亚硝胺类遗传毒性杂质的监管策略及思考

如何对药品中存在致癌风险的亚硝胺类杂质进行控制,已成为企业和监管部门关注的热点。本文对亚硝胺类杂质的常见类型、来源、致癌性作用特点进行梳理,并结合EMA、FDA、ICH及我国相关遗传毒性杂质控制指导原则,对制定符合我国国情的亚硝胺类杂质的监管限度和监管工作提出建议。尽管国外已陆续出台了一系列针对药品中亚硝胺类杂质的含量限定的指南性文件,但众多亚硝胺类杂质的毒性剂量、人体暴露量尚不明确,且药物合成工艺存在差异,我国无法完全照搬欧美等国的监管方法。当前应深入研究亚硝胺类杂质的遗传毒性和致癌性,从而制定符合我国国情的监管限度值和药品中亚硝胺杂质监管策略;此外,本文从解决实际问题的角度出发,讨论如何根据已有指导原则,确定在已知毒理学数据、毒理学数据不足和短期使用药物不同情况下亚硝胺类杂质的监管限度。本文将为药物生产和杂质评价与研究和监管领域相关人员提供借鉴。

Regulatory Strategies and Reflections on Genotoxic Impurities of Nitrosamines

How to control the carcinogenic nitrosamine impurities in drugs has become a hot concern for enterprises and regulatory authorities.The common types,sources,and characteristics of carcinogenicity of nitrosamine impurities had been sorted out,and suggestions were put forward for the establishment of regulatory limits and regulatory work of nitrosamine impurities in line with China’s national conditions based on EMA,FDA,ICH and relevant guidelines for the control of genotoxic impurities in China.Although a series of guidelines on the content limits of nitrosamine impurities in drugs have been issued successively overseas,the toxic doses and human exposures of numerous nitrosamine impurities still remain unclear,and there are differences in the drug synthetic procedure.It is impossible to completely copy the regulatory methods of America or European countries.At present,we should thoroughly study the genotoxicity and carcinogenicity of nitrosamine impurities so as to formulate a regulatory limit value and a regulatory strategy for nitrosamine impurities in drugs in line with China’s national conditions.In addition,from the perspective of solving practical problems,this article discusses how to determine the regulatory limits of nitrosamine impurities in different situations of known toxicological data,insufficient toxicological data,and short-term drug use based on existing guidelines.This article will provide references for those involved in the field of drug manufacturing,impurity evaluation and research and regulation.