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Recent Revision of EMA Nitrosamine Guideline | 2023

Most awaited revision (ver 16) of EMA nitrosamine guideline is published on Jul 07, 2023 with new scientific approach to derive acceptable intakes for N-nitrosamine including NDSRI. A big relief for industry to derive limits based on carcinogenic potency score prediction published acceptable limits for >50 new nitrosamines.

A. Recommended carcinogenic potency categorization approach to calculate potency score to predict the category:

-5 potency categories proposed based on SAR concepts by assessing structure of nitrosamine

-category 1-18 ng/day

category 2-100 ng/day

category 3-400 ng/day

category 4, 5-1500 ng/day

B. Recommended enhanced Ames test conditions to test nitrosamines mutagenicity due to sensitivity concerns with current conditions:

-if this well conducted enhanced ames test result is negative, nitrosamine can controlled at TTC level 1.5 μg/day

-if in vivo mutagenetic study results are negative, nitrosamine can controlled as normal imp at ICH Q3A/ICH Q3B limits

However, the overall principle of the Article 5(3) referral should still be considered, notably that “the presence of N-nitrosamines in human medicinal products shall be mitigated as much as possible.” Therefore, manufacturers are encouraged to improve their processes, even if they result in only very small amounts (<10% AI) of multiple nitrosamines, as processes and controls should be designed to prevent if possible or mitigate as much as possible the presence of N-nitrosamines in APIs and FPs.

Note: The current Question and Answer document on its implementation, will replace the previous letter entitled ‘Information on nitrosamines for marketing authorisation holders’ (EMA/189634/2019, published on 19 September 2019).

Read also: Health Canada Guidance on Nitrosamine Impurities

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