Advances in hPSC expansion towards therapeutic entities: A review

For use in regenerative medicine, large‐scale manufacturing of human pluripotent stem cells (hPSCs) under current good manufacturing practice (cGMPs) is required. Much progress has been made since culturing under static two‐dimensional (2D) conditions on feeders, including feeder‐free cultures, conditioned and xeno‐free media, and three‐dimensional (3D) dynamic suspension expansion. With the advent of horizontal‐blade and vertical‐wheel bioreactors, scale‐out for large‐scale production of differentiated hPSCs became possible; control of aggregate size, shear stress, fluid hydrodynamics, batch‐feeding strategies, and other process parameters became a reality. Moving from substantially manipulated processes (i.e., 2D) to more automated ones allows easer compliance to current good manufacturing practices (cGMPs), and thus easier regulatory approval. Here, we review the current advances in the field of hPSC culturing, advantages, and challenges in bioreactor use, and regulatory areas of concern with respect to these advances. Manufacturing trends to reduce risk and streamline large‐scale manufacturing will bring about easier, faster regulatory approval for clinical applications. Dynamic suspension culture systems in the form of bioreactors, unlike static ones, can overcome unfavourable environmental culture conditions, assisting hPSCs to remain pluripotent and undifferentiated, or promoting their differentiation and expansion to desired cell types. They reduce medium consumption and workload, have high scalability, and allow easy online sampling for quality control analysis or other needed testing. Depending on the type of bioreactor chosen, their use permit robust expansion of large‐scale hPSCs with high‐quality, relatively homogeneous cultures, and controlled production to meet manufacturing needs for clinical trials. Closed, single‐use, well‐monitored, minimally manipulated systems will easier meet regulatory standards in bringing hPSC therapies to the clinics.