FDA issued Revision 2 of the guidance for industry Control of Nitrosamine Impurities in Human Drugs.  As a class of compounds, nitrosamines are potent genotoxins both in vitro and in several animal species.  Some nitrosamines are listed as probable or possible human carcinogens by the International Agency for Research on Cancer (IARC) (1). Nitrosamine formation in a number of drug products was reported in 1972 (1). FDA began investigating the presence of nitrosamine impurities in certain drug products starting in 2018 with the discovery of the presence of N-nitrosodimethylamine (NDMA) in the angiotensin II receptor blocker, valsartan. Since then, several drugs in various classes have been found to contain nitrosamine impurities. The updated guidance includes recommendations for root causes, sources, mitigation, and control strategies for nitrosamines in human drugs. It also includes new sections concerning nitrosamine drug substance-related impurities (NDSRIs).  

Of note, nitrosamine impurities do not share structural similarity to the active pharmaceutical ingredient (API, e.g., NDMA) and are found in many different drug products, while NDSRIs share structural similarity to the API and are generally unique to each API (e.g., N-Nitroso-ketamine). NDSRIs are also addressed in the FDA guidance for industry Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) (August 2023), also known as the “RAIL guidance”. Facet has worked with several organizations to evaluate and propose control strategies for nitrosamine impurities in their products. If you have concerns about nitrosamines or product impurities more broadly, Facet’s CMC experts can help you create and implement a strategy for phase-appropriate compliant manufacturing.

  1. Lijinsky W, Conrad E. & Van de Bogart R.  Formation of carcinogenic nitrosamines by interaction of drugs with nitrite.  In Bogovski P, Preussmann R, Walker EA, editors.  N-Nitroso Compounds–Analysis and Formation. P.  Lyon:  IARC; 1972.  Scient. Publ. no. 3, p. 130.