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EMA: Q&A on nitrosamines revised on risk of multiple impurities

EMA: Q&A on nitrosamines revised on risk of multiple impurities

The European Medicines Agency (EMA) issued a revised Version 7 of its Q&A guidance on nitrosamines dated January 22, 2022. The revision includes a new nitrosamine for testing and an updated section on testing and control of multiple impurities in one product. For such a case, a step-by-step decision tree is presented in Annex 1.

Details on multiple impurities (Q&A 10):

The new nitrosamine for testing is N-nitrosodipropylamine (NDPA) with a daily limit of 26,5 ng/day.

To address the limit calculation when more than one nitrosamine is identified in the same product two approaches are possible. Both should not exceed the acceptable risk level of 1:100.000 (see ICH M7(R1) guideline):

  1. The total daily intake of all identified N-nitrosamines should not exceed the acceptance intake (AI) of the most potent N-nitrosamine identified
  2. The total risk level calculated for all identified N-nitrosamines is not to exceed the 1 in 100,000 risk of cancer according to ICH M7(R1). With this option, either a fixed or flexible approach for calculation of AI may be used.

    Fixed approach: fixed AI limits (in ppm/ppb) are set for individual nitrosamines and no limit for total N-nitrosamines is needed.
    Flexible approach: each N-nitrosamine should be specified at its AI limit in ppm/ppb and an additional limit for total N-nitrosamines is required.

However, the approach chosen needs to be justified by the MAH/applicant. The newly added decision tree (Annex 1) should be helpful for further orientation.


All documents and necessary templates can be accessed via the EMA website on nitrosamine impurities.


EMA: Q&A on nitrosamine impurities