scholarly journals MSC Manufacturing for Academic Clinical Trials: From a Clinical-Grade to a Full GMP-Compliant Process

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1320
Author(s):  
Chantal Lechanteur ◽  
Alexandra Briquet ◽  
Virginie Bettonville ◽  
Etienne Baudoux ◽  
Yves Beguin
Keyword(s):  
Large Scale ◽  
Raw Materials ◽  
Good Manufacturing Practice ◽  
Phase Iii ◽  
Scale Production ◽  
Clinical Grade ◽  
Advanced Therapy Medicinal Product ◽  
Long Term Storage ◽  
Advanced Therapy ◽  
New Variant

Following European regulation 1394/2007, mesenchymal stromal cell (MSCs) have become an advanced therapy medicinal product (ATMP) that must be produced following the good manufacturing practice (GMP) standards. We describe the upgrade of our existing clinical-grade MSC manufacturing process to obtain GMP certification. Staff organization, premises/equipment qualification and monitoring, raw materials management, starting materials, technical manufacturing processes, quality controls, and the release, thawing and infusion were substantially reorganized. Numerous studies have been carried out to validate cultures and demonstrate the short-term stability of fresh or thawed products, as well their stability during long-term storage. Detailed results of media simulation tests, validation runs and early MSC batches are presented. We also report the validation of a new variant of the process aiming to prepare fresh MSCs for the treatment of specific lesions of Crohn’s disease by local injection. In conclusion, we have successfully ensured the adaptation of our clinical-grade MSC production process to the GMP requirements. The GMP manufacturing of MSC products is feasible in the academic setting for a limited number of batches with a significant cost increase, but moving to large-scale production necessary for phase III trials would require the involvement of industrial partners.

scholarly journals Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: Off-the-shelf GMP-manufactured donor-independent ATMP

2020 ◽  
Author(s):  
Seda Ballikaya ◽  
Samar Sadeghi ◽  
Elke Niebergall-Roth ◽  
Laura Nimtz ◽  
Jens Frindert ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Manufacturing Process ◽  
Ex Vivo ◽  
Good Manufacturing Practice ◽  
Process Data ◽  
Advanced Therapy Medicinal Product ◽  
Drug Products ◽  
Advanced Therapy ◽  
Immunomagnetic Isolation

Abstract Background: Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an easily accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated not only with skin-related but also systemic inflammatory and/or degenerative processes.Methods: We developed and validated Good Manufacturing Practice-compliant expansion and manufacturing process by which ABCB5+ MSCs derived from surgical discard skin tissues are processed to an advanced-therapy medicinal product (ATMP) for clinical use. Enrichment for ABCB5+ MSCs is achieved in a three-step process involving plastic adherence selection, expansion in a highly efficient MSC-selecting medium and immunomagnetic isolation of the ABCB5+ cells from the mixed culture.Results: Product Quality Review data covering 324 cell expansions, 728 ABCB5+ MSC isolations, 66 ABCB5+ MSC batches and 85 final drug products reveal high process robustness and reproducible, reliable quality of the manufactured cell therapy product.Conclusion: We have successfully established an expansion and manufacturing process that enables the generation of homogenous ABCB5+ MSC populations of proven biological activity manufactured as a standardized, donor-independent, highly pure and highly functional off-the-shelf available ATMP, which is currently tested in multiple clinical trials.

scholarly journals Cell Banking of HEK293T cell line for clinical-grade lentiviral particles manufacturing

2020 ◽  
Author(s):  
Unai Perpiña ◽  
Cristina Herranz ◽  
Raquel Martin-Ibañez ◽  
Anna Boronat ◽  
Felipe Chiappe ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Hek293t Cell ◽  
Good Manufacturing Practice ◽  
Clinical Grade ◽  
Cell Bank ◽  
Advanced Therapy ◽  
Working Cell ◽  
Cell Banks ◽  
Hek293t Cell Line

Abstract Background: Cell banks are widely used to preserve cell properties as well as to record and control the use of cell lines in biomedical research. The generation of cell banks for the manufacturing of Advanced Therapy Medicinal Products, such as cell and gene therapy products, must comply with current Good Manufacturing Practice regulations. The quality of the cell lines used as starting materials in viral-vector manufacturing processes must be also assessed.Methods: Three batches of a Master Cell Bank and a Working Cell Bank of the HEK293T cell line were manufactured under current Good Manufacturing Practices regulations. Quality control tests were performed according to product specifications. Process validation includes the training of manufacturing personnel by performing simulation tests, and the continuous measurement of environmental parameters such as air particles and microorganisms. Cell number and viability of cryopreserved cells were periodically measured in order to define the stability of these cellular products.Results: All batches of HEK293T Master and Working Cell Banks met the acceptance criteria of their specifications showing the robustness and homogeneity of the processes. In addition, both Master and Working Cell Banks maintained the defined cell viability and concentration over a 37 month-period after cryopreservation. Conclusions: Manufacturing cell banks under Good Manufacturing Practice regulations for their use as raw materials or final cellular products is feasible. HEK293T cell banks were used to manufacture clinical-grade lentiviral particles for Chimeric Antigen Receptor T-cell based clinical trials.

Optimal Design and Techno-Economic Analysis for Corncob Particles Briquettes: A Literature Review of the Utilization of Agricultural Waste and Analysis Calculation

2021 ◽  
Author(s):  
Asep Bayu Dani Nandiyanto ◽  
Nissa Nur Azizah ◽  
Gabriela Chelvina Santiuly Girsang
Keyword(s):  
Optimal Design ◽  
Literature Review ◽  
Economic Analysis ◽  
Large Scale ◽  
Net Present Value ◽  
Raw Materials ◽  
Agricultural Waste ◽  
Raw Material ◽  
Variable Cost ◽  
Scale Production

Corncob is usually disposed of directly as waste, creating problems in the environment, while it can be converted into valuable materials. This research aimed to evaluate the literature review on briquette production from agricultural waste (using non-binder and cold press with a binder) and the current works on techno-economic analysis, to propose an optimal design for the production of briquette from corncob waste, and to perform a techno-economic analysis based on the selected optimal processing method. The engineering perspective based on stoichiometry and mass balance showed the potential corncob briquette manufacture in both home and large scales due to the possible use of inexpensive and commercially available equipment and raw materials. The economic perspective [based on several economic evaluation factors (i.e., gross profit margin, payback period, break-even point, cumulative net present value, return of investment, internal rate return, and profitability index) under ideal and non-ideal conditions by considering internal (i.e., sales, raw materials, utilities, and variable cost) and external aspects (i.e., tax)] confirmed the prospective development of the project in the large-scale production with a lifetime of more than 18 years. The main issue in the project is the raw material (i.e. tapioca flour), giving the most impact on the project’s feasibility. Even in severe conditions, the project is feasible. The great endurance was also confirmed in the case of a higher tax rate. This study demonstrates the importance of producing corncob-based briquettes for improving the economic value and giving alternatives for problem solvers in the utilization of agricultural waste.

An Improved And Suitable Method For Large Scale Produdcion Of Α-Monochlorocyclodecanone

2021 ◽  
Vol 18 ◽  
Author(s):  
Wenhua Ou ◽  
Ruolin Wang ◽  
Ruonan Liu ◽  
Hong Huang
Keyword(s):  
Silica Gel ◽  
Large Scale ◽  
Raw Materials ◽  
Separation Method ◽  
Suitable Method ◽  
Scale Production ◽  
Reaction Conditions ◽  
Environment Friendly ◽  
Large Scale Production ◽  
Ideal Approach

: α-Monochlorocyclododecanone was synthesized from cyclododecane and 1,3-Dichloro-5,5-dimethylhydantoin (DCDMH) catalyzed with silica gel in MeOH. The product was obtained by crystallization with nearly 85% yield. The presented method used cheap raw materials, mild reaction conditions, simple separation method and environment-friendly process. Additionally, the current synthesis provided an ideal approach for large-scale production.

Strength and Impotence. The Developing Countries and the Development in New Territories

1974 ◽  
Vol 9 (2-3) ◽  
pp. 167-177
Author(s):  
Willy Østreng
Keyword(s):  
Large Scale ◽  
Raw Materials ◽  
Developed Countries ◽  
Economic Effects ◽  
Scale Production ◽  
Underdeveloped Countries ◽  
The North ◽  
Large Scale Production ◽  
The Developed Countries ◽  
The Third World

This article examines the possible political and economic effects of large-scale mineral extraction from the seabed. The findings presented indicate that development in new territories may conceivably serve to exacerbate existing conflict dimensions, notably the North/South dimension in global politics. Because of the developed countries' monopoly on know-how and economic capability, exploration and exploitation of the inorganic resources of the ocean floor has de facto been the exclusive domain of these countries. On the basis of this the author shows that if large-scale production of seabed resources should become a reality in the near future, the underdeveloped countries will be forced to watch it from the sidelines. As a consequence, the exploitation of offshore raw materials will probably contribute to the further widening of the gap between developed and underdeveloped countries. Further commenting on the fact that the latter today are the main producers of the most promising seabed resources, the author expresses the view that exploitation will have a detrimental effect on the economics of the Third World countries, since it might lead to overproduction and price reductions.

scholarly journals Large-Scale Production of Lentiviral Vectors: Current Perspectives and Challenges

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1051
Author(s):  
Eduardo Martínez-Molina ◽  
Carlos Chocarro-Wrona ◽  
Daniel Martínez-Moreno ◽  
Juan A. Marchal ◽  
Houria Boulaiz
Keyword(s):  
Viral Vectors ◽  
Large Scale ◽  
Lentiviral Vectors ◽  
Good Manufacturing Practice ◽  
Scale Production ◽  
Gene Therapies ◽  
Packaging Cell ◽  
Large Scale Production ◽  
Target Production

Lentiviral vectors (LVs) have gained value over recent years as gene carriers in gene therapy. These viral vectors are safer than what was previously being used for gene transfer and are capable of infecting both dividing and nondividing cells with a long-term expression. This characteristic makes LVs ideal for clinical research, as has been demonstrated with the approval of lentivirus-based gene therapies from the Food and Drug Administration and the European Agency for Medicine. A large number of functional lentiviral particles are required for clinical trials, and large-scale production has been challenging. Therefore, efforts are focused on solving the drawbacks associated with the production and purification of LVsunder current good manufacturing practice. In recent years, we have witnessed the development and optimization of new protocols, packaging cell lines, and culture devices that are very close to reaching the target production level. Here, we review the most recent, efficient, and promising methods for the clinical-scale production ofLVs.

scholarly journals Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: off-the-shelf GMP-manufactured donor-independent ATMP

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Seda Ballikaya ◽  
Samar Sadeghi ◽  
Elke Niebergall-Roth ◽  
Laura Nimtz ◽  
Jens Frindert ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Manufacturing Process ◽  
Ex Vivo ◽  
Good Manufacturing Practice ◽  
Process Data ◽  
Advanced Therapy Medicinal Product ◽  
Drug Products ◽  
Advanced Therapy ◽  
Immunomagnetic Isolation

Abstract Background Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an easily accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated not only with skin-related but also systemic inflammatory and/or degenerative processes. Methods We have developed a validated Good Manufacturing Practice-compliant expansion and manufacturing process by which ABCB5+ MSCs derived from surgical discard skin tissues are processed to an advanced-therapy medicinal product (ATMP) for clinical use. Enrichment for ABCB5+ MSCs is achieved in a three-step process involving plastic adherence selection, expansion in a highly efficient MSC-selecting medium, and immunomagnetic isolation of the ABCB5+ cells from the mixed culture. Results Product Quality Review data covering 324 cell expansions, 728 ABCB5+ MSC isolations, 66 ABCB5+ MSC batches, and 85 final drug products reveal high process robustness and reproducible, reliable quality of the manufactured cell therapy product. Conclusion We have successfully established an expansion and manufacturing process that enables the generation of homogenous ABCB5+ MSC populations of proven biological activity manufactured as a standardized, donor-independent, highly pure, and highly functional off-the-shelf available ATMP, which is currently tested in multiple clinical trials.

scholarly journals Phage Therapy Regulation: From Night to Dawn

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 352 ◽  
Author(s):  
Alan Fauconnier
Keyword(s):  
Large Scale ◽  
Phage Therapy ◽  
Resistance To Change ◽  
Regulatory Framework ◽  
Global Perspective ◽  
Western World ◽  
Medicinal Products ◽  
Advanced Therapy Medicinal Product ◽  
Advanced Therapy ◽  
And Personalized Medicine

After decades of disregard in the Western world, phage therapy is witnessing a return of interest. However, the pharmaceutical legislation that has since been implemented is basically designed for regulating industrially-made pharmaceuticals, devoid of any patient customization and intended for large-scale distribution. Accordingly, the resulting regulatory framework is hardly reconcilable with the concept of sustainable phage therapy, involving tailor-made medicinal products in the global perspective of both evolutionary and personalized medicine. The repeated appeal for a dedicated regulatory framework has not been heard by the European legislature, which, in this matter, features a strong resistance to change despite the precedent of the unhindered implementation of advanced therapy medicinal product (ATMPs) regulation. It is acknowledged that in many aspects, phage therapy medicinal products are quite unconventional pharmaceuticals and likely this lack of conformity to the canonical model hampered the development of a suitable regulatory pathway. However, the regulatory approaches of countries where phage therapy traditions and practice have never been abandoned are now being revisited by some Western countries, opening new avenues for phage therapy regulation. As a next step, supranational and international organizations are urged to take over the initiatives originally launched by national regulatory authorities.

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