New Update of Appendix 1 of the Nitrosamines Guideline - EMA/42261/2025/Rev. 11

    New Update of Appendix 1 of the Nitrosamines Guideline - EMA/42261/2025/Rev. 11

    Regulatory Affairs Pharma & Biotech Toxicology

    Thursday, 04 December 2025

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    Pablo Palomar, Senior Toxicology Officer at QbD Group

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    On 01/12/2025, the European Medicines Agency (EMA) released an update to Appendix 1 (EMA/42261/2025/Rev. 11) of the Nitrosamines Guideline. This appendix lists nitrosamines for which an established Acceptable Intake (AI) is available.

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    New Update of Appendix 1 of the Nitrosamines Guideline | QbD Group

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    What's new?

    This update introduces the Acceptable Intake (AI) values for new nitrosamine drug substance–related impurities (NDSRIs) associated with the manufacturing processes of several active substances (levodropropizine, cytisine, lumefantrine, mifepristone, tapentadol, and selumetinib). In addition, the acceptable intake for the nitrosamine arising from the use of the fragrance ingredient methyl N-methylanthranilate has also been established.

    What does this mean to you?

    If you market medicines containing any of the substances listed above, you should verify if the potential presence of these new NDSRIs has already been assessed. If not, it is important to promptly update your NRA to account for these risks, particularly for methyl N-methylanthranilate, mifepristone, and tapentadol, which may lead to nitrosamines classified as CPCA category 1 or 2. Some regulatory agencies may request confirmatory testing even when no direct risk of formation has been identified.

    If you have already assessed these NDSRIs and identified a risk, review whether the AI values used in your previous evaluation have changed, as updated limits may impact the conclusions of past confirmatory analyses.

    Toxicology - Nitrosamine

    Toxicology - Nitrosamine

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