药品中遗传毒性杂质的评估和控制

目的 综述药品遗传毒性杂质控制相关指南和法规，为制药企业执行国际标准和准则提供一些建议和思路。方法 通过查找数据库如Pubmed、Medline及欧洲药品管理局(European Medicines Agency，EMA)、美国食品药品监督管理局(US Food and Drug Administratio，U.S.FDA)、人用药品注册技术要求国际协调会议(ICH)等网站，比较各指南法规关于遗传毒性控制限度和控制措施的异同点，为遗传毒性杂质的控制提供一个可行性步骤。结果 通过比较发现，EMA、U.S.FDA和即将出版的ICH M7指南在关键原则的应用方面如毒理学关注阈值(threshold of toxicological concern，TTC)、风险评估步骤、杂质5分类法等基本相同，但现行EMA和U.S.FDA法规存在分歧，不利于其有效执行，而ICH M7将为遗传毒性杂质的控制提供一个可行框架。结论 目前还缺乏完善有效的遗传毒性控制指南，ICH M7将解决U.S.FDA 和EMA 指南间分歧，更好地指导制药企业遗传毒性杂质的控制。

Evaluation and Control of Genotoxic Impurities in Active Pharmaceutical Ingredients

OBJECTIVE To provide a general overview of the regulatory guidelines on the control of genetoxic impurities in Active Pharmaceutical Ingredients, and provide some practical advices for following guidelines. METHODS Literatures about the topic of genotoxic impurities from databases such as Pubmed, Medline, websites of EMA, U.S.FDA and ICH were searched, then analysized and compared the current guidelines on this topic, and provided a controlling strategy for these impurities. RESULTS The guidelines of EMA, U.S.FDA and ICH (current step 2) maintained consistent in critical principles such as threshold of toxicological concern (TTC), risk assessment and the classification system for impurities. But the difference on other aspects between current guidelines of EMA and U.S.FDA would get them difficult to be implemented in a consistent manner for pharmaceutical manufacturers. and ICH M7, now the step 2 version, would provide a practical framework that could be applied for the control of genotoxic impurities. CONCLUSION The current guidelines can not provide a perfect strategy for the control of genotoxic impurities, and the ICH M7 that may replace the current guidelines of EMA and U.S.FDA, and will provide a better way for the pharmaceutical manufacturers to control the genotoxic impurities.