N-亚硝胺类基因毒性杂质的研究进展

A Review of Research Progress on N-nitrosamine Genotoxic Impurities

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。

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.