The European Pharmacopoeia (Ph. Eur.) is seeking feedback on its new general chapter on the analysis of N-nitrosamine impurities in active substances (2.4.36).
In line with the Decision of the European Commission on 2 April 2019 (Annex I to the European Commission Decision C(2019) 2698 final) and the decisions taken by the European Pharmacopoeia Commission, the chapter focuses on the analysis of N-nitrosamines in angiotensin-II-receptor antagonists (sartans) containing a tetrazole group, for which there are 5 Ph. Eur. monographs (valsartan, losartan potassium, candesartan cilexetil, irbesartan and olmesartan medoxomil). Manufacturers of these sartans with a tetrazole ring have to implement a control strategy for N-nitrosamines and from April 2021, the batches of active substance they produce must not contain quantifiable levels (corresponding to less than 0.03 ppm) of the 2 principal N-nitrosamine impurities: NDMA and NDEA.
The general chapter proposes three procedures relying on more or less sophisticated instruments (from GC-MS, to LC-MS/MS and GC-MS/MS) and that, in total, cover seven N-nitrosamine impurities: N-nitroso-dimethylamine (NDMA), N-nitroso-diethylamine (NDEA), N-nitroso-dibutylamine (NDBA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA); N-nitroso-diisopropylamine (NDiPA), N-nitroso-ethyl-isopropylamine (NEiPA) and N-nitroso-dipropylamine (NDPA). The three procedures have been validated as limit tests with a target concentration of 30 ppb, for the listed active substances. It was considered important to include a varied set of procedures using different instruments, thus covering the needs of many quality control laboratories in Europe and beyond.
The new general chapter was elaborated with the help of several Official Medicines Control Laboratories (OMCLs) and is based on the work performed within their European Network since the beginning of the N-nitrosamine incident in summer 2018, to ensure that methods are available to control these impurities.