The Nitrosamine "Saga": Lessons Learned from Five Years of Scrutiny

The onset of the N-nitrosamine (NA)saga in 2018was chiefly related to certain small dialkyl N-nitrosaminesoriginating from the synthesis of the active pharmaceutical ingredient(API). However, the subsequent comprehensive assessments performedon APIs, formulated drug products, and packaging put a different typeof NAs in the limelight: a diverse range of complex so-called nitrosaminedrug-substance-related impurities (NDSRIs). They may form due to thepresence of potentially nitrosatable secondary or tertiary amine moietiesin APIs or API impurities and nitrosating agents formed from low levelsof nitrite present as impurities. The unique properties of the aminefunctional group make it irreplaceable in the synthesis of APIs. Whilenitrite levels may be reduced, the formation of NAs in drug productscannot be completely prevented, and the class default acceptable intake(AI) of 18 ng/day currently poses significant challenges in termsof both viable control and analysis at such low levels. Even so, NAexposure through pharmaceuticals is expected to be orders of magnitudelower than the exposure via food or endogenous formation. While robustcarcinogenicity data are available for many of the small, simple NAs,there is a distinct absence of such data for most NDSRIs. Many workinggroups have therefore been established to share data and rapidly improveknowledge (whether in terms of toxicity data, structure-activityrelationships, or analytical techniques), to define best practicesto assess the genotoxic potential of NDSRIs, and to advance methodsto calculate AIs based on solid scientific rationales. Ultimately,to protect patients from true cancer risk and secure access to importantmedicines, it is crucial for manufacturers and health authoritiesto pursue efforts to implement NA control strategies that are equallyeffective and realistic. As patient safety is paramount, the pharmaceuticalindustry is committed to ensuring that the medicines it supplies aresafe and effective. Where legitimate safety concerns exist, it isundisputed that appropriate actions must be taken, which could includewithdrawal of products from the market.