Francis Natalie, Aho Joy, Ben-Nun Inbar Friedrich, Bharti Kapil, Dianat Noushin, Makovoz Bar, Nouri Parivash, Rothberg Janet, Song Hannah, Zamilpa Rogelio, Lakshmipathy Uma, Allickson Julie
Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK.
Product Management and Strategy, NMDP BioTherapies, Minneapolis, USA.
Cytotherapy. 2025 Apr 7. doi: 10.1016/j.jcyt.2025.04.058.
Approval of induced pluripotent stem cells (iPSCs) for the manufacture of cell therapies to support clinical trials is now becoming realized after more than 20 years of research and development. However, manufacturing these therapies at the scale required for patient treatment, as well as for key clinical trial enabling activities such as preclinical and stability studies, remains a challenge. In 2022 the International Society for Cell and Gene Therapy (ISCT) established a Working Group on Emerging Regenerative Medicine Technologies, an area in which iPSC-derived technologies are expected to play a key role. In this article, the Working Group provides an overview of the considerations and challenges facing stem cell therapy developers, including development-stage specific manufacturing processes, the decision on when to implement automation, the choice of technology and different requirements of expansion and differentiation aspects of the process, and the integration of automation for both manufacturing and analytics in an end-to-end manufacturing process. The role of scalable manufacturing technologies in the application of quality-by-design approaches to product development, and the use of design-of-experiment approaches for increased product characterization, is discussed. Finally, we provide an in-depth review of the different technologies that have been used for expansion and differentiation of iPSC-derived therapies to date, including compatibility with good manufacturing practice requirements and process analytical technologies. We hope that this overview will summarize the existing knowledge in the field and reduce the challenges that therapy developers face in translating their research into clinical and commercial scale manufacturing.
经过20多年的研发，诱导多能干细胞（iPSC）被批准用于制造细胞疗法以支持临床试验，这一目标如今正在实现。然而，按照患者治疗所需规模，以及开展关键临床试验支持活动（如临床前和稳定性研究）所需规模来制造这些疗法，仍然是一项挑战。2022年，国际细胞与基因治疗协会（ISCT）成立了新兴再生医学技术工作组，诱导多能干细胞衍生技术有望在这一领域发挥关键作用。在本文中，该工作组概述了干细胞疗法开发者面临的考量因素和挑战，包括特定开发阶段的制造工艺、决定何时实施自动化、技术选择以及该过程在扩增和分化方面的不同要求，以及在端到端制造过程中制造与分析自动化的整合。讨论了可扩展制造技术在将质量源于设计方法应用于产品开发中的作用，以及使用实验设计方法来增加产品特性描述。最后，我们深入回顾了迄今为止用于诱导多能干细胞衍生疗法扩增和分化的不同技术，包括与良好生产规范要求和过程分析技术的兼容性。我们希望这一概述能总结该领域的现有知识，并减少疗法开发者在将其研究转化为临床和商业规模制造过程中所面临的挑战。
