EMA Q&A Rev. 19 (EMA/409815/2020 Rev.19)

EMA Q&A 10 now says:
If the nitrosamine is not included in Appendix 1, MAH/MA applicants can also refer to a CPCA category from another source e.g. CPCA categories published by other regulatory authorities, but this will need confirmation to allow control of the substance at the level corresponding to that category.

It does not specify if that confirmation can also happen at the national competent authority level or requires confirmation of the CPCA exercise by the NcWP.

At the same time Q&A 22 wasn’t updated to for example reflect more explicitly that under such a scenario a Q&A 22 application can be agreed right away.

Was this a reconfirmation of the territory specificity of the guided AI lists (with a possible lowering of the CPCA exercise documenting requirements in submissions (just cite the entry in another limit list)) and that a CPCA-based limit is the point of departure typically or indicating that FDA and HC guided AI lists can be used to agree a Q&A 22 application ahead of NcWP CPCA exercise assessment (which was confirmed in the past to be still needed).

And what about the “e.g.”, does that mean CPCA exercises from software tools (e.g. Lhasa’s CPCA assessment functionality) can be used? (Again, in all cases this would have to be immediate use to have added value to Q&A 21?).

Other (textual, non content) changes

  • Moving of Annexes to Appendixes
  • ICH M7(R1) to ICH M7(R2)

Note: on direct applicability of CPCA, we discussed during the 12 July 2023 EMA NIOG-IP meeting:

Question 1 : Is there direct applicability of company derived CPCA-limits in absence of Appendix 1 published AIs? Answer: Submission and NS OEG assessment remains required, acceptance will lead to publication of the limit in Appendix 1.

EFPIA: I’ll bring in some of the questions together with my colleagues. When we as a company are dealing with an NDSRI and have done CPCA exercise per the guidance to determine the CPCA category and related AI based on categorization and thus come up with an identified limit, let’s say category 4 and 1500 ng/day, maybe we even have a negative EAT-protocol based Ames test in hands, is that it then? We don’t have to sort of check if our assessment based on Q&A 10 and Annex 2-3 is sort of OK? We can define the AI using the predefined EMA process and get 400 ng/day, 100 ng/day,…, and that’s it, we don’t need to submit something and engage further on the acceptability of that limit? I think you don’t need to discuss it, because the model is quite clear and well laid out. The AI is the AI.

Leon van Aerts (NS OEG): Well, you do have to submit your data! Because as we see it, you are dealing with a nitrosamine, you have to do the analytical testing efforts to show the levels of presence and you do need the AI to set your analytical threshold. You need to submit the AI as part of step 2 and all the data including the CPCA assessment showing what should be the right AI, when done properly the CPCA is confirmed by NS OEG, but we will check the CPCA exercise done by the application to determine if it was done correctly by the applicant.

EFPIA: Of course we would be submitting the associated analytical testing data on the NDSRI. It is really about the debate if we have to check in with NS OEG on if we have the correct AI. But of course we will submit it and at that point a verification will be done of the company AI (based on CPCA).

Rhys Whomsley (NS OEG): After assessment of the CPCA exercise in the submission, the CPCA AI will be published in the Appendix 1 of EMA Q&A with AIs.

EFPIA: Great example, you are referring to an NDSRI that has an established AI in Appendix 1: we would clearly use those, there is no discussion on the applicability of Appendix 1. Certainly for the European markets.