Nitrosamine Alerts: EMA Published an Updated Version for the Q&A Documents on Nitrosamine Impurities

Nitrosamine Alerts: EMA continues updating the document “Questions and answers for marketing authorisation 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”.

7th July 2023. Q&A document rev.16 introduces new amendments to chapter 10: which limits apply for nitrosamines in medicinal products?

Establishment of the Acceptable Intakes (AIs). When identifying new nitrosamines, we consider two scenarios:

1.If there are sufficient substance-specific animal carcinogenicity data, calculate the TD50. Then use it to derive a substance-specific limit for lifetime exposure.

2.If there is not enough substance-specific data

• Use the Carcinogenic Potency Categorization Approach (CPCA) to establish the AI (Annex 2).
• A negative result in an enhanced Ames test (EAT, Annex 3) allows control of the N-nitrosamine at 1.5 µg/day.
• If a surrogate nitrosamine is available with robust carcinogenicity data, the TD50 from the surrogate substance can serve as a point of departure for derivation of AI by SAR and read across.
• A negative result in a relevant in vivo mutagenicity study can allow control of the N-nitrosamine as a non-mutagenic impurity.

The Appendix 1 “Acceptable intakes established for N-nitrosamines” has been updated with 60 new specific AIs reported for several NDSRIs and some ‘small’ nitrosamines. Some of their AIs have been raised compared to those published in previous revisions:

• MeNP: from 26.5 ng/day (Rev.4) to 400 ng/day;
• N-Nitroso-Dabigatran: from 18 ng/day (Rev.10) to 400 ng/day;
• N-Nitroso-Rasagiline: from 18 ng/day (Rev.9) to 100 ng/day.

Please refer to the Questions & Answers document to the updated “Appendix 1: Acceptable intakes established for N-nitrosamines” and for complete information.