Marketing authorisation holders of medicinal products containing chemically-synthesized and biological APIs are required to perform a confirmatory assessment (Step 2) of their products for nitrosamine impurities following the three-step "Call for Review" as part of the referral procedure under Article 5(3) of Regulation (EC) 726/2004, if a potential risk of impurities has been identified in a previous risk assessment (Step 1).
Additions to the Nitrosamine Contamination Reporting Form
Change Notifications/Variations The template includes reference to a checkbox in the XML delivery file for variations in the eSubmission Portal to be used for reporting changes made to reduce nitrosamine impurities in the manufacturing process in accordance with Step 3 of the Call for Review.
Limit values of newly identified nitrosamines For reporting limits of new nitrosamines that were not considered in the CHMP statement on the Art. 5(3) procedure, the following two selection fields should be used as an alternative: - General class specific TTC (18 ng/day) in line with CHMP article 5(3) Q&A is being applied. - Substance specific AI limit (including SAR considerations) is being applied
Additions in the Q&A document from the EMA and CMDh
The table with daily limits of different nitrosamines in question 10 of the Q&A document (Which limits apply for nitrosamines in medicinal products?) has been extended by the compound N-nitroso-varenicline, NNV. Its limit of 37.0 ng/day was derived from structure-activity-relationship (SAR) estimations (original publication in the International Journal of Environmental Research and Public Health).