自体嵌合抗原受体T细胞(CAR-T)治疗产品药学变更实践与思考  

Case Studies and Recommendations on CMC Changes of Autologous CAR-T Cell Therapy Products

作　　者：曹晓平 王武成 方淑平 王金辉 王永增 林右晨 封华 李付英 常桂红 周新腾 王国旭 王越 CAO Xiao-ping;WANG Wu-cheng;FANG Shu-ping;WANG Jin-hui;WANG Yong-zeng;LIN You-chen;FENG Hua;LI Fu-ying;CHANG Gui-hong;ZHOU Xin-teng;WANG Guo-xu;WANG Yue(Nanjing Legend Biotech Co.,Ltd.;JW Therapeutics(Shanghai)Co.,Ltd.;Jiangsu Simcere Pharmaceutical Co.,Ltd.;Nanjing IASO Biotherapeutics Co.,Ltd.;Juventas Cell Therapy Ltd.;Eli Lilly Suzhou Pharmaceutical Co.Ltd.;CARsgen Therapeutics Holdings Limited;Fosun Kite Biotechnology Co.,Ltd.;Beijing Shangzhi Hegui Science and Technology Co.,Ltd.;China Society for Drug Regulation)

机构地区：[1]南京传奇生物科技有限公司 [2]上海药明巨诺生物科技有限公司 [3]江苏先声药业有限公司 [4]南京驯鹿生物医药有限公司 [5]合源生物科技(天津)有限公司 [6]礼来苏州制药有限公司 [7]科济药业控股有限公司 [8]复星凯特生物科技有限公司 [9]北京尚质合规科技有限公司 [10]中国药品监督管理研究会

出　　处：《中国食品药品监管》2024年第9期16-25,共10页China Food & Drug Administration Magazine

基　　金：2023年中国药品监督管理研究会课题(2023-Y-Y-012)。

摘　　要：近年来我国在嵌合抗原受体T细胞(CAR-T cell)治疗领域的研究非常活跃。由于该领域技术迭代快,生产工艺复杂,药学研究和变更方面的经验相对有限,CAR-T产品药学变更的评估、研究以及申报、审评对企业和监管机构提出了多方面的挑战。本课题组聚焦于自体CAR-T细胞治疗产品药学变更案例及其共性问题与挑战,进行了行业调查、法规与案例收集和研讨以及变更管理工具评估,并提出了多项建议,期望为企业和监管机构管理CAR-T药学变更提供参考。相关法规收集与分析结果显示,我国和美国在法规方面均走在前沿,总体原则均为基于科学和风险;在细节和实践上,监管机构均处于持续研究、探讨和完善的阶段。行业调研结果显示,企业药学变更主要目的之一是降低成本以提高产品可及性,主要挑战包括企业和监管机构对变更理解的差异、沟通机制以及审评审批时长。收集的药学变更案例包括多种变更情形,其中针对扩大生产产能,建议基于适当产品与工艺知识经验、风险管控和无菌验证,可使用同步验证,适当时使用模拟验证辅助。就上市后变更管理工具,建议试行ICH Q12批准后变更管理方案(PACMP)帮助管理自体CAR-T细胞治疗产品上市后药学变更。In recent years,research in the field of chimeric antigen receptor T(CAR-T)cell therapy in China has been active.Due to the rapid iteration of technologies in this field,complex manufacturing processes,and relatively limited experience in pharmaceutical research and changes,the evaluation,research,submission,and review of chemistry,manufacturing,and controls(CMC)changes in CAR-T products present various challenges for both companies and regulatory agencies.The Cell and Gene Therapy Products Committee of the China Society for Drug Regulation organized a task force comprising several leading domestic cell therapy companies to focus on case studies and common challenges related to CMC changes in autologous CAR-T products.The group conducted industry surveys,collected regulatory data and case studies,and evaluated change management tools,providing recommendations for companies and regulatory agencies to manage CMC changes for CAR-T products.Regulatory analysis revealed that both China and the United States are at the forefront of policy development,with general principles based on science and risk.However,both regulatory agencies are still exploring and refining details and practices.Industry surveys indicated that one of the main purposes of CMC changes is to reduce costs and improve product accessibility,with major challenges including differences in understanding between companies and regulatory agencies,communication mechanisms,and approval timelines.The collected CMC change cases involves various scenarios,including capacity expansion.For such changes,it is recommended to use concurrent validation based on appropriate product and process knowledge,risk control,and sterile validation,with simulation validation as an auxiliary when necessary.For postmarket change management tools,the study suggests piloting ICH Q12 Post-Approval Change Management Protocol(PACMP)to help manage post-market CMC changes for autologous CAR-T cell therapy products.

关 键 词：自体 嵌合抗原受体T细胞 细胞治疗产品 药学变更 生产产能 验证策略 批准后变更管理方案 

分 类 号：R95[医药卫生—药学]