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Warning letters, 483s, Recalls, Import Alerts, Audit observations
EMA updates Q&A document on N-Nitrosamines. In the Rev 16 (dated 7 July 2023) limits of N-Nitrosamines in medicinal product is updated, introduces the Carcinogenic Potency Categorization Approach (CPCA) for N-Nitrosamines.
For N-nitrosamines without sufficient substance specific data the Carcinogenic Potency Categorization Approach (CPCA) should be used to establish the acceptable intake (AI). The Carcinogenic Potency Categorization Approach for N- nitrosamines is described in Annex 2. CPCA is based on structure-activity relationship (SAR) concepts and/or AI limits based on previously-conducted surrogate analyses. A prediction of the mutagenic potential and carcinogenic potency of an N-nitrosamine can be generated based on its structural features that directly increase or decrease the favourability of the activation mechanism -α-hydroxylation mechanism – of metabolic activation.
The CPCA applies to N-nitrosamines bearing a carbon atom on both sides of the N-nitroso group, and where the carbon is not directly double bonded to a heteroatom (i.e., N-nitrosamides, N-nitrosoureas, N-nitrosoguanidines and other related structures are excluded). Additionally, the potency categorization approach does not apply to Nnitrosamines where the N-nitroso group is within an aromatic ring (e.g., nitrosated indole). For Nnitrosamines containing two N-nitroso groups, the group with the highest predicted carcinogenic potency (i.e., the group with the lowest numerical potency category) defines the AI for the entire molecule.
Five potency categories are defined based on number of Hydrogens on alpha carbons, Deactivating features and Activating features with Potency Category 1 assigned lowest AI of 18ng/day and Category 5 assigned highest AI of 1500ng/day. Deactivating features increase potency score to higher category (higher AI) and activating features decrease potency score to lower category (lower AI). Several examples of application of CPCA are also given with different molecules and structures which will greatly help MAH applicants in arriving at the Potency Category and AI for molecules they are evaluating.
EMA Q&A Document on N-Nitrosamines (Rev 16, dated 7 July 2023)
EMA has further updated the Q&A document. In the update dated 28 July 2023, EMA explains that with new approaches for setting nitrosamines limits using the carcinogenic potency categorisation approach (CPCA), the approach for a universal temporary AI (t-AI) while a formal AI is established is no longer considered necessary and content under Q&A 21 is deleted. This removes the provision for adopting temporary AI (t-AI) of 178 ng/day (total nitrosamines), till a formal AI is established for newly identified N-Nitrosamines (as per the Q&A document dated 7 July 2023). The approach to be followed is to use of an interim limit as described in Q&A 22, based on less-than lifetime (LTL) approach where upto 12 months (13.3 x AI) and > 12months (6.7 x AI) limit shall be applied. However limit should not exceed 1.5 µg/day.
Access the latest update @ https://tinyurl.com/EMAupdate
EMA updated Q&A on Nitrosamines to Rev. 18 (2 October 2023). In the latest update of the Q&A on Nitrosamines, EMA has updated only the Q&A 3. The update states that though deadlines for Call For Review has passed, MAHs that have not reported identified Nitrosamine impurities to the relevant authority should do so on priority; MAHs can continue to use the templates previously established..https://tinyurl.com/896u5r56
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