Europe – Nitrosamines : Update from the CEP procedure

In June 2018, a manufacturer detected N-nitrosodimethylamine (NDMA) in valsartan active substance batches. This led to multiple regulatory actions addressing the presence of NDMA and other nitrosamine impurities, initially in valsartan but later extended to many other active substances. As 2020 draws to an end, the European Directorate for the Quality of Medicines & HealthCare (EDQM) wishes to provide a summary of the current situation with regard to nitrosamine impurities in substances covered by certifications of suitability to the European Pharmacopoeia monographs (CEPs).

After receiving the initial notification about the presence of NDMA in batches of valsartan, the EDQM began to review the CEP granted for the active substance in question, together with all other valsartan CEPs. On 5 July 2018, the European Commission (EC) launched a review of valsartan-containing medicinal products in accordance with Article 31 of Directive 2001/83/EC, which was to be carried out by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

The EDQM immediately contacted all holders of CEPs for valsartan and asked them to provide the requisite information on their substance. The information and data received were assessed and, where necessary, action was taken on CEPs leading, in some cases, to their suspension. It was then realised that all sartans containing a tetrazole ring in their structure could also be affected. Five of these substances are the subject of Ph. Eur. monographs and have been granted CEPs. In September 2018, in addition to the review already underway for valsartan, the EC referral was expanded to medicines containing sartans with a tetrazole ring, which affected the CEPs for candesartan cilexetil, irbesartan, losartan potassium and olmesartan medoxomil. The EDQM contacted the CEP holders for all these substances and asked them to investigate the issue…