Process Design for Human Mesenchymal Stem Cell Products in Stirred-Tank Bioreactors

Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) are gaining importance as so-called advanced therapy medicinal products. However, the manufacturing of such products is challenging due to their complexity and sensitivity to intrinsic and environmental parameters, which determine their therapeutic functionality. MSCs respond strongly to their microenvironment, which modulates cell behavior and induces the secretion of EVs. It is therefore necessary to mimic the physiological niche of MSCs in vitro in order to ensure therapeutic efficacy. In this chapter, we discuss the critical quality attributes of MSCs and EVs, and the critical process parameters during in vitro manufacturing. We consider the suitability of different bioreactor types, focusing on stirred-tank bioreactors that are typically used for MSC expansion. For EV production, we also consider hollow-fiber and fixed-bed reactors. We describe how the production of MSCs and EVs can be enhanced by process modifications, and identify topics that require further investigation.