Potential for the Formation of N‑Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Regulatory requests that marketing authorization holders for chemically synthesized active substances risk assess their medicines for the potential presence of N-nitrosamines have led to a renewed interest in amine nitrosation. We have used published mechanistic and kinetic studies of amine nitrosation to assess the risk that traces of nitrite in the water used during active pharmaceutical ingredient (API) manufacturing could give rise to significant levels of N-nitrosamines. We conclude that the levels of nitrite typically found in water used for API manufacture are very low ( 9.5) in the majority of cases. The use of less basic amines, elevated processing temperatures, or low pH conditions in combination with elevated levels of nitrite have the potential to generate levels of N-nitrosamines that could lead to significant quantities being present in the isolated API if the downstream processing does not provide an adequate purge. The kinetic models described may be used to risk assess specific situations or processes. For example, the addition of traces of dimethylamine to a nitrosation reaction is predicted to lead to the rapid, quantitative formation of N-nitroso dimethylamine. Simple tertiary alkylamines can nitrosate via a dealkylative process, which is significantly slower than secondary amine nitrosation. Therefore, they do not represent a risk of N-nitrosamine formation under conditions where there is no significant risk of secondary amine nitrosation.