The presence of nitrosamines in medicinal products (MP) gained the attention of health authorities with the discovery of N-nitrosodimethylamine (NDMA) in valsartan in 2018 (see also our other post). Nitrosamines are known to be mutagenic and carcinogenic. After the first discovery, more nitrosamines were discovered in other commonly prescribed MP and health authorities issued several industry and regulatory guidances requesting manufacturers to “assess the risk of nitrosamine formation or presence during the manufacture of human medicines.” Furthermore, when a risk is identified, “the risk of presence of nitrosamine impurities should be mitigated.”
Nitrosamines are a family of compounds with a common chemical structure of R1N(-R2)-N=O, yielding a distinctive bonding of a nitroso group to an amine. The chemical formation of nitrosamines requires the presence of both nitrosating agents and amine-substrates at significant levels and under conditions promoting the nitrosating reaction. This reaction is far more likely to occur with secondary and tertiary amines than primary or quaternary amines.
Nitrosamine impurities may be formed and get incorporated into the active substance or final MP through reagent, catalyst, solvent, raw materials or even equipment and primary packaging & labelling used in the process of manufacturing. Therefore, it is essential for industry to develop robust risk assessment processes and control strategies to ensure that MP administered to patients are safe.