Abstract

Mesenchymal stem cells (MSCs) are advanced therapy medicinal products used in cell therapy applications. Several MSC products have already advanced to phase III clinical testing and market approval. The manufacturing of MSCs must comply with good manufacturing practice (GMP) from phase I in Europe and phase II in the US, but there are several unique challenges when cells are the therapeutic product. Any GMP-compliant process for the production of MSCs must include the expansion of cells in vitro to achieve a sufficient therapeutic quantity while maintaining high cell quality and potency. The process must also allow the efficient harvest of anchorage-dependent cells and account for the influence of shear stress and other factors, especially during scale-up. Bioreactors are necessary to produce clinical batches of MSCs, and bioprocess development must therefore consider this specialized environment. For the last 10 years, we have investigated bioprocess development as a means to produce high-quality MSCs. More recently, we have also used bioreactors for the cocultivation of stem cells with other adult cells and for the production of MSC-derived extracellular vesicles. This review discusses the state of the art in bioprocess development for the GMP-compliant manufacture of human MSCs as products for stem cell therapy.

Highlights

  • In order to provide enough Mesenchymal stem cells (MSCs) for cell therapy, donor cells must be isolated from tissue and expanded in vitro to reach a population of 1–9 × 108 cells, which is the typical dose for adult treatment [6]

  • The success or failure of MSC therapy depends on this in vitro expansion process, which was first studied in detail following the failure of the MSC product Prochymal in phase III trials for graft versus host disease (GvHD) [4], whereas a similar product succeeded in phase II

  • Manufacturing must be compliant with good manufacturing practice (GMP) regulations that have been tailored for advanced therapeutic medicinal products (ATMPs), following strict criteria for product specification and release for clinical use

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Summary

Manufacturing cell therapy products

Cell therapy is a growing clinical research and healthcare sector in which living cells are introduced into a patient in an attempt to ameliorate or cure a disease. This chapter will focus on one specific type of stem cell (MSCs), which are variously defined as mesenchymal stem cells, mesenchymal stromal cells, or (most recently) medicinal signaling cells [1]. These various definitions reflect the controversial origin and functionality of MSCs and uncertainty about their clinical potential [2, 3]. The success or failure of MSC therapy depends on this in vitro expansion process, which was first studied in detail following the failure of the MSC product Prochymal in phase III trials for graft versus host disease (GvHD) [4], whereas a similar product succeeded in phase II. One reason proposed for the contrasting outcomes of each trial was the substantial differences in the MSC expansion step at the manufacturing scale, highlighting the specialized and complex nature of MSCs [4]

Definition of MSCs and current approved products
The therapeutic properties of MSCs
The critical quality attributes of MSCs
Identity
Potency
Sterility and purity
Expansion of human MSCs in vitro
CPPs that affect MSC manufacturing
Culture medium
Conditions in the culture vessel
Growth surface, cell harvest, and storage
MSC manufacturing for clinical trials
The expansion of MSCs in bioreactors
Remaining challenges
Additional processes that require MSCs
Production of MSC-derived extracellular vesicles
Cocultivation of MSCs with other cells
Findings
Conclusions
Full Text
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