A Review on Nitrosamines Impurities in Pharmaceuticals-From Contamination Sources to Analytical Determination

Nitrosamines (NA) are potent genotoxic impurities, continuously reported due to their mutagenic and carcinogenic effects in animal species. Recently, these substances were detected as contaminants in various pharmaceutical products, prompting several product recalls due to risks to public health. Certain derivatives Of Angiotensin II Receptor Blockers (ARBs), such as losartan, valsartan, and olmesartan, have been identified as problematic in the presence of NAs, primarily due to contamination-related factors. Other drugs and classes, including nizatidine, metformin, quetiapine, sitagliptin, and amitriptyline, have also been reported as potential sources of NA contamination during pharmaceutical production. This review aims to provide a comprehensive reference for scientists, technical analysts, and regulatory bodies regarding NAs, focusing on their possible presence in drug synthesis and pharmaceutical production. The review integrates published information concerning contamination sources, genotoxic effects, physicochemical properties, regulatory guidelines, analytical methods, and sample pre-treatment strategies. An updated overview of regulatory aspects highlights the need for continuous revisions, considering available analytical technologies capable of detecting NAs at the lowest possible concentrations. The established detection limits must align with regulatory recommendations, which take into account daily drug intake and its relationship with toxicological effects. Much of the information published in the literature is applicable to drug products, and it is important to develop new strategies in regulatory, scientific, and technical areas that address the new challenges arising from a focus on continuous prevention. Future pharmaceutical product design should allocate more resources to preventing NA formation, prioritizing the selection of molecules with lower contamination risks or adopting alternative synthetic routes. This integrative perspective enhances comprehension and serves as complementary material for new investigations concerning NA and pharmaceuticals.