Dhansekar Neha, Rale Pratiksha, Ghalsasi Yogesh
Department of Chemistry, K J Somaiya College of Science and Commerce, Vidyavihar, Mumbai-77, India.
Curr Drug Saf. 2025;20(4):404-414. doi: 10.2174/0115748863324951241028050225.
The presence of N-nitrosamine impurities in pharmaceutical products is well known. In 2019, it resulted in drug recall by the Food and Drug Administration (FDA). Soon, several groups identified the presence of many N-nitrosamines (NAs) in various Active Pharmaceutical Ingredients (APIs) and drug formulations worldwide. Moreover, in the last two years, another type of NAs was identified and detected in several pharmaceutical products. These are easily formed from the parent drug molecule and are known as Nitrosamine drug-related substances (NDSRIs). The amine group plays a major and unique role in the synthesis of many drug molecules, and hence, it is practically impossible to eliminate the presence of NAs and NDSRIs from drug products. The risk assessment of the health hazard to the patient was done, and the FDA has set the maximum daily acceptable intake (AI) at 18 ng/day for NAs. This limit poses a significant challenge in isolating, identifying and quantifying NAs and NDSRIs in APIs and formulations. For small, simple NAs, a lot of toxicological information and carcinogenetic data is available; however, for NDSRIs, such data is practically absent. This review article attempts to gather the toxicological data for a few NAs and NDSRIs and tries to assess the genotoxicity potential of some NDSRIs. The possible sources of NAs and NDSRIs, including synthetic methodology and processes, impurities associated with intermediates or raw materials, stability of the API, packaging materials, imprinting inks, and excipients, are also discussed. A summary of different analytical techniques used for the detection of these NAs and NDSRIs in different pharmaceutical products has also been included. Finally, various strategies employed for the minimization of these impurities along with additional control strategies to mitigate NAs and NDSRIs below acceptable limits, have also been discussed.
药品中存在N-亚硝胺杂质是众所周知的。2019年，这导致了美国食品药品监督管理局（FDA）召回药品。很快，多个团队在全球范围内的各种活性药物成分（API）和药物制剂中发现了多种N-亚硝胺（NAs）的存在。此外，在过去两年中，另一种类型的NAs在几种药品中被识别和检测到。这些很容易从母体药物分子形成，被称为亚硝胺类药物相关物质（NDSRIs）。胺基在许多药物分子的合成中起着主要且独特的作用，因此，要从药品中消除NAs和NDSRIs的存在几乎是不可能的。已对患者健康危害进行了风险评估，FDA将NAs的每日最大可接受摄入量（AI）设定为18 ng/天。这一限值在分离、鉴定和定量API及制剂中的NAs和NDSRIs方面构成了重大挑战。对于小型、简单的NAs，有大量的毒理学信息和致癌数据；然而，对于NDSRIs，此类数据几乎不存在。这篇综述文章试图收集一些NAs和NDSRIs的毒理学数据，并试图评估一些NDSRIs的遗传毒性潜力。还讨论了NAs和NDSRIs的可能来源，包括合成方法和工艺、与中间体或原材料相关的杂质、API的稳定性、包装材料、印字油墨和辅料。还包括了用于检测不同药品中这些NAs和NDSRIs的不同分析技术的总结。最后，还讨论了为尽量减少这些杂质所采用的各种策略以及将NAs和NDSRIs降低到可接受限值以下的额外控制策略。
