药物基因毒性杂质及其检测方法研究现状

Research progress in genotoxic impurities of drugs and detection methods

基因毒性杂质(GTI)主要来源于原料药的合成过程或储藏运输等环节,其在痕量水平即可造成DNA损伤并诱发细胞癌变,因此近年来受到了广泛关注。各国法规对不同种类的GTI均提出了严格的限量标准和控制策略,因此发展灵敏可靠的检测方法应用于原料药中GTI的筛查、定量及表征具有重要意义。本文介绍了药物中GTI的警示结构及其分类、常见来源和毒理学限量标准,重点结合国内外研究进展对气相色谱及其联用技术、液相色谱及其联用技术、电化学传感和表面增强拉曼光谱等新型技术应用于药物GTI的检测进行评述,并探讨基于警示结构或生物效应导向的通量筛查策略和方法,以期为药物GTI的有效监测研究提供参考。

In recent years,genotoxic impurity(GTI)which is detected in drug substances or is produced during storage and transportation has raised concerns.GTI can cause DNA damage at very low concentration levels and even lead to cancer,which is why laws and regulations stipulate corresponding control strategyies for the limitation of a wide range of GTI.So far many detection methods have been developed for screening,quantification and characterization of GTI in drug substances.This review introduces the structural classification,common sources,limit standards of GTI and focuses on the GTI detection methods currently available,including gas chromatography,liquid chromatography,their corresponding mass spectrometry combination technologies,electrochemical sensing and surfaceenhanced Raman spectroscopy.Screening strategies based on alert structure prediction or biological effect orientated detection are also outlined in the hopes of providing reference for rigorous control and efficient monitoring of GTI in drugs.