Hello,
revision 17 of EMA Q&A is already uploded on EMA page.
Changes:
Amendment of Q&A 22 on approach to control presence of Nnitrosamine exceeding the AI while CAPAs are being implemented to extend the scope to authorised products for chronic use and clarify the applicable limits and exemptions. Amendment of Q&A 20 and Q&A 21on approach to control presence of nitrosamine while the AI is being established to clarify that as the AIs can be established with the new carcinogenic category approach (CPCA) the approach for a universal
temporary AI (t-AI) while a formal AI is established is no longer considered necessary
Amendment of Q&A 20 and Q&A 21 on approach to control presence of nitrosamine while the AI is being established to clarify that as the AIs can be established with the new carcinogenic category approach (CPCA) the approach for a universal temporary AI (t-AI) while a formal AI is established is no longer considered necessary
Amendment of Q&A 22 on approach to control presence of N-nitrosamine exceeding the AI while CAPAs are being implemented to extend the scope to authorised products for chronic use and clarify the applicable limits and exemptions.
Q&A 20: What are the regulatory steps taken by authorities following the identification of an N-nitrosamine exceeding the AI?
Q&A 21: What is the approach to control the presence of nitrosamines until a substance specific AI is established? [Note: This is the Q&A that introduced the t-AI of 178 ng/day. All the content was deleted and the following was added]:
Considering the new approaches for setting nitrosamines limits using the carcinogenic potency categorisation approach (CPCA) and the enhanced AMES test (EAT) protocol (see Q&A 10 above), the approach for a universal temporary AI (t-AI) while a formal AI is established is no longer considered necessary, as such the contents of this question has been deleted in July 2023.
Q&A 22: What is the approach to control presence of N-nitrosamine exceeding the AI during CAPA implementation?
The approach is applicable to all authorised products that have:
a duration of treatment not exceeding 10 years;
and
CAPA implementation timeline of up to 3 years from the establishment and publication of the AI (nevertheless MAHs are expected to expedite CAPAs implementation).
*In any case the limit should not exceed 1.5 µg/day unless the established AI (Table 1, Q&A10) is > 1.5 µg/day or the nitrosamine concerns a category 5 according to CPCA or the nitrosamine is shown to be negative in an enhanced Ames test (EAT).
The approach is not applicable to the below instances where other approaches may be considered on a case-by-case basis in consultation with the appropriate regulatory authority:
Authorised medicines taken for a lifetime (>10 years);
CAPA implementation exceeding 3 years from the establishment and publication of the AI;
*New/ongoing regulatory applications
This, I would say gives some breath to chronic use products. Until it is more clear how to override CPCA limits with read across surrogates.
Any thoughts on the step 2 resubmission requests from CMDh and the absence of a general step 3 deadline shift (whereas the deadlines remain part of the Q&A)? Will we have to wait until 16 September for clarity on the step 3 deadline shift or do we expect a possibility for ad hoc agreements in CMDh and CHMP on Rev. 18 allowing publication in August (usually the standard monthly meetings are not planned in August (written procedures at CHMP, no meeting for CMDh))?
Or is the broadening of Q&A 22 possibilities the de facto deadline shift and will it stop here?
*In any case the limit should not exceed 1.5 µg/day unless the established AI (Table 1, Q&A10) is > 1.5 µg/day or the nitrosamine concerns a category 5 according to CPCA or the nitrosamine is shown to be negative in an enhanced Ames test (EAT).
It means nitrosamines with Category 5 or negative in the EAT can be set at a higher limit than 1.5 µg/day as an interim limit through LTL if the authority allows. At least 6.7 x 1.5 = 10.05 µg/day can be applied for them during the CAPA implementation. In addition that it can be applied to products for chronic use, as @Diego_HM pointed out.
P&R 20 e 21:
Agora, pela nova redação, uma vez que os limites AI’s (ingestão aceitável) podem ser estabelecidos por meio da categorização carcinogênica (CPCA), a adoção de um AI temporário universal (t-AI) enquanto um AI formal é estabelecido não é mais considerada necessária.
P&R 22:
A nova redação visa ampliar o alcance das medidas de controle para a presença de N-nitrosamina que excede o AI durante a implementação das Ações Corretivas e Preventivas (CAPAs) para abranger produtos autorizados destinados a uso crônico. Também esclarece os limites e isenções aplicáveis nesse contexto.
The approach is intended to be evaluated by the lead authority during the assessment of the case and
is expected to be communicated by the lead authority to the concerned MAH as part of assessment
conclusions. In terms of retrospective application, where more restrictive interim limits were previously
agreed for some products as part of case assessment, upon request from the MAH, the lead authority
can re-assess interim limits taking into consideration this approach to control presence of N-nitrosamine
exceeding the AI during CAPA implementation.
如之前建立的临时限值更严格，是不是可以通过CAPA重新评估限值，但是具体怎么实施没有明确
I assume that as the * is on “AI” and not on “Interim Limit” it is the AI itself that cannot exceed 1.5 ug/day and the interim limit can therefore be up to 13.3 x 1.5 ug/day / 6.7 x 1.5 ug/day.
Thanks Naomi for response. It is still a puzzle to me. Also the two scenarios (*is for AI or Interim limit) and two very different interpretations. So please i request other team members to provide opinions.
I’m sorry for my delayed response. AI of nitrosamines classified as category 5 or with negative EAT is 1.5 ug/day at EMA. And 1.5 ug/day does not “exceed” 1.5 ug/day. If * is on “AI”, the meaning of the footnote looks strange.
Just for simple understanding- overall interim AI by LTL approach can exceed 1.5 microgram/day if a nitrosamine AI is established greater than 1.5 microgram/day
(or) falls under CPCA category 5 (or) negative in EAT.
But it is worthy to note this might need agency concurrence and also the product shall be critical in health market for patient benefit!
