药品中N-亚硝胺类有害杂质

Occurrence of N-Nitrosamines as Harmful Impurities in Pharmaceuticals

自从2018年“缬沙坦事件”以来,药品中的N-亚硝胺类有害杂质日益受到关注。N-亚硝胺类是一类强致癌物,已有十余种亚硝胺类被国际癌症研究所(International Agency for Research on Cancer, IARC)列入致癌物清单。其中,N-二甲基亚硝胺(N-nitrosodimethylamine, NDMA)、N-二乙基亚硝胺(N-nitrosodiethylamine, NDEA)被列为2A类致癌物。本文对N-亚硝胺物质的毒理学特性、致癌机理、检测方法进行了介绍,分析了缬沙坦、雷尼替丁、二甲双胍等常用药品中产生亚硝胺类杂质的原因,梳理了欧盟、美国和我国在药品中亚硝胺杂质方面的监管要求和措施。论文估算了召回前上述药品中亚硝胺杂质带来的致癌风险:缬沙坦中亚硝胺杂质浓度最高(NDMA含量为未检出~20.19μg/片,NDEA含量为未检出~1.31μg/片),导致额外致癌风险最高,其中位值为4.69×10-6,75百分位值则高达5.61×10-4,提示至少有25%的药品存在过高的致癌风险;雷尼替丁和二甲双胍中亚硝胺杂质则低得多,其致癌风险接近或低于10-6安全水平。不合格药品中亚硝胺杂质带来的致癌风险远高于来自食品和饮用水中的亚硝胺类污染物,甚至高于烟草中亚硝胺导致的致癌风险,因此,需要引起高度重视。加强监管后,2020年后我国原料药和成品药中未出现亚硝胺杂质超标的报道。本文可为药品生产、健康评价与研究和监管领域相关机构人员提供参考。

Since the"valsartan event"in 2018,the occurrence of N-nitrosamine as genotoxic impurities in pharmaceuticals has become a hot topic for academia,industry,and the public.N-nitrosamines are a class of strong carcinogens,and more than ten nitrosamines have been included in the International Agency for Research on Cancer(IARC)carcinogen list,with N-nitrosodimethylamine(NDMA)and N-nitrosodiethylamine(NDEA)listed as Class 2A carcinogens.In this article,the toxicological characteristics,carcinogenic mechanism,and detection methods of N-nitrosamines are summarized.The causes of nitrosamine impurities in drugs such as valsartan,ranitidine,and metformin are reviewed as well as the regulatory requirements and measures for nitrosamine impurities in drugs in the European Union,the United States,and China.The carcinogenic risk caused by nitrosamine impurities in the above mentioned drugs is estimated.Valsartan has the highest concentration of nitrosamine impurities(NDMA content:not detected~20.19μg/tablet;NDEA content:not detected~1.31μg/tablet),resulting in the highest extra cancer risk(CR):the median CR value is 4.69×10^(-6) while the 75thpercentile CR value is as high as 5.61×10^(-4)which means at least 25% of tablets can bring high cancer risk.Ranitidine and metformin have much lower nitrosamine impurities,and their cancer risk is close to or below the 10^(-4)safety level.The carcinogenic risk caused by unqualified pharmaceuticals with nitrosamines impurities is much higher than that caused by nitrosamines in food and drinking water,and even slightly higher than that caused by tobacco nitrosamines.Therefore,the health effect due to unqualified pharmaceuticals needs to be regarded seriously.Since 2020,there is no problem of excessive nitrosamine impurities in raw materials and finished drugs thanks to enhanced administration.This article provides references for professionals from the relevant institutions in the fields of pharmaceutical production,health evaluation,research,and regulation.