From laboratory to clinic: Bridging regulatory and manufacturing gaps in stem cell-based therapies

Advanced therapy medicinal products (ATMPs), encompassing therapies derived from mesenchymal stem cells, induced pluripotent stem cells, and their extracellular vesicles, hold substantial transformative potential for clinical applications. However, their translation from bench to bedside and eventual commercialization is hindered by considerable scientific, manufacturing, and regulatory challenges. This review examines these challenges using a structured framework that synthesizes evidence from recent studies, international guidance documents, and regulatory agency reports. We provide an overview of the global regulatory environment and harmonization efforts that influence ATMP oversight, highlighting the frameworks established by major agencies and international initiatives. Technical discussions cover cell sourcing, scalable bioprocess engineering - including bioreactors, closed system technologies, and tangential flow filtration - product quality attributes, and real-time in-process monitoring, incorporating emerging artificial intelligence-driven process analytical technologies. Special focus is given to advanced considerations such as induced pluripotent stem cells tumorigenicity, emphasizing the risks posed by residual undifferentiated cells and the importance of sensitive assays and genetic integrity evaluation; mesenchymal stem cell-derived exosome production, with attention to scale-up strategies, isolation techniques, and quality control standards; global harmonization of good manufacturing practice and ATMP standards; and artificial intelligence-enabled process analytics for automated, closed-cell culture systems. The review further explores potency assays, product comparability, supply chain logistics, and forward-looking trends, including point-of-care manufacturing and digital twin approaches, aiming to equip researchers, developers, and regulators with strategies to advance ATMP development safely and efficiently, ensuring robust therapeutic efficacy and patient safety for next-generation cell and exosome therapies.