ICH M7指导原则下DNA反应性/致突变性杂质的控制水平

Analysis of control limit of DNA reactive/mutagenic impurities under ICH M7

药物中的DNA反应性杂质水平应按照M7指导原则中的策略进行控制。杂质的分类基础是已有的相关致突变性及致癌性数据,当特定化合物的数据缺乏时,则需借助于定性的结构活性关系(QSAR)信息来判断。毒理学关注阈值(TTC)的概念来自于FDA对食品中所含的微量化合物的控制策略,由致癌性已知的物质的半数致瘤率(TD_(50))暴露量线性外推至使肿瘤发生率增加1/106(早期临床研发阶段)及1/105(药物研发较后阶段)的杂质暴露水平,当DNA反应性杂质水平低于TTC时,由于杂质暴露导致肿瘤发生的额外风险是可以忽略不计的。本文对化学药物中常见杂质及食品中微量污染物中的警示结构进行了比较和分析,并基于对M7的理解对其暴露阈值提出了一些建议。

The exposure level of DNA reactive impurities in pharmaceutical substances and products are controlled by the strategies under ICH M7. The principle of classification of impurities is based on the available data including mutagenic and carcinogenic studies,with the help of QSAR analysis when lack of study result for specific chemicals. The TTC concept was extrapolated from FDA control strategy of trace chemicals in food to the DNA reactive impurities from the pharmaceuticals,and exposure at the lifetime or staged TTC level would not increase cancer risk higher than 1 in 106（ early development stage） and 1 in 105（ later stage）. Common alerting structures from impurities in chemical drugs and trace contaminants of food were compared and analyzed,some suggestions were presented for the exposure thresholds based on the understanding of ICH M7.