The European Pharmacopoeia (Ph. Eur.) Commission has adopted a new general chapter on the analysis of N-nitrosamine impurities in active substances (2.5.42, previously listed as 2.4.36). The general chapter should be seen as an analytical toolbox that proposes three procedures relying on more or less sophisticated instruments (GC-MS, LC-MS/MS and GC-MS/MS). It was considered important to include a varied set of procedures using different instruments, thus covering the diverse needs of many quality control laboratories in Europe and beyond.
The procedures have been validated for the listed active substances either as a limit test with a target concentration of 30 ppb (procedures A and B), or as a quantitative test (procedure C by GC-MS/MS). The general chapter focuses mainly on the analysis of N-nitrosamine impurities in angiotensin-II-receptor antagonists (sartans) containing a tetrazole group, for which there are five Ph. Eur. monographs (valsartan, losartan potassium, candesartan cilexetil, irbesartan and olmesartan medoxomil). Users may apply the given procedures to other substances or to medicinal products after having demonstrated the suitability for the intended purpose with additional validation.
The three procedures cover a total of 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).
In order to support the implementation of the general chapter, seven reference standards have been established and are available from the European Directorate for the Quality of Medicines & HealthCare (EDQM).
The general chapter will be published in Ph. Eur. Supplement 10.6 in July 2021.