use.•The best 9Be carrier for low-level 10Be/9Be applications is a customised one from minerals like phenakite.•The best 9Be carriers for medium- and high-level 10Be/9Be applications are currently from Australian Chemical Reagents (ACR) or from LGC.•As 9Be carriers from Scharlab of different batches (LOT) contain 10Be/9Be at different levels, it is advisable to buy a bigger number of bottles of the same LOT of commercial carriers after being identified to have reasonably low isotope ratios.

Design model for a value chain-oriented quality management in global tooling

The globalization of production has current effects on the tooling industry. Customer proximity, fast reaction times and a worldwide service range are significant selling propositions for market positioning of a toolmaking company. Nevertheless, high quality standards are indispensable to distinguish from the international competition. The developed quality management model includes three design modules giving different approaches for quality improvement in tool manufacturing. Additionally, digitalization solutions to support the implementation of quality gates in single batch production are presented. Furthermore, five main target aspects have been developed for a framework of a value chain-oriented QM model for global producing tooling companies.

Support Vector and Locally Weighted regressions to monitor monoclonal antibody glycosylation during CHO cell culture processes, an enhanced alternative to Partial Least Squares regression

Since monoclonal antibodies (mAb) are sensitive to the manufacturing process, several mAb variants can be the result of a single batch production. The most critical source of heterogeneity is glycosylation which has a profound impact on safety and efficacy of the final product. Implementation of monitoring and control of the process using the Quality by Design (QbD) approach may help to ensure mAb specifications, although its implementation is limited by the availability of real-time specific measurements. All current approaches to elucidate mAb glycoforms require sampling and labour-intensive efforts. Thus, glycosylation analysis is often performed with the objective of detecting quality defects at the end of the culture process. In this work, the capability of Near Infrared spectroscopy and chemometric treatment to accurately monitor mAb glycosylation during CHO cells cultures using in situ probes is shown for the first time. Real-time monitoring of glycosylation, in terms of high mannose isoforms, fucosylated, sialylated and galactosylated isoforms as well as non-glycosylated mAb, has been successfully performed by the novel use of Locally Weighted Regression (LWR) and Support Vector Regression (SVR). These encouraging results open the way for the implementation of control systems on the impact of cell culture operating parameters on mAb heterogeneity, particularly glycosylation, during CHO cell culture processes through the QbD approach.

Improving Concentration of Healthy Fatty Acids in Milk, Cheese and Yogurt by Adding a Blend of Soybean and Fish Oils to the Ration of Confined Dairy Cows

Compared to pasture based sistems, milk produced in confined dairy systems is characterized by a high saturated fat (SF) content with a lower concentration of healthy fatty acids (FA) such as vaccenic (VA, trans-11C18:1), conjugated linoleic cid (cis-9, trans-11 C18:2, CLA), α-linolenic (cis-9, cis-12, cis-15C18: 3), eicosapentaenoic (EPA, C20:5) and docosahexaenoic (DHA, C22:6) whose presence in milk and dairy products can be increased by feeding polyunsaturated FA (PUFA). The aim of the study was to determine the differences in milk composition and FA profile between a regular (Reg) milk (Reg-Milk), a Reg-Dambo type cheese (Reg-DCh) and a Reg yogurt (Reg-Yog) with that obtained after including a blend (7:1) of soybean (SO) and fish (FO) oils in the total mixed ration (TMR) of lactating dairy cows. The experiment was carried out at the Talar Farm located at Laguna del Sauce, Maldonado Department, Punta del Este, Uruguay Republic during a period of 30 experimental days using a single production batch of 29 Holstein cows. Within this batch, one group of 8 cows (1.88 ± 0.99 calves) in early lactation (135 ± 19 days postpartum) was selected to individually measure milk yield and composition. During the first 7 days of the experiment, cows were fed a TMR without oil-blend inclusion to obtain the Reg-Milk, Reg-DCh and Reg-Yog. From the 8th day onwards, the oil blend was added to the TMR at 4% DM (1.0 kg oil blend cow-1 day-1) and after 23 days of feeding, the modified milk (Mod-Milk) was analyzed and collected to elaborate the modified Dambo-type cheese (Mod-DCh) and Mod-yogurt (Mod-Yog). Milk yield was recorded daily in the selected 8 cows and milk composition was determined over two consecutive days prior to the start of blend-oil supply (Reg-Milk) and at the end of oil supplementation (Mod-Milk) on days 29th and 30th. Milk-tank samples of Reg-Mi and Mod-Mi were also collected and analyzed for chemical composition and milk FA profile. Cheese and yogurt were assayed for its FA profile. Differences in milk yield and composition and in the FA profile before and after oil-feeding were stated using the Student T-test for paired observations. Milk production (kg·cow-1·day-1) slightly (-6.7%) decreased (P -1 g leading to a lower (P -1·day-1) of fat corrected milk (4%FCM) from 32.83 (before) to 29.63 after oil. Milk protein content (g 100 g-1) increased (P -1·day-1) (P -1 in Mod-Mi as it was observed (P -1). Yield of NFS tended (P -1·day-1after oil supply. Content of atherogenic FA (C12:0 to C16:0) was significantly (P -1 (Mod-Mi) with a concomitant decrease (P -1 FA) of elaidic (trans-9 C18:1) and trans-10 C18:1 FA was low in Reg-Mi (0.22 and 0.34 respectively) but tended (P -1 FA) of VA resulted higher (+110%, P -1 FA) increased (P -1) of α-linolenic were higher (P cis-9 C18:1) content (g 100 g-1) remained unchanged (P < 0.504) averaging 21.99 in Reg-Mi and 22.86 in Mod-Mi. Composition of FA of the Mod-DCh was highly correlated (R2 = 0.999) with FA profile from its original Mod-Mi. A serving of the M-DCh (30 g) theoretically involved a 12.1% reduction in total fat consumption with 16.9% less in SF intake compared to the Reg-Ch. A serving of the M-DCh could putatively increase total CLA consumption by 72.7% compared to the Reg-DCh. Compared to Reg-Yo, a portion (178 g) of the Mod-Yo could increase (69.4%) total CLA intake. The nutritional value of milk fat was improved by feeding a blend of PUFA oils to confined dairy cows and the consumption of the mofified dairy products obtained could promote a lower intake of the potentially atherogenic saturated FA and some increase in healthy FA ingestion.

An integrated bioprocess for fermentative production of protopanaxadiol by recycling ethanol waste during down-stream extraction process

Abstract: Solvent recovery and reutilization in bioprocess have great potential to reduce production cost and environmental harm. However, solvent recovery process is often energy-intensive and costly. In this study, we developed an integrated bioprocess for fermentative production of protopanaxadiol (PPD) from ethanol waste recycled in down-stream extraction process, achieving solvent recovery and reutilization in a cost-effective manner. In this integrated process, PPD isolation and purification were achieved by foam separation and resin chromatography, respectively; ethanol solution used as PPD extractant and chromatography eluent was recycled to be reused directly as yeast carbon source for PPD biosynthesis. Notably, in 3 batches of 5 L-fermentation productions, the recycled ethanol could compensate 81.3% of the ethanol used in fermentation. Since the lost PPD during chromatography elution was returned into the next-batch fermentation together with the recycled ethanol, the overall yield of 3-batch production (85.78%) was higher than the yield of single batch production (∼75%). This study demonstrates a promising integrated bioprocess for triterpene compounds production from ethanol waste.

A modified particle swarm optimization algorithm for location problem

In the Weber location problem which was proposed for optimal location of industrial enterprises, the aim is to find the location of a point such that the sum of weighted distance between this point and a finite number of existing points is minimized. This popular model is widely used for optimal location of equipment and in many sophisticated models of cluster analysis such as detecting homogeneous production batches made from a single production batch of raw materials. The well-known iterative Weiszfeld does not converge efficiently to the optimal solution when the solution either coincides or nearly coincides with one of the demands point which is not the optimum. We propose a modified Particle Swarm Optimization (PSO) algorithm. The velocity update of the PSO is modified to enlarge the search space and enhance the global search ability. The preliminary results of these algorithms are analyzed and compared.

Production planning methodology in hybrid systems

The aim of this study is to present a methodology of resource planning under deterministic constraints. Most small and medium-sized enterprises are representatives of the MTO group. This results from a shorter product life time due to the changing expectations of customers. This, in turn, contributes to the separation of R & D departments in organizational structures of enterprises and close cooperation between industry and research units specializing in the field of operation of a given producer. More and more products are designed to be unique so as to suit client’s requirements. Similarly, the process of manufacturing such a product will be unique. From the point of view of management, the preparation of production and the production itself in this case has more features of a project-type task than typical production.Many enterprises, in particular small and medium-sized ones, the activity of which is flexible in terms of the offered products create a hybrid system encompassing series production, single-batch production and projects.The article presents a new approach to the topic of scheduling in such hybrid systems combining MTS, Projects and MTO. The presented method of scheduling is based on the assumptions of the Theory of Constraints. In small and medium-sized enterprises, which fight for every order, it is necessary to use production scheduling methods that are characterized by flexibility, transparency and reasonably low labour intensity, taking into account numerous resource constraints involved in production in a hybrid system. In this system we face a decision-making process which forces us to answer the question: can a new order be accepted to be fulfilled in a strictly defined deadline.

Removal of chloride impurities from titanium sponge by vacuum distillation

Thermodynamics analysis and affecting factors of vacuum distillation on removal of chloride impurities from titanium sponge were studied. The theoretical results show that volatilization ability of Mg,MgCl2, TiCl2 and TiCl3 are very strong under vacuum when distillation temperature is more than 800 °C. And chloride impurities could be removed more effectively by improving volatilization rate of MgCl2 at 900 °C–1050 °C with lower residual system pressure. Experimental results showed that chlorine content in the titanium sponge significantly increased with the increasing of system pressure and chlorine content in magnesium reductant. Meanwhile, the removal of chlorine from titanium sponge was very temperature and distillation time dependent. In addition, the chloride impurities were more difficult to be removed with the decreased porosity of titanium sponge. Finally, optimized parameters for distillation furnace with single batch production capacity of 7.5t titanium sponge were achieved. The chlorine content in final titanium sponge product can be controled at or lower than 0.06 wt% when the distillation temperature, system pressure, and distillation time were 980 °C–1000 °C, 0.1 Pa–3 Pa and 150 h–157 h respectively.

Characterization of Influenza Virus Pseudotyped with Ebolavirus Glycoprotein.

ABSTRACTWe have produced a new Ebola virus pseudotype, E-S-FLU, that can be handled in biosafety level 1/2 containment for laboratory analysis. The E-S-FLU virus is a single-cycle influenza virus coated with Ebolavirus glycoprotein, and it encodes enhanced green fluorescence protein as a reporter that replaces the influenza virus hemagglutinin. MDCK-SIAT1 cells were transduced to express Ebolavirus glycoprotein as a stable transmembrane protein for E-S-FLU virus production. Infection of cells with the E-S-FLU virus was dependent on the Niemann-Pick C1 protein, which is the well-characterized receptor for Ebola virus entry at the late endosome/lysosome membrane. The E-S-FLU virus was neutralized specifically by an anti-Ebolavirus glycoprotein antibody and a variety of small drug molecules that are known to inhibit the entry of wild-type Ebola virus. To demonstrate the application of this new Ebola virus pseudotype, we show that a single laboratory batch was sufficient to screen a library (LOPAC1280; Sigma) of 1,280 pharmacologically active compounds for inhibition of virus entry. A total of 215 compounds inhibited E-S-FLU virus infection, while only 22 inhibited the control H5-S-FLU virus coated in H5 hemagglutinin. These inhibitory compounds have very dispersed targets and mechanisms of action, e.g., calcium channel blockers, estrogen receptor antagonists, antihistamines, serotonin uptake inhibitors, etc., and this correlates with inhibitor screening results obtained with other pseudotypes or wild-type Ebola virus in the literature. The E-S-FLU virus is a new tool for Ebola virus cell entry studies and is easily applied to high-throughput screening assays for small-molecule inhibitors or antibodies.IMPORTANCE Ebola virus is in the Filoviridae family and is a biosafety level 4 pathogen. There are no FDA-approved therapeutics for Ebola virus. These characteristics warrant the development of surrogates for Ebola virus that can be handled in more convenient laboratory containment to study the biology of the virus and screen for inhibitors. Here we characterized a new surrogate, named E-S-FLU virus, that is based on a disabled influenza virus core coated with the Ebola virus surface protein but does not contain any genetic information from the Ebola virus itself. We show that E-S-FLU virus uses the same cell entry pathway as wild-type Ebola virus. As an example of the ease of use of E-S-FLU virus in biosafety level 1/2 containment, we showed that a single production batch could provide enough surrogate virus to screen a standard small-molecule library of 1,280 candidates for inhibitors of viral entry.

Improved model for detection of homogeneous production batches of electronic components

Supplying the electronic units of the complex technical systems with electronic devices of the proper quality is one of the most important problems for increasing the whole system reliability. Moreover, for reaching the highest reliability of an electronic unit, the electronic devices of the same type must have equal characteristics which assure their coherent operation. The highest homogeneity of the characteristics is reached if the electronic devices are manufactured as a single production batch. Moreover, each production batch must contain homogeneous raw materials. In this paper, we propose an improved model for detecting the homogeneous production batches of shipped lot of electronic components based on implementing the kurtosis criterion for the results of non-destructive testing performed for each lot of electronic devices used in the space industry.

Procedures for the GMP-Compliant Production and Quality Control of [18F]PSMA-1007: A Next Generation Radiofluorinated Tracer for the Detection of Prostate Cancer.

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [18F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [18F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [18F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [18F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [18F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [18F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.

Erratum to: Decision-Support Method for the Choice Between Single-Use and Multi-Use Technologies in Sterile Drug Product Manufacturing

Single-use technology has been applied to sterile drug product manufacturing processes as a new technology in contrast with the conventional multi-use technology. This study proposes a decision-support method for choosing between these two technologies in sterile drug product manufacturing. The proposed method consists of four steps: create process evaluation models, calculate evaluation results, perform what-if analysis, and interpret results. We created models for evaluating the production cost and life cycle CO2 emissions of processes using either technology. “What-if” analysis quantifies the effect of the input parameters on the evaluation results, which supports more informed decision-making. Here, it is recommended that the filling speed, which was found to have a significant impact on filling accuracy—a critical quality attribute of sterile drug products—should be investigated. As a case study, the method was applied in two cases of technology selection: (i) single-batch production of a product with different batch sizes and (ii) single-batch production with different production patterns. The single-use technology showed its economic superiority in producing small batches and in producing multiple small-scale products, whereas in the environmental evaluation, it was always better than multi-use technology. What-if analyses revealed the impact of changing input parameters on the economy, environment, and quality. Our method can support the choice of single-use and multi-use technologies in plants having both technologies independently. In the case study, economic evaluation showed a critical point in each design case, whereas the environmental evaluation result was always better in single-use technology.

Fast deterministic algorithm for EEE components classification

Authors consider the problem of automatic classification of the electronic, electrical and electromechanical (EEE) components based on results of the test control. Electronic components of the same type used in a high- quality unit must be produced as a single production batch from a single batch of the raw materials. Data of the test control are used for splitting a shipped lot of the components into several classes representing the production batches. Methods such as k-means++ clustering or evolutionary algorithms combine local search and random search heuristics. The proposed fast algorithm returns a unique result for each data set. The result is comparatively precise. If the data processing is performed by the customer of the EEE components, this feature of the algorithm allows easy checking of the results by a producer or supplier.

An optopneumatic piston for microfluidics.

We demonstrate an optopneumatic piston based on glass capillaries, a mixture of PDMS-carbon nanopowder, silicone and mineral oil. The fabrication method is based on wire coating techniques and surface tension-driven instabilities, and allows for the assembly of several pistons from a single batch production. By coupling the photothermal response of the PDMS-carbon mixture with optical excitation via an optical fiber, we demonstrate that the piston can work either as a valve or as a reciprocal actuator. The death volume of the pistons was between 0.02 and 1.56 μL and the maximum working frequency was around 1 Hz. Analysis of the motion during the expansion/contraction of the piston shows that this machine can be described by a phenomenological equation analogous to the Kelvin-Voight model used in viscoelasticity, having elastic and viscous components.

OPTIMIZING CATFISH FEEDING AND STOCKING STRATEGIES OVER A TWO-YEAR PLANNING HORIZON

Rising costs of feed ingredients in recent years have resulted in record increases in catfish feed prices. Since understocked channel catfish (Ictalurus punctatus) do not reach market size until the second year of production, static one-year economic models and analyses may not be adequate. A previous mixed-integer profit-maximizing model was extended to include a second year to evaluate the effects of varying feeding frequencies on farm management decisions, particularly on adjustments in the second year. Production options considered included frequency of feeding (every day, every other day, and every third day), multiple-batch production from four different fingerling sizes, and single-batch production from three different stocker sizes. Every day feeding was identified as the profit-maximizing feeding strategy on farms using multiple-batch production but unfavorable market prices, high feed prices, and operating capital constraints reduced feeding frequencies. Every day feeding remained the optimal strategy for farms in single-batch foodfish production. Market and capital constraints reduced the scale of farms operating in single-batch foodfish production, but did not change the optimal every day feeding strategy. Farms maximized profits by transitioning from multiple batch to single batch over the two-year period.

Modelling the effect of chilling on the occurrence of Salmonella on pig carcasses at study, abattoir and batch levels by meta-analysis

The effect of chilling on the occurrence of Salmonella on pig carcasses was investigated at study, abattoir and batch level by meta-analysis. Both the fixed-effects and random-effects model confirmed (p<0.05) the significant effect of chilling in decreasing Salmonella occurrence on pig carcasses; although the random-effects solution was preferred to account for the significant variability in effect size (p<0.001) estimated from the 13 primary studies considered, the 32 abattoirs surveyed, and the 51 sampled batches. Conservatively, it can be said that chilling reduces the Salmonella incidence on pig carcasses by a mean ratio of ~1.6 (95% CI: 1.0–2.6). Multilevel meta-analysis models investigating study characteristics that could explain the heterogeneity (τ2) in the true effect size among primary studies (τ2=0.578), among surveyed abattoirs (τ2=0.431), and among sampled batches (τ2=0.373), revealed that study size (represented by the moderating variables of ‘total sample size’ and ‘number of batches sampled in an abattoir’) and ‘carcass swabbed area’ have a significant impact (p<0.05) on the measured effect size of chilling. The fact that swabbed area explained between 56 and 62% and total sample size between 23 and 38% of the total heterogeneity in the chilling true effect size, indicates that differences in experimental design greatly affect our substantive conclusion about the effect of chilling on Salmonella occurrence. This inconsistency to elucidate the effect of chilling arises because of the many factors influencing both the performance of the chilling operation and the measurement itself. Meta-analysis was not only instrumental to show that small-size studies (i.e., only one batch sampled per abattoir, total number of sampled carcasses per batch<50) and small swabbed areas (<100cm2) lead to imprecise and even conflicting conclusions, but most importantly, enabled definition of the characteristics of a well-designed study having a minimum statistical power to produce precise results. A sound experimental design derived by multilevel meta-analysis consists of swabbing carcass areas of at least 500cm2 from 25 pre-chill and 25 post-chill carcasses from a single production batch, with a minimum of two batches sampled per surveyed abattoir. If the survey were to be conducted in more than one abattoir, the total sample size should not be less than 400. Two methods to test for publication bias, a common problem in meta-analysis, suggested that whilst the presence of unpublished small-size studies is probable, it is not likely that this would significantly bias the overall chilling effect estimated in this study.

Phase 3 readiness for autologous cell therapies: unique software applications for training, scheduling and manufacturing of ixmyelocel-T

Aastrom is developing ixmyelocel-T, a patient-specific, expanded multicellular therapy for use in the treatment of severe chronic cardiovascular diseases. It is an autologous product derived from patient bone marrow, regulated as a biologic and manufactured in a centralized facility under Good Manufacturing Practices (GMP). For Phase 3 readiness, drug developers targeting autologous cell therapies must identify optimal strategies to manufacture cell therapies safely while being able to manufacture at a higher volume without compromising quality. While most pharmaceutical manufacturing processes can take advantage of sharing a single production batch among multiple patients, this is not the case for autologous cell therapies. The core steps for manufacturing cannot be shared, so companies need to look for other ways to achieve efficiencies while meeting quality standards, including computerization, process automation, and engineering integration. Prior to Phase 3 startup, the final process must be locked, specifications finalized and GMP system development must be completed (e.g. quality systems, materials management, facilities). In addition, specific for autologous products, patient and sample identification tracking, training systems, and scheduling must be in place. Not only do activities within the manufacturing facility need to be managed to insure quality, but also the initial collection of patient material and preparation of the final product at the clinical site. Quality assurance for the manufacture if the product does not end until the product has been administered to the patient. Web-based applications have been developed and applied to manage training and scheduling of clinical site activities and coordination with activities at the manufacturing site. Additional software applications have been developed to efficiently execute manufacturing support systems such as batch record issuance, scheduling and work-flow management. Together these system enable increased capacity and mitigate risks such as chain of identity, which are both challenges for autologous cell therapy. ABSTRACT