Variation for new spec due to updated EMA Guideline

Dear Community

granted that EMA has recently published an updated version of Appendix 1, and since no such detail is found in EMA Guideline for nitrosamines, could you please share your thoughts on what variation should be submitted for an updated AI and by extension an updated/ higher limit in API/FP? Especially considering that nitrosamine issue affect supply-related aspects.

Thank you for your time :slight_smile:

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If you already submitted a limit for a nitrosamine in your dossier and the updated limit is wider, formally the variation is a type II variation:

B.II.d.1 Change in the specification parameters and/or limits of the finished product. e) Change outside the approved specifications limits range

The same is valid also for the API (with ASMF). However, if the API is covered by the CEP procedure, the variation becomes only a variation for:

B.III.1 Submission of a new or updated Ph. Eur. certificate of suitability or deletion of Ph. Eur. certificate of suitability: 1. New certificate from an already approved manufacturer (Type IAin)

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Dear Giovanni
thank you for your feedback.

this is what I also thought. however at the same time I find it a little bizarre. I mean… since an AI is revised (now increased) it is supposed that its safety has been already assessed.
As such, why we should go for a type II variation which requires more time and assessment on the limit submitted (which it has been already done by EMA actually) ?

I agree with you. The nitrosamines issue is a new problem and no specific variaton is available among the “classic” type IA and IB variations.
However, you could try to submit a wider (approved) AI also through an “unforeseen” variation (type B.II.d.1.z), according to Article 5 of Commission Regulation (EC) 1234/2008.
Classification of changes: questions and answers
If the wider AI ariser directly from EMA decisions, I think that this may be accepted.

Instead, if the wider limit arises from an Enhanced Ames Test performed by your company, I think that the type II variation is more correct because the authority need to deeply evaluate the documentation and evaluate the correctness of the AET procedure.


I strictly refer to new limits as introduced due to EMA - Appendix 1 updates.
I trust that this gap might be fulfilled in the upcoming revisions of Q&A since more and more updates may be available from now and on.

Thank you for your consideration to my topic and wishing you a nice day ahead :slight_smile:



I will look this gap differently. If you have specifications in place with the existing limit and if you are complying, then why do we need to widen the limit based on EMA’s wider limit. We are incorporating the test and limit when product is complying to the test, once incorporated then widening may be a concern with agency’s perspective. If nitrosamine test is not part of specifications as product is not complying, then definitely we can use wider limit directly in specifications and comply the requirement.
Above is my personal view for discussion purpose.

I can see your point of view. However, acceptable limit is always of a supply-related interest as well. So since EMA allows us (API manufacturers and FP manufacturers) to increase the Acc. Limit, why not, right? Let alone that limit for NTTP (for example) was set in the most conservative way as read across to NTPH…
However, I would love to hear for others opinion on that :slight_smile:

Thank you once more for your kind feedback :slight_smile:

Being a formulator, I always love to have wider limit :slightly_smiling_face:
My point of discussion is, EMA asks for tightening of impurity limits (other than nitrosamine as on date) during review based on the actual available stability data of product though these impurities are qualified and specified in Pharmacopoeia product monograph. it means EMA expects that quality of product manufacturing for dossier submission should be maintained during commercial hence many a time we have to accept the tighter limits than monograph. In this relation, once we agree and product complies with tighter nitrosamine impurity then agency may not accept to wider the limit. There is lot of scope to understand the agency’s expectations and supplier’s concerns.