Department of Chemistry, Jawaharlal Nehru Technological University Anantapur, Ananthapuramu, Andhra Pradesh 515002, India.
Analytical Research and Development, IPDO, Dr. Reddy's Laboratories Limited, Hyderabad 500090, India.
Chem Res Toxicol. 2024 Sep 16;37(9):1456-1483. doi: 10.1021/acs.chemrestox.4c00234. Epub 2024 Aug 19.
Since 2018, N-nitrosamine impurities have become a widespread concern in the global regulatory landscape of pharmaceutical products. This concern arises due to their potential for contamination, toxicity, carcinogenicity, and mutagenicity and their presence in many active pharmaceutical ingredients, drug products, and other matrices. N-Nitrosamine impurities in humans can lead to severe chemical toxicity effects. These include carcinogenic effects, metabolic disruptions, reproductive harm, liver diseases, obesity, DNA damage, cell death, chromosomal alterations, birth defects, and pregnancy loss. They are particularly known to cause cancer (tumors) in various organs and tissues such as the liver, lungs, nasal cavity, esophagus, pancreas, stomach, urinary bladder, colon, kidneys, and central nervous system. Additionally, N-nitrosamine impurities may contribute to the development of Alzheimer's and Parkinson's diseases and type-2 diabetes. Therefore, it is very important to control or avoid them by enhancing effective analytical methodologies using cutting-edge analytical techniques such as LC-MS, GC-MS, CE-MS, SFC, etc. Moreover, these analytical methods need to be sensitive and selective with suitable precision and accuracy, so that the actual amounts of N-nitrosamine impurities can be detected and quantified appropriately in drugs. Regulatory agencies such as the US FDA, EMA, ICH, WHO, etc. need to focus more on the hazards of N-nitrosamine impurities by providing guidance and regular updates to drug manufacturers and applicants. Similarly, drug manufacturers should be more vigilant to avoid nitrosating agents and secondary amines during the manufacturing processes. Numerous review articles have been published recently by various researchers, focusing on N-nitrosamine impurities found in previously notified products, including sartans, metformin, and ranitidine. These impurities have also been detected in a wide range of other products. Consequently, this review aims to concentrate on products recently reported to contain N-nitrosamine impurities. These products include rifampicin, champix, famotidine, nizatidine, atorvastatin, bumetanide, itraconazole, diovan, enalapril, propranolol, lisinopril, duloxetine, rivaroxaban, pioglitazones, glifizones, cilostazol, and sunitinib.
自 2018 年以来，N-亚硝胺杂质已成为全球药品监管领域广泛关注的问题。这种关注源于它们的污染、毒性、致癌性和致突变性，以及它们存在于许多活性药物成分、药物产品和其他基质中。人类中的 N-亚硝胺杂质会导致严重的化学毒性作用。这些包括致癌作用、代谢紊乱、生殖危害、肝脏疾病、肥胖、DNA 损伤、细胞死亡、染色体改变、出生缺陷和妊娠丢失。它们特别已知会导致各种器官和组织（如肝脏、肺、鼻腔、食道、胰腺、胃、膀胱、结肠、肾脏和中枢神经系统）的癌症（肿瘤）。此外，N-亚硝胺杂质可能导致阿尔茨海默病和帕金森病以及 2 型糖尿病的发展。因此，通过使用 LC-MS、GC-MS、CE-MS、SFC 等先进分析技术增强有效的分析方法来控制或避免它们非常重要。此外，这些分析方法需要具有足够的灵敏度和选择性，以及合适的精密度和准确度，以便在药物中适当检测和定量实际的 N-亚硝胺杂质含量。美国 FDA、EMA、ICH、WHO 等监管机构需要更加关注 N-亚硝胺杂质的危害，为药品制造商和申请人提供指导和定期更新。同样，药品制造商在生产过程中应更加警惕避免使用亚硝化剂和仲胺。最近，许多研究人员发表了大量关于以前通知产品中发现的 N-亚硝胺杂质的综述文章，包括沙坦类、二甲双胍和雷尼替丁。这些杂质也在广泛的其他产品中被检测到。因此，本综述旨在集中关注最近报道含有 N-亚硝胺杂质的产品。这些产品包括利福平、畅沛、法莫替丁、尼扎替丁、阿托伐他汀、布美他尼、伊曲康唑、代文、依那普利、普萘洛尔、赖诺普利、度洛西汀、利伐沙班、吡格列酮、格列酮、西洛他唑和舒尼替尼。
