23-25 April 2024
The CMDh (Coordinating Group for the Mutual Recognition Procedure/Centralised Approval Procedure for Medicinal Products for Human Use) Questions & Answers on implementation of outcome of Art.31 referral on angiotensin II receptor antagonists (sartans) containing a tetrazole group provides guidance to marketing authorisation holders of sartan medicinal products on submitting change requests required in the context of the "Call for Review" related to nitrosamine impurities.
This document was updated last in December 2021 and addresses the response to question 7, which explains and defines change notifications and their classification - "Which variations are necessary to lift the conditions on the MA?"
Specifically, it addresses updates related to "Condition B" and "Condition D".
Regulatory submissions for all sartan medicinal products (angiotensin II receptor antagonists) that contain a tetrazole ring as a molecular structural element must meet four conditions (A - D).
The marketing authorisation holder must ensure that the manufacturing process of the active substances used has been reviewed with regard to the risk of formation of nitrosamine impurities and, if necessary, modified in such a way that this risk is largely minimised.
The marketing authorisation holder shall ensure that the manufacturing process of the finished product has been reviewed with regard to the risk of formation of nitrosamine impurities and, if necessary, has been modified in such a way that this risk is substantially minimised.
The marketing authorisation holder shall ensure that a control strategy is in place for the batches of active substance used.
- The marketing authorisation holder shall establish the following finished product specification for N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA): NDMA (96 ng/day); NDEA (26.5 ng/day).
- This specification can only be omitted if evidence is provided that the nitrosamine levels are consistently at ≤ 10% of these limits and the reason for the contamination is known and well understood.
- Skip testing is only justified if it is demonstrated that the nitrosamine levels are consistently at ≤ 30% of these limits and the reason for the contamination is known and well understood.
- If both nitrosamines are present at the same time, the cumulative risk must not exceed the 1:100,000 risk of developing cancer if the drug is taken for life.
Alternative approach: The sum of both nitrosamines must not exceed the limit of the most toxic nitrosamine, NDEA. The marketing authorisation holder shall plausibly justify the choice of approach.
- The authorisation holder must ensure that the control strategy for all nitrosamines is updated accordingly.
Update of "Condition B"
The marketing authorisation holder has the following two options - depending on the result of the confirmatory test for nitrosamine impurities in the finished product - to fulfil or lift "Condition B":
- No nitrosamine impurities were detected or the test showed levels <10% of the acceptable intake (AI): After submission of the responses according to Step 2 of the Call for Review, the result of the risk assessment must be submitted using the "No nitrosamine detected response template" as a variation of type IA C.I.11.a.
- Nitrosamine impurities >10% of the AI have been detected: in addition to the submission of a variation concerning the manufacturing process, the introduction of a limit in the finished product specification is required. In doing so, the marketing authorisation holder must follow the guidance provided in the Q&A document on Art. 5(3) Referral (Question 10).
Update of "Condition D"
This update refers to the possibility for the marketing authorisation holder to waive the specification by applying for a variation of type IB C.I.11.z and submitting supporting data. However, such data may only refer to NDMA and NDEA in such an application. Data on any other nitrosamine species present must be submitted in a separate variation application, grouped if necessary.