For existing CEPs, an assessment of the risk for nitrosamines formation is required to be made, using quality risk management principles, as outlined in the ICH Q9 guideline. The principles described in the ICH M7 guideline and Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products EMA/409815/2020, in relation to toxicology assessment, control strategy and changes to the manufacturing process for active substances used in human medicinal products, should be applied. Where no risk is identified, EDQM does not have to be informed however companies may decide to introduce the risk assessment in their CEP dossier via a minor revision.

Where a risk is identified, the companies should inform EDQM of the risk and of the plan and timescales to introduce any required changes to reduce the risk, such as amendment of the manufacturing process or changes to specifications and introduction of controls. Confirmatory testing should be carried out using appropriately validated and sensitive methods and EDQM should be informed immediately, i.e. before submitting a revision application, if the tests confirm the presence of a nitrosamine impurity, irrespective of the amount detected, and the test results should be provided.

CEP holders should apply for a revision to their application(s) in a timely manner to introduce the required changes. Revision applications for existing CEPs should be submitted at the latest by 1 October 2023 or at an earlier time if otherwise justified.

Any request for revision should address the risk of nitrosamine contamination if the revised process modifies or introduces such a risk (e.g. new route of synthesis or new risk identified).

A risk assessment for nitrosamine impurities should be submitted at renewal of the CEP if it has not already been submitted.

A risk assessment for nitrosamine impurities should be submitted for a sister file. EDQM reminds CEP holders that they should provide the appropriate information relating to the risk evaluation they have performed for their CEP to their customers in all cases (even if no risk has been identified) such that the Marketing Authorisation Holders can use this information to fulfil their responsibilities for the respective medicinal products.