Hi,
I have a question which I might miss, or it may be a gap in current guidelines.
Once an acceptable intake is established in Appendix 1, what are the expected timelines for its implementation in the already approved products (via variation) ?
During the very first guideline and “call for review”, specific timetable had been reported and the MAH shall followed them. Now, these timelines have been passed, and if I am not mistaken, no clear guidance is given in that way.
Hope you could help me figure out, or please share any experience of yours.
Thank you!
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It would be great to hear for any experience of yours on this matter.
Perhaps you could also share any data from the Guidelines (or literature) that I may have missed
The current EMA guidance indicates that MAHs are expected to update their risk assessments and implement any required changes once an AI is published, re-visit nitrosamine risk assessments, and conduct confirmatory testing as appropriate.
While as per Health Canada.
If the AI was already before Aug 1, 2025, MAHs have up to 3 years from Aug 1, 2025 to complete CAPA implementation (i.e., until Aug 1, 2028).
If the AI is published after Aug 1, 2025, MAHs have up to 3 years from the AI’s publication date to complete CAPA implementation.
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yes but still it is not clear whether it is expected to submit a variation as soon as the Appendix 1 is revised. or this is expected to be implemented after 3 y.
have you any experience with Authorities in this regard?
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no authority has yet raised this question. my understanding is based on published guidance
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Hi Eleni,
Once an acceptable intake is established in Appendix 1, the timeline is 3 years for CAPA implementation from the date of publication of the AI limit in the Appendix. However, as you mention the deadline has now passed. As per my knowledge each health authority is dealing with this issue on a case-by-case basis depending on submission from Marketing Authorization Holders. There are several factors involved in the decision process like Potency category of the nitrosamine, detected levels, indication of the drug, availability of alternative drugs in the market for the same indication, MAH’s response to CAPA plan etc.
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Thank you Sushant.
Considering that Appendix 1 is constantly updated including new NDSRIs for already approved drugs in EU and FDA, I think that this should be described in more detail in Guidelines. Speaking for EU, not all drugs are centralized approved (e.g. generics, or VAM) so the matter of handling is a authority-by-authority case, with any decision variability may this cause.
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This is a very good question. It seems that no deadline was specified. Personally, I think it should be shorter than three years. Appendix 1 is constantly being updated. The guidelines should clearly specify a specific schedule.
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