Multiple Manufacturing Sites Research Articles

Successful transport across continents of GMP-manufactured and cryopreserved culture-expanded human fetal liver-derived mesenchymal stem cells for use in a clinical trial

IntroductionCell therapy has been increasingly considered to treat diseases, but it has been proven difficult to manufacture the same product at multiple manufacturing sites. Thus, for a wider implementation an alternative is to have one manufacturing site with a wide distribution to clinical sites. To ensure administration of a good quality cell therapy product with maintained functional characteristics, several obstacles must be overcome, which includes for example transfer of knowledge, protocols and procedures, site assessment, transportation and preparation of the product. MethodsAs the preparatory work for a clinical trial in India using fetal mesenchymal stem cells (fMSCs) developed and manufactured in Sweden, we performed a site assessment of the receiving clinical site, transferred methods, developed procedures and provided training of operators for handling of the cell therapy product. We further developed a Pharmacy Manual to cover the management of the product, from ordering it from the manufacturer, through transport, reconstitution, testing and administration at the clinical site. Lastly, the effect of long-distance transport on survival and function of, as well as the correct handling of the cell therapy product, was evaluated according to the pre-determined and approved Product Specification. ResultsFour batches of cryopreserved human fetal liver-derived fMSCs manufactured according to Good Manufacturing Practice and tested according to predetermined release criteria in Sweden, were certified and transported in a dry shipper at −150 °C to the clinical site in India. The transport was temperature monitored and took three–seven days to complete. The thawed and reconstituted cells showed more than 80% viability up to 3 h post-thawing, the cell recovery was more than 94%, the cells displayed the same surface protein expression pattern, differentiated into bone, had stable chromosomes and were sterile, which conformed with the data from the manufacturing site in Sweden. ConclusionsOur study shows the feasibility of transferring necessary knowledge and technology to be able to carry out a clinical trial with a cell therapy product in distant country. It also shows that it is possible to transport a cryopreserved cell therapy product over long distances and borders with retained quality. This extends the use of cryopreserved cell therapy products in the future.

A concept for continuous virus manufacture using a moving bed bioreactor: Growth of MDCK cells to confluence on paper as a model support

A moving-bed bioreactor (MBB) could intensify growth of adherent mammalian cells for viral vaccines. A continuously fed sterile paper passing through a thin liquid layer as a flexible cell substrate is a new concept for bioprocess intensification (BPI). Paper could enable cell expansion with reduced footprint and reduced media consumption as the first stage of a 2-stage growth + infection continuous process. This study focused only on cell growth (stage 1). We report a simple 32 mm paper disc method to evaluate growth of adherent Madin Darby canine kidney cells (MDCK CCL-34) adapted to 5% FBS to confluence on unmodified papers to screen substrates. Bibulous paper was found to be the best substrate for proliferation of MDCK. An MBB process was simulated using paper discs to test growth to confluence (stage 1). Growth was characterized using staining, image analysis; confocal microscopy. Cells grew on the surface of bibulous paper to a confluence of >90% in 192 h. Extending this concept by stabilizing MDCK on paper (end of stage 1) by engineering cells to survive freezing or lyoprotection would enable live cells to be shipped as modules to multiple manufacturing sites for infection resulting in rapid, reproducible viral vaccine manufacture.

Large scale manufacturing for T- cell therapies using the clinimacs prodigy™

Background & Aim Cell & Gene therapies have evolved considerably since they first emerged, and so too must the associated manufacturing processes. First approvals were predominantly stem cell therapies aimed at treating very rare conditions. Now, with the increased knowledge and experience gained through development of these early therapies, the focus of the field has shifted, and indications expanded. As an industry we are now seeking to establish treatment options for more prevalent issues such as in oncology. As disease targets diversify however, increased patient numbers bring greater challenges. Prior to progressing candidates through R&D pipelines effective scale-up strategies for fit-for-purpose manufacturing processes must be established. Increased automation and use of closed end to end culture systems are essential to reduce operator intervention and risk of contamination while increasing process robustness and reproducibility across multiple manufacturing sites to meet product demand. Importantly this shift will drive down cost of goods and ultimately improve patients access to medicines. Methods, Results & Conclusion Miltenyi Biotec have developed a commercially available T-Cell Transduction (TCT) process for use on their CliniMACS Prodigy™. Critically this system encompasses end-to-end processing on one automated platform, although cell expansion is limited by the size of the culture chamber. Here we will highlight efforts to scale-up the system and develop a fit-for-purpose platform process that can satisfy emerging T-cell engineered therapies’ manufacturing requirements. Together with Miltenyi, we have co-developed a large-scale culture chamber for use with the CliniMACS Prodigy™. This has increased capacity for cell expansion and substantially increased the flexibility of the platform to treat indications requiring a range of transduced T-cell numbers. Here we will discuss the data package obtained during the development of this large-scale culture chamber and how it compares to the established standard-size process.

Ensuring Product Quality, Consistency and Patient Supply over Time for a Large-Volume Biologic: Experience with Remicade®.

Biologics are produced from living organisms in complex, multi-stage manufacturing processes and contain inherent variability, which must be understood and controlled during manufacturing to avoid unexpected changes in key quality attributes that may contribute to clinically meaningful differences. The process must also meet large commercial demand, while simultaneously being able to accommodate change without sacrificing product consistency. The four key components of successful biologics manufacturing are (1) a stable, well-defined proprietary cell line; (2) a good manufacturing practice (GMP)-compliant supply chain with a process control strategy defining acceptable levels of variability for target product/process attributes and capable of managing complex material flows; (3) a tightly controlled procedure for implementation of proposed process changes that ensures product consistency; and (4) built-in redundancy and flexibility providing the ability to adapt rapidly to unexpected developments. This report describes the requirements for the manufacturing and distribution of biologics, using Remicade® (infliximab, Janssen Biotech, Horsham, PA, USA) as an example of best practices. Since Remicade’s first marketing approval in 1998, Janssen has manufactured > 150 million vials used to treat > 2.6 million patients around the world for a variety of inflammatory diseases. Remicade displays a highly consistent quality attribute profile and meets all product/process specifications across multiple manufacturing sites and process scales. Janssen’s experience with Remicade demonstrates that deep product knowledge, extensive manufacturing experience, diligent product/process monitoring and a sustained commitment to compliance and research are required to ensure quality, consistency and uninterrupted patient supply for large-volume biologics over the long term.

An analysis of mathematical models for multi-site production and distribution planning

In today's competitive globalised market, it is imperative for enterprises to improve their efficiency, provide better service to customers, and facilitate better production and distribution activities. To do so, organisations are opting for producing at multiple manufacturing sites situated at geographically distinct locations. In the last two decades, there has been seen an increasing trend in articles working in the field of multi-site production and distribution planning. This paper defines multi-site production and distribution planning problem and provide direction for researchers and practitioners to understand the field and develop mathematical models in this area. The main objective of this paper is to analyse the existing mathematical models for identification of current research trend and future research directions. The literature is classified based on the problem formulation approach, aspects of the model, solution approach and applications. Following the classification of the articles; discussion, research findings and future research directions are indicated.

The Effect of Processing Parameters on the Physical and Microwave Electrical Properties of Low Temperature Co-fired Ceramics

Low Temperature Co-fired Ceramics (LTCC) represent a multilayer electronic packaging technology with the ability to incorporate many electrical components such as conductive, resistive, and dielectric materials, into a single monolithic package. Example devices would include capacitors, inductors, resistors, antennae, transformers, hybrid circuits, etc. In general, the LTCC package consists of a glass/ceramic dielectric and compatible conductive inks (Au, Ag, etc.). The dielectrics and conductors are patterned/laminated to form the desired 3D structure and then co-fired to complete densification. The resulting monolithic block is mechanically robust with a high density of (often buried) electrical components. Typically, LTCC systems have found implementation in circuitry utilizing the RF and microwave frequency ranges. In general, the material design and processing parameters, and knowledge of how these affect the final mechanical and electrical properties of the LTCC package are needed for successful circuit design. The electronic performance of an LTCC dielectric/conductor system (Ferro L8) was investigated as a function of processing parameters (peak fire temperature, temperature ramp rate, furnace air flow, etc.). Comparisons were also made between multiple manufacturing sites as the mentioned processing parameters vary slightly from site to site even with nominally identical set points due to differences in furnace design, fab layout, etc. Material properties of fired parts such as effective permittivity and electrical losses were measured both on bare dielectric using resonant cavity methods and on the dielectric/conductor system as a whole using microstrip transmission line methods to frequencies as high as 50 GHz. Correlations were made between electrical performance and models based on material properties. The effects of varied processing parameters and processing sites were also studied and used to help establish process understanding and improvement with respect to high frequency electrical performance. As an example, optimization of electrical performance could be achieved by adjusting the nominal furnace temperature set point at a specific site where losses were slightly high even with identical processing parameters to those at another manufacturing site.

A decision-making mechanism considering carbon footprint and cost to fulfil orders for multi-site global companies

As global warming becomes increasingly serious, some proper measures should be taken to avoid the possible devastating effects. To address this issue, corporations may take CO2 emission into consideration when they are engaged in operations planning. In this study, we attempt to optimise order fulfilment which considers carbon footprint as well as cost as objectives for global companies with multiple manufacturing sites. A two-phased decision-making mechanism is adopted: in the first phase, inappropriate manufacturing sites are manually excluded to reduce computation time; in the second phase, multi-objective genetic algorithm (MOGA) is employed to find solutions which illustrate the interactions between total carbon footprint and total cost. In order to examine the effectiveness of the proposed approach, this study performs a variety of experiments partly based on real data from a famous global company in Taiwan. The research findings show that the proposed mechanism can obtain feasible solutions effectively and efficiently. When the site number increases, the total carbon footprint decreases, and influences the environment positively.

Performance Evaluation of Green Supply Chains: A DEA-based Approach for the Chemical Industry

Traditionally, researchers and practitioners measure the performance of green supply chains from the aspects of economy and environment. Nowadays, human capital is given much attention in Corporate Social Resposibility (CSR) but is often not included in the performance measures. This research covers the an application of data envelopment analysis (DEA) slacks-based model to a multinational chemical manufacturer to minimize both input and bad output variables of both the environmental aspect, covering energy consumption, water intake, carbon dioxide(CO 2 ), voltile organic compound(VOC), solid waste, and the social aspect covering employees’ working hours and total recordable (injury and illness) rate. The model also maximizes the good output, finished good products, to satisfy customers and other stakeholders. This technique results in a more holistic result and decision making model for benchmarking the performance of multiple manufacturing sites in a multinational company in Asia .

Regulatory challenges for the manufacture and scale-out of autologous cell therapies

While many clinician- and industry-led autologous cellular therapies are demonstrating benefits to patients in clinical trials, few products have been commercially approved. Progress towards production and commercialization still faces substantial translational challenges under existing regulatory frameworks. Manufacturing and supply of more-than-minimally manipulated (MTMM) autologous cell based therapies presents a number of unique challenges driven by complex supply logistics and the need to scale-out production to multiple manufacturing sites or potentially near to the patient within hospital settings. The existing regulatory structure in Europe and the U.S imposes a requirement to establish and maintain comparability. Under a single market authorisation this is likely to become an insurmountable burden for the roll-out of manufacturing processes to more than two or three sites unless new enabling manufacturing and regulatory science can be established to bridge the comparability challenge.

A Genetic Algorithm for Directed Graph-based Supply Network Planning in Memory Module Industry

A memory module industry's supply chain usually consists of multiple manufacturing sites and multiple distribution centers. In order to fulfill the variety of demands from downstream customers, production planners need not only to decide the order allocation among multiple manufacturing sites but also to consider memory module industrial characteristics and supply chain constraints, such as multiple material substitution relationships, capacity, and transportation lead time, fluctuation of component purchasing prices and available supply quantities of critical materials (e.g., DRAM, chip), based on human experience. In this research, a directed graph-based supply network planning (DGSNP) model is developed for memory module industry. In addition to multi-site order allocation, the DGSNP model explicitly considers production planning for each manufacturing site, and purchasing planning from each supplier. First, the research formulates the supply network's structure and constraints in a directed-graph form. Then, a proposed genetic algorithm (GA) solves the matrix form which is transformed from the directed-graph model. Finally, the final matrix, with a calculated maximum profit, can be transformed back to a directed-graph based supply network plan as a reference for planners. The results of the illustrative experiments show that the DGSNP model, compared to current memory module industry practices, determines a convincing supply network planning solution, as measured by total profit.

Application of deglycosylation and electrophoresis to the quantification of influenza viral hemagglutinins facilitating the production of 2009 pandemic influenza (H1N1) vaccines at multiple manufacturing sites in China

The single radial immunodiffusion (SRID) method currently used to determine the hemagglutinin (HA) content of the inactivated influenza vaccines depends on the availability of reference HA antigen and corresponding anti-serum, updated and provided annually by World Health Organization (WHO) collaborative centers. Particularly early in a pandemic outbreak, reference reagents could be the bottleneck in vaccine development and release. Therefore, other reliable tests capable of quantifying HA content could substantially shorten the time needed for vaccine formulation. Here electrophoretic separation of deglycosylated samples in conjunction with densitometry was used to quantify HA contents of H1N1 vaccine at multiple manufacturing sites. We found the overall consistency between the alternative method and traditional SRID was 88–122% in seven lots of vaccine bulks from four subtypes (types) of influenza vaccine, confirming its suitability to quantify HA content. Moreover, we used the alternative method to prepare a national HA antigen reference in China for quality control of 2009 pandemic influenza A (H1N1) vaccines prior to the arrival of the WHO SRID reference standards, subsequently confirming good agreement between both methods. The alternative method for vaccine quantification enabled the Chinese health authority to approve H1N1 vaccine 1 month earlier than otherwise possible.

ANALYSIS OF FIRST MILLENNIUMbcGLASS VESSELS AND BEADS FROM THE PICHVNARI NECROPOLIS, GEORGIA*

The Pichvnari necropolis on the Black Sea coast of Georgia lies in an area known in the late first millennium as ‘Colchis’, on part of the trade route leading to the Orient. The burials of the necropolis date to the late fifth centurybcand frequently contain grave goods, including extremely well‐preserved polychrome glass beads and core‐formed vessels. This paper presents a study of these vessels both stylistically and archaeologically and using SEM–WDS and LA–ICPMS. It reveals that the vessels have compositional differences that may point to multiple manufacturing sites. One of the vessels appears stylistically unique and may exhibit one of the earliest uses of manganese as a decolorizer. Major and minor element data for the vessels suggest that they may belong to the same ‘Levantine’ group as many Roman glass objects, suggesting that a source of sand on the coast of the Levant could have been used in their production. The beads clearly show glass with both natron‐ and plant ash‐based flux with distinct rare earth compositions, showing multiple sites of production, some of which were probably either in the Middle East or the Indian subcontinent.

Integrated multi-site production-distribution planning in supply chain by hybrid modelling

Allocation of production volumes among multiple manufacturing sites and distribution of products among distribution channels involves many quantitative and qualitative variables and constraints. An integrated multi-product, multi-period, multi-site production-distribution planning subject to the production and distribution constraints, distribution system and local customers demand is considered in this paper. To do this, we took advantage of a hybrid mathematical-simulation model to solve the proposed problem. A mathematical model has been developed to solve the problem, aiming to decrease the costs of set up, production, inventory, distribution and transportation. Because of stochastic factors such as unexpected delays, queuing and machine failure, operation time provided by mathematical model cannot reflect dynamic characteristic of real-world systems and optimal solution of mathematical model is not acceptable in practice. Therefore, we took advantage of a hybrid mathematical-simulation approach to explore the behaviour of the real-world system. Through the computational experiments, we demonstrated that the number of iterations to converge hybrid procedure would lessen when we consider the production-distribution problem in an integrated manner. Also, supply chain overall costs will be reduced through the integration of production and distribution problems. Finally, the solution is a realistically optimal solution for the proposed integrated production-distribution planning problem.

Concentration of transforming growth factor‐beta in an infant formula from five countries and human milk from Mexico and the US

Transforming growth factor‐beta (TGF‐beta) is found in human milk and is thought to be a key growth factor for the development of the immune system and oral tolerance in neonates. In this study, the concentration of total TGF‐beta (isoforms beta‐1 and beta‐2) was determined in human milk obtained from mothers in the US and Mexico, and compared to that found in an infant formula (Enfamil LIPIL powder) marketed in 5 countries. Human milk samples (n=260) were collected at specific times over the first 26 weeks of lactation from three cohorts of 20 healthy mothers who delivered term babies. Infant formula powder samples (n=25) representing multiple manufacturing sites were obtained from the US, Mexico, Thailand, China, and Philippines. TGF‐beta isoforms were quantified by a specific ELISA method validated for each type of sample. When pooled across the cohorts and collection times, human milk exhibited a geometric mean of 2,700 pg/ml and a 95% confidence interval of 550 ‐ 13,000 pg/ml. The mean concentration of TGF‐beta in the reconstituted infant formula was 4,900 pg/ml with a range of 2,800 ‐ 9,900 pg/ml. These data demonstrate that TGF‐beta is present in infant formula at a level within the range found in human milk.

Managing product variety in multinational corporation supply chains

PurposeFor manufacturing enterprises, today's business environment is characterised by globally dispersed supply and manufacturing networks. In addition, the level of variety in products continues to increase in almost all sectors. Greater understanding of the management of product variety in international operations is required. Aims to discuss this issue.Design/methodology/approachA generic simulation model representing a multinational corporation (MNC) supply chain is used to investigate the impact on supply chain performance of increasing product variety in combination with supply lead‐time and demand uncertainty in an international setting. The simulation focuses on the upstream activities of production planning, inbound supply and manufacturing. The structure and logic of the simulation model are based on insights obtained from an empirical study of real MNC supply networks.FindingsThe study shows that increasing the level of product variety has a detrimental impact on supply chain performance. In the presence of supply lead‐time and demand uncertainty, high levels of variety result in much longer flow times and much higher system inventory relative to more stable conditions. The impact is greatest when variety involves critical materials which are required early in the production process and that entail long set‐up times.Research limitations/implicationsThe study could be extended to incorporate more advanced inventory control models, the inclusion of downstream activities, multiple manufacturing sites and multiple potential supply routes.Practical implicationsImplications for the selection of suppliers and for inventory control policies are discussed in the context of international operations. The potential value of postponement strategies and the need in some cases for fundamental product and process redesign to mitigate the negative impacts of variety are highlighted.Originality/valueManaging product variety in the context of international operations has received very little attention to date in the research literature. This study quantifies the potential impact of increasing product variety on supply chain performance in an international setting.

Evaluation of in-line electron beam system requirements and capabilities

Medical device manufacturers have recently began to study and implement in-line electron beam irradiators for device sterilization instead of relying heavily on centralized locations serving multiple manufacturing sites. Before deciding to install such a system, the sterilization needs should be systematically considered. The evaluation includes • Technical specifications for in-line systems, including energy requirements balanced against size and shielding requirements. • Economics of in-line systems, balancing capital expenditure and increased operational costs at a single location versus costs of transporting products to the central location and the operational costs, including institutional and quality assurance requirements on operating a system.