肼杂质限度论证及控制策略研究—以水合肼用于药物合成工艺实际运作为例..docx

摘要为了将化学合成类新药的安全风险控制在可接受状态，进行杂质遗传毒性评估 判断十分重要。遗传毒性杂质极低的限度要求，对工艺和检测分析提出了更高的挑 战，也成为药品进入欧美市场的技术挑战和潜在壁垒。国内目前合成类首创新药相 对较少，若是合成药产业继续发展首创新药的比例提高，监管机构将来可能会有这 方面关注与考量。设定遗传毒性杂质的可接受限度，需考虑研发所处的阶段，包括 风险管理，适当的检测仪器与技艺精湛的检验人员，对杂质的认识和对工艺的理解， 熟悉相应的法规与指南。本论文以肼杂质为例，检索文献数据，对杂质认识评估归类，运用风险管理工 具，确定其可接受限度。遗传毒性物质分两种情况：一种情况是无法获得试验数据 支持某一阈值的，通常基于风险的 TTC（毒理学关注阈值）；另一种情况是已有文献 试验数据阈值支持某一限度的。第二种情况表明细胞自身保护机制能起作用，遗传 毒性风险相对要小，允许摄入的限度通常比 TTC 更高。若是出现推算结果比 TTC 更 低的情况，需理解这些数据的含义，结合其它领域的信息，论证应用 TTC 限度的合 理性。通过分析归纳总结，肼杂质按 TTC 控制可满足要求。再基于药品最大日剂量以 及具体生产工艺，明确风险控制限度目标，确定控制策略。为选取合适的合成工艺， 识别关键质量属性、确定关键工艺参数，规避或控制遗传毒性杂质方面的风险提供 参考。关键词: 遗传毒性；肼杂质；可接受限度；毒理学关注阈值（TTC）Study on the Control Strategies and Justification for the Acceptance Limits of Hydrazines in Active Pharmaceutical Ingredients-- Hydrazine Hydrate Used in Synthetic Process as Perspective In order to assess and control the safety risk of new chemically synthesized drugs, it is very critical to investigate and determine the potential genotoxic impurities, which will require the well-controlled manufacture process and well-developed analytical methodologies to support. Evaluation and investigation of potential genotoxic impurities is becoming a critical technical challenge and potential barrier for new drugs entering into the US and EU regulatory drug markets. Almost all of the chemically synthesized drugs marketed in China had also been approved by EU and/or US and marketed for many years and been proved to be safe, and SFDA has not paid too much effort/attention to this topic over those approved drugs. How to set up an appropriate genetoxic impurity acceptance limit during the drug development phase requires all the considerations related to drug development, including risk control concept, adequate equipments, skilful analysts, understanding the regulation and guidelines, investigating and evaluating the impurity itself, full knowledge to the manufacture process.In this article, the genotoxic hydrazines is used as an example to demonstrate and discuss how to