Automated Manufacturing Processes and Platforms for Large-scale Production of Clinical-grade Mesenchymal Stem/ Stromal Cells

Abstract

Mesenchymal stem/stromal cells (MSCs) hold immense potential for regenerative medicine due to their remarkable regenerative and immunomodulatory properties. However, their therapeutic application requires large-scale production under stringent regulatory standards and Good Manufacturing Practice (GMP) guidelines, presenting significant challenges. This review comprehensively evaluates automated manufacturing processes and platforms for the scalable production of clinical-grade MSCs. Various large-scale culture vessels, including multilayer flasks and bioreactors, are analyzed for their efficacy in MSCs expansion. Furthermore, automated MSCs production platforms, such as Quantum^® Cell Expansion System, CliniMACS Prodigy^®, NANT001/ XL, CellQualia™, Cocoon^® Platform, and Xuri™ Cell Expansion System W25 are reviewed and compared as well. We also underscore the importance of optimizing culture media specifically emphasizing the shift from fetal bovine serum to humanized or serum-free alternatives to meet GMP standards. Moreover, advances in alternative cryopreservation methods and controlled-rate freezing systems, that offer promising improvements in MSCs preservation, are discussed as well. In conclusion, advancing automated manufacturing processes and platforms is essential for realizing the full potential of MSCs-based regenerative medicine and accomplishing the increasing demand for cell-based therapies. Collaborative initiatives involving industry, academia, and regulatory bodies are emphasized to accelerate the translation of MSCs-based therapies into clinical practice.

Keywords: Cell Therapy; Good Manufacturing Practice (GMP); Large-scale Production; Mesenchymal stem/Stromal Cells (MSCs).

Fig. 1

Complex overview of bioprocessing strategies for large-scale production of clinical grade mesenchymal stem/ stromal cells (MSCs). MSCs expansion platforms (Quantum ® Cell Expansion System, CliniMACS Prodigy ® , NANT001/ XL, CellQualia ™ , Cocoon ® Platform, and Xuri ™ Cell Expansion System W25) require the following inputs: sample or isolated cells, culture media, washing reagent (phosphate buffer saline), dissociation reagent (trypsine, TrypLE), and optional supplements. Downstream processes such as cell harvest, quality control (purity, identity, potency, and safety of final product), cryopreservation, and product formulation are also essential parts of clinical-grade MSCs manufacturing. Created with BioRender.com

Fig. 2

Cell cryopreservation mechanism as a crucial step for cell-based therapy manufacturing. Processes that lead to cell damage during cryopreservation involve specific mechanisms. To prevent this injury, it’s essential to add the right amount of appropriate cryoprotective agents (CPAs) to cell suspensions and apply optimal cooling rates. Created with BioRender.com