Manufacturing, Characterization and Control of Cell-Based Medicinal Products: Challenging Paradigms Toward Commercial Use

Salmikangas, Paula; Menezes-Ferreira, Margarida; Reischl, Ilona; Tsiftsoglou, Asterios S.; Kyselovič, Ján; Borg, John J.; Ruiz, Sol; Flory, Egbert; Trouvin, Jean‐Hugues; Celis, Patrick; Ancans, Janis; Timón, Marcos; Pante, G.; Śladowski, Dariusz; Lipnik‐Štangelj, Metoda; Schneider, Christian K.

doi:10.2217/rme.14.65

Cited by 41 publications

(41 citation statements)

References 31 publications

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“…Such process changes include a media component change, a donor/starting material change, a manufacturing platform change and the introduction of a new manufacturing site. A recent publication by current and former members and experts of the Committee for Advanced Therapies, EMA has emphasized that demonstrating comparability maybe “difficult for cell-based medicinal products” [3]. …”

mentioning

confidence: 99%

Comparability: Manufacturing, Characterization and Controls, Report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

Williams

Archer²,

Archibald

et al. 2016

Regen. Med.

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This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this ‘may be difficult for cell-based medicinal products’. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates.

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mentioning

confidence: 99%

Comparability: Manufacturing, Characterization and Controls, Report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

Williams

Archer²,

Archibald

et al. 2016

Regen. Med.

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“…Indeed, it will be extraordinarily challenging to perform reductionist mechanistic experiments in human subjects that will conclusively define substantive MOA of MSC-like cells in vivo and meet modern standards of ethical conduct in clinical trials. Nonetheless, all attempts should be made to develop potency measurements that reflect the product’s relevant biological properties and that can also serve as a measure of comparability between production lots [5]. Therefore, defining hypothesis-driven MOA based on correlative in vitro experiments and buttressed, where feasible, with comparative biology approach in animal systems will inform the choice of potency assays to be developed.…”

Section: International Regulatory Authority Guidance On Potency Testsmentioning

confidence: 99%

International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials

et al. 2016

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Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an “open-access” manner, such as through publication or database collection.

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“…All the above-mentioned steps are time-consuming, laborious, and costly 3 . In addition, all in vitro processing of cells intended for patient transplantation are highly regulated and requires well-trained and accredited personnel and laboratories 4 .…”

Section: Introductionmentioning

confidence: 99%

Minced Tissue in Compressed Collagen: A Cell-containing Biotransplant for Single-staged Reconstructive Repair

Chamorro

Zeiai

Engberg

et al. 2016

JoVE

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Conventional techniques for cell expansion and transplantation of autologous cells for tissue engineering purposes can take place in specially equipped human cell culture facilities. These methods include isolation of cells in single cell suspension and several laborious and timeconsuming events before transplantation back to the patient. Previous studies suggest that the body itself could be used as a bioreactor for cell expansion and regeneration of tissue in order to minimize ex vivo manipulations of tissues and cells before transplanting to the patient. The aim of this study was to demonstrate a method for tissue harvesting, isolation of continuous epithelium, mincing of the epithelium into small pieces and incorporating them into a three-layered biomaterial. The three-layered biomaterial then served as a delivery vehicle, to allow surgical handling, exchange of nutrition across the transplant, and a controlled degradation. The biomaterial consisted of two outer layers of collagen and a core of a mechanically stable and slowly degradable polymer. The minced epithelium was incorporated into one of the collagen layers before transplantation. By mincing the epithelial tissue into small pieces, the pieces could be spread and thereby the propagation of cells was stimulated. After the initial take of the transplants, cell expansion and reorganization would take place and extracellular matrix mature to allow ingrowth of capillaries and nerves and further maturation of the extracellular matrix. The technique minimizes ex vivo manipulations and allow cell harvesting, preparation of autograft, and transplantation to the patient as a simple one-stage intervention. In the future, tissue expansion could be initiated around a 3D mold inside the body itself, according to the specific needs of the patient. Additionally, the technique could be performed in an ordinary surgical setting without the need for sophisticated cell culturing facilities. Video LinkThe video component of this article can be found at

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Manufacturing, Characterization and Control of Cell-Based Medicinal Products: Challenging Paradigms Toward Commercial Use

Cited by 41 publications

References 31 publications

Comparability: Manufacturing, Characterization and Controls, Report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

Comparability: Manufacturing, Characterization and Controls, Report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials

Minced Tissue in Compressed Collagen: A Cell-containing Biotransplant for Single-staged Reconstructive Repair

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