25 March 2024

EMA: Update of Q&A for MAH on Nitrosamine Impurities

The presence of nitrosamine impurities in medicinal products has raised safety concerns regarding the consumption of various pharmaceuticals. These contaminants can develop at any phase, from the initial synthesis of the drug substance through the entire lifespan of the product, especially when an amine interacts with a nitrosating agent under favourable conditions.


Addressing this health risk, on 15th January 2024, the European Medicines Agency (EMA) introduced updates to its “Questions and answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products”.


The update to Q&A 9, clarifies analytical methods’ sensitivity in detecting nitrosamine impurities. Specifically, the Limit of Quantification (LoQ) for these methods must be at or below the acceptable limit for the respective nitrosamine to assure proper quantification of all potentially harmful impurities.


The EMA has introduced a distinction in the management of nitrosamine impurities in Q&A 3 and 10, specifically addressing non-mutagenic nitrosamines (NMIs). NMIs, identified through negative in vivo mutagenicity studies like the Ames test, are to be managed according to ICH Q3A(R2) and ICH Q3B(R2) guidelines, without the need for step 2 confirmatory testing submission.


The EMA has delineated two primary scenarios for the detection of new nitrosamines; for nitrosamines with sufficient substance-specific animal carcinogenicity data, a substance-specific acceptable intake (AI) limit is calculated using the TD50 to determine lifetime exposure limits. In cases where sufficient substance-specific data are unavailable, the Carcinogenic Potency Categorization Approach (CPCA) is recommended to establish the AI unless other robust data suggest a different AI.


For the assessment of nitrosamines not listed in Appendix 1 of the guidance document, the EMA now provides specific timelines and conditions under which the Ames test results are acceptable. This includes a stipulation that all Ames assays initiated after August 2023 must comply with the Enhanced Ames Test (EAT) conditions, with a submission deadline for these assays set for January 31st, 2024.