药学学报, 2019, 54(7): 1317-1324
卢加琪, 韦薇, 刘伯宁, 罗建辉. 间充质干细胞的研究进展与药学评价[J]. 药学学报, 2019, 54(7): 1317-1324.
LU Jia-qi, WEI Wei, LIU Bo-ning, LUO Jian-hui. Research progress, chemistry, manufacturing and controls considerations of mesenchymal stem cell products[J]. Acta Pharmaceutica Sinica, 2019, 54(7): 1317-1324.

卢加琪, 韦薇, 刘伯宁, 罗建辉
国家药品监督管理局药品审评中心, 北京 100022
截至2018年12月,世界范围内有900余个间充质干细胞(mesenchymal stem/stromal cell,MSC)研究项目正在开展或完成了临床研究,其数量一直占据各类干细胞疗法临床试验数量的第1位。近年来国内多个间充质干细胞产品开展了非注册临床研究,并开始按照药品申报临床试验。科学界对间充质干细胞的生物学功能及临床治疗效果在不断认知积累中,其体外培养观测到的功能受到体内实际生存环境的限制未能充分显现。不同组织来源间充质干细胞的培养方法、传代代次、细胞表型和功能均有差异,且制剂工艺、临床给药方式和剂量也显著影响临床疗效。间充质干细胞的体外培养条件、诱导方式与回输人体后微环境的差异性,使产品中的细胞难以保持分离前的原始状态。因此,间充质干细胞的来源、制备工艺和复杂性、多样性、变异性等特点,及其存在争议的定义和功能,也给按照药品审评审批带来了挑战。本文综述了国内外间充质干细胞的药物研发进展和临床研究现状,讨论了间充质干细胞的生产原材料、生产工艺、质量研究等药学评价要点,以期为国内间充质干细胞产品的药学评价提供参考。
关键词:    间充质干细胞      临床研究      生产工艺      质量控制      药学评价     
Research progress, chemistry, manufacturing and controls considerations of mesenchymal stem cell products
LU Jia-qi, WEI Wei, LIU Bo-ning, LUO Jian-hui
Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China
The number of clinical trials for mesenchymal stem cell (MSC) products ranked the top among all stem cell products, with more than 900 trials ongoing or completed by 2018. In China, many MSC clinical trials have started as "the third type of medical technique" and the dossiers of MSC products have been submitted to National Medical Products Administration (NMPA). The biological function and therapeutic effect of MSCs are constantly being recognized in scientific communities. However, the observed functions of MSCs in vitro are not fully reproduced in the living microenvironment in vivo. There are substantial variations among tissue origins, cellular phenotypes and biological functions. Different formulations, delivery methods, manufacture processes or doses all greatly affect the clinical efficacy. It is difficult for MSCs to maintain the naive state due to the differences between in vitro culture conditions and in vivo microenvironment. Meanwhile, there is no widely accepted scientific definition for MSCs until now, due to the complexity of manufacturing process and variable sources. Consequently, the regulation of MSC products is a challenge for drug administrative agencies. In this article, we review the research progress of MSC products around the world, and summarize the considerations in evaluating the chemistry, manufacturing and controls (CMC) section of MSC product applications, with respect to raw materials, manufacture processes and quality control. We hope that the information summarized here will provide insights for the development and evaluation of MSC products.
Key words:    mesenchymal stem cell    clinical research    manufacture process    quality control    chemistry, manufacture and control evaluation   
收稿日期: 2019-02-23
DOI: 10.16438/j.0513-4870.2019-0135
通讯作者: 罗建辉,Tel:86-10-85243072,E-mail:luojh@cde.org.cn
Email: luojh@cde.org.cn
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1.刘伯宁, 曹越, 卢加琪, 罗建辉.关于嵌合抗原受体修饰T细胞产品药学评价的思考[J]. 药学学报, 2018,53(10): 1637-1644