N-亚硝胺类基因毒性杂质的研究进展

自“缬沙坦事件”之后,N-亚硝胺类基因毒性杂质引起了业界的广泛关注。本文概述了药物中N-亚硝胺类基因毒性杂质和相关检测方法的研究进展,以及近20年来国内外有关药物中基因毒性杂质监管指南的完善历程。N-亚硝胺类基因毒性杂质作为一类高反应活性的基因毒性杂质,主要来源于药物合成过程中发生的副反应,以及药物在储存或者运输过程中发生的氧化或还原等反应。所有的动物实验表明,N-亚硝胺类具有很强的致癌性。在理论上,所有药物都存在N-亚硝胺类杂质或被N-亚硝胺类杂质污染的风险,由于该类化合物在药物中常以痕量形式存在,在分析检测过程中药物基质干扰大,因此建立便捷、高效的分析方法是非常有必要的。

A Review of Research Progress on N-nitrosamine Genotoxic Impurities

Since the "valsartan incident", N-nitrosamines genotoxic impurities have attracted wide attention in pharmaceutical industry. This article reviews the research progress of N- nitrosamines genotoxic impurities in drugs and associated analytical methods for their determination, as well as the improvement of regulatory guidelines on genotoxic impurities in drugs in recent 20 years. As a type of highly reactive genotoxic impurities, N-nitrosamines are mainly derived from side reactions during drug synthesis and degradation reactions such as oxidation or reduction during drug product storage or shipping period. All animal experiments have shown that N-nitrosamines have strong carcinogenicity. Theoretically, all drug substances have the risk of containing N-nitrosamine impurities or contamination by N-nitrosamine impurities. As these compounds are often present in trace levels in drugs, the interference of drug matrix is significant during the determination process. Therefore, it is necessary to establish a precise and cost-effective analytical method.