关于人多能干细胞来源细胞治疗产品药学评价的思考

Chemistry,manufacturing,and controls regulatory considerations for human pluripotent stem cell-derived cellular products

近年来,按照药品研发并申报临床试验的干细胞治疗产品数量增加,其研发技术与评价体系快速发展。国际上人多能干细胞(human pluripotent stem cell,hPSC)来源的干细胞治疗产品正处于Ⅰ/Ⅱ期临床试验阶段,相关产品包括hPSC分化产生的神经元、视网膜色素上皮细胞、胰岛beta细胞等,给药途径多为局部移植,一般用于退行性疾病、遗传病相关功能细胞的修复和替换,目前尚无同类产品上市。由于多能干细胞具有多向分化潜能,兼具在体内形成畸胎瘤的能力,hPSC来源的细胞产品与其他干细胞产品相比,其成瘤性风险相对高、诱导分化周期长、生产工艺复杂、质量表征手段仍在快速更新中,对其人体应用的科学评价构成了挑战。结合近期干细胞治疗产品临床试验申报资料审评和沟通交流过程中出现的问题,参考相关技术指导原则,本文围绕hPSC来源的细胞治疗产品的生产工艺和质量研究,提出现阶段的药学审评考虑点,以期增进研发者和监管方的交流。

In recent years,the number of clinical trials of stem cell products has increased,and the research and development technology and evaluation system have developed rapidly.Human pluripotent stem cell(hPSC)-derived cellular products are in the phaseⅠ/Ⅱstage of clinical trials.Related products include hPSC-derived neurons,retinal pigment epithelial cells,pancreatic beta cells,etc.They are generally used for the repair and replacement of functional cells related to degenerative diseases and genetic diseases via local transplantation.So far,no similar products have been officially approved on market.As hPSC possesses multi-directional differentiation potential and the ability to form teratoma in vivo,compared with other stem cell products,hPSC-derived cellular products have relatively higher risk of tumorigenicity,longer differentiation induction cycle,more complex production process,together with the rapidly updating quality characterization methods,which pose challenges to the scientific evaluation of their human applications.Based on the problems in the recent review and communication of clinical trial applications of stem cell products,and with reference to the relevant technical guidelines,this paper proposes the chemistry,manufacturing,and controls review considerations on the manufacturing process and quality study of hPSC-derived cellular products.We hope to improve the communications between developers and regulators.