11 March 2022

Nitrosamine risk assessments

IPEC’s position on the role of excipients when conducting nitrosamine risk assessments for drug products 

The International Pharmaceutical Excipients Council Europe (IPEC Europe) has published a summarizing position paper on The Role of Excipients in Determining N-Nitrosamine Risks for Drug Products. The document describes the IPEC position on the role of excipients when conducting N-nitrosamine risk assessments for medicinal products.

The presence of N-nitrosamines* in drug products continues to be a global concern. In July 2020, the EMA published an assessment report that placed all medicinal products (including, biologics, vaccines, ATMPs, and recombinant therapeutic proteins) into scope of the nitrosamine risk assessment. Other regulatory agencies (Health Canada, Swiss Medic, and ANVISA) have also placed biologics within scope of the nitrosamine risk assessments. In September 2020, the US Food and Drug Administration (US FDA) published its guidance on nitrosamines that applies to any drug product containing chemically synthesized active pharmaceutical ingredients and drug products at risk.

Excipients are considered as a potential risk factor during the drug product risk assessment. Even though excipient manufacturers are under no specific regulatory requirement to provide risk assessments on nitrosamines to regulatory agencies, the IPEC considers a risk-based cooperation between the pharmaceutical manufacturer and an excipient supplier appropriate. The focus of published position paper is to expand on the potential contribution excipients may or may not have on the formation of nitrosamines in final drug products. The presence of nitrites and vulnerable amines in excipients are also considered. Excipient suppliers should carefully evaluate the potential risk related to their excipients. This will assist medicinal product manufacturers to fulfil their regulatory obligation which is to conduct risk assessments for their drug products.

*N-nitrosamines are a class of organic compounds that include examples that are associated with a potential for a significant carcinogenic risk (part of the “cohort of concern” in ICH Guideline M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk). Beginning in July 2018, the European Medicines Agency (EMA) reported the recall of several products containing Valsartan due to N-nitrosodimethylamine (NDMA) contamination.