In June 2018 EU authorities were notified that a Chinese API manufacturer has detected the presence of N-nitrosodimethylamine, NDMA, in batches of Valsartan. NDMA is a genotoxic and carcinogenic agent in animals and is classified as a Class 2A carcinogen to humans. After a referral under Article 31 of Directive 2001/83/EC triggered by the European Commission the CHMP assessed the impact of the presence of this impurity on the benefit-risk balance of sartan-containing drug products and issued a recommendation whether the concerning marketing authorisations can still be maintained or should be suspended.
Building on this Article 31 referral EMA together with the EU Network and international partners was continuing the review to identify whether there are any consequences for medicinal products apart from the class of sartans. As a result of this the CHMP issued a document entitled “Nitrosamine impurities in human medicinal products” as part of the procedure under Article 5(3) of Regulation EC (No) 726/2004.. This assessment report contains comprehensive recommendations on how to detect and mitigate the risk of Nitrosamine Impurities in human medicinal products containing chemically synthesised APIs as well as biological medicinal products.
In a subsequent assignment the CHMP was requested by the European Commission to assess the impact of the outcome of the Article 5(3) assessment on Nitrosamines regarding angiotensin-II-receptor antagonists (sartans) which resulted in a final assessment report with respect to Candesartan, Irbesartan, Losartan, Olmesartan and Valsartan. This assessment report contains changes to the current conditions to the Marketing Authorisations for sartans such as limits for Nitrosamine Impurities to be implemented for the finished products and deadlines to be met.
As a consequence the five European Pharmacopoeia monographs on sartans with a tetrazole ring, namely Valsartan, Losartan Potassium, Irbesartan, Candesartan ciletexil and Olmesartan medoxomil have been revised to align them with the above mentioned final assessment report. The implementation date of these monographs is 1 April 2021.