Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phayathai Rd., Bangkok 10330, Thailand.
Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phayathai Rd., Bangkok 10330, Thailand.
J Pharm Sci. 2021 Sep;110(9):3118-3128. doi: 10.1016/j.xphs.2021.04.021. Epub 2021 May 11.
Nitrosamine-contaminated medicinal products have raised safety concerns towards the use of various drugs, not only valsartan and all tetrazole-containing angiotensin II receptor blockers, but also ranitidine, metformin, and other medicines, many of which have been recalled and prone to shortage. At any stages, from drug substance synthesis throughout each product's lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions. Consequently, drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products in the market. This review encompasses various critical elements contributing to successful control measures against current and upcoming nitrosamine issues, ranging from accumulated knowledge of their toxicity concerns and potential root causes, precise risk evaluation, as well as suitable analytical techniques with sufficient sensitivity for impurity determination. With all these tools equipped, the impact of nitrosamine contamination in pharmaceuticals should be mitigated. An evaluation aid to tackle challenges in risk identification, as well as suitable industry-friendly analytical techniques to determine nitrosamines and other mutagenic impurities, are among unmet needs that will significantly simplify the risk assessment process.
受污染的含亚硝胺药物已引起人们对各种药物使用的安全担忧，不仅包括缬沙坦和所有含四唑的血管紧张素 II 受体阻滞剂，还包括雷尼替丁、二甲双胍和其他药物，其中许多药物已被召回且容易短缺。在药物合成的各个阶段以及每个产品的整个生命周期中，如果胺与共存的亚硝化剂在适当条件下反应，这些杂质都可能会产生。因此，世界各国的药物监管机构都为市场上的所有药物产品制定了严格的亚硝胺污染控制指南。本综述涵盖了成功控制当前和即将出现的亚硝胺问题的各种关键因素，包括对其毒性问题和潜在根本原因的积累知识、精确的风险评估以及具有足够灵敏度的合适分析技术来确定杂质。有了所有这些工具，就可以减轻亚硝胺污染对药物的影响。风险识别方面的评估辅助工具，以及用于确定亚硝胺和其他致突变杂质的适合行业的分析技术，都是尚未满足的需求，这将大大简化风险评估过程。
