Furthermore, a notable update has been made to Q&A 10, introducing Ames test acceptability timelines. This addition establishes a structured framework for evaluating the acceptability of Ames tests, providing users with clear guidance on timelines associated with this critical aspect of assessment.
A negative result in a relevant well-conducted in vivo mutagenicity study can allow control of the N-nitrosamine as a non-mutagenic impurity (NMI), i.e. according to ICH Q3A(R2) and ICH Q3B(R2) limits.
If the active substance itself is mutagenic or clastogenic at therapeutic concentrations, N-nitrosamine impurities should be controlled at limits for non-mutagenic impurities according to ICH M7(R2).
I want to focus on the Enhanced Ames Tests. Dr. Martin Walter, Non-Clinical Assessor at the Austrian Medicines and Medical Devices Agency and Austrian delegate at the EMA explained on the webinar that near-EAT might be accepted on a case-by-case basis. But following EAT will be necessary shortly.
Question 3: Our current Ames test is not completely in line with the Enhanced Ames Test (EAT) guidelines, in this case, how should a risk assessment be conducted for a completed Ames test when used in the context of hyaluronic acid (HA) fillings?
Answer: This depends on how the Ames test was actually conducted. We have had some cases where we have also accepted regular Ames tests that approximated an EAT, so in principle a “near-EAT” study can be accepted on a case-by-case basis. At any rate it is important to have nitrosamine positive controls in your study (at least one, ideally two), and the inclusion of rat and hamster S9 is also important.
In the context of the above, I’d like to know if the non-mutagenic Nitrosamines mentioned in the latest update of the Q&A document on nitrosamines are those in category 5 ?
It refers to “NMI” (= non-mutagenic impurity) listed nitrosamines in Appendix 1 of the Q&A. These NMI listings would be based on a properly conducted negative in vivo mutagenicity test that has been reported by an applicant to the authorities and are at the moment a numerus clausus list (cf. Appendix 1).
At the moment “NMI” principles for CPCA category 5 or negative EAT listed nitrosamines do not apply and these remain in scope of the call for review.
Q&A 3 and Q&A 10 have undergone updates to incorporate detailed guidance on the handling of non-mutagenic nitrosamine impurities.
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