Nitrosated Active Pharmaceutical Ingredients - Lessons Learned?

The occurrence of N-nitrosodialkylamines in active pharmaceutical ingredients (APIs) and drug products in the last years was a kind of eye opener with regard to quality of drugs. We became aware of the fact that quality control tests described in the international pharmacopoeias might not be sufficient. The N-nitrosodialkylamines found were neither so-called (structurally) related substances, nor residual solvents or heavy metals; hence they were not limited by a compendial test, but by the ICH guideline M7 of mutagenic impurities. Additionally, nitrosamine drug-substance-related impurities (NDSRIs) were detected, mostly within the process of risk assessment required by regulatory authorities. Here, the APIs containing a vulnerable amino moiety had reacted with nitrites being a contaminant of an excipient. This review deals with the formation, toxicity, and mitigation of NDSRISs.