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).
|
Name of the CRS |
Catalogue code |
|---|---|
|
N-nitroso-dibutylamine |
Y0002261 |
|
N-nitroso-diethylamine |
Y0002258 |
|
N-nitroso-diisopropylamine |
Y0002263 |
|
N-nitroso-dimethylamine |
Y0002259 |
|
N-nitroso-dipropylamine |
Y0002264 |
|
N-nitroso-ethyl-isopropylamine |
Y0002262 |
|
N-nitroso-N-methyl-4-aminobutyric acid |
Y0002260 |
The new general chapter has been created with the help of several Official Medicines Control Laboratories (OMCLs) and is based on the work performed within the European OMCL Network since the detection of N-nitrosamine impurities in a number of active substances in summer 2018.
It should be noted that the chapter does not present an exhaustive list of analytical procedures for testing N-nitrosamine impurities. Depending on the analytical challenge and on the testing needs, other validated procedures may be found more appropriate.
Given the exceptional circumstances created by the COVID-19 pandemic and the regulatory expectations for the control of N-nitrosamine impurities, the EDQM and the Ph. Eur. Commission decided to make the chapter immediately available on the EDQM website. The general chapter will be published in Ph. Eur. Supplement 10.6 in July 2021.
In addition, in view of the global use of medicines that have been found to contain nitrosamine impurities, the Ph. Eur. and USP will work towards convergence to ensure that their public quality standards are consistent.
In January, the EDQM plans to hold a webinar to update its stakeholders on the different activities linked with N-Nitrosamine impurities. Don’t miss out on this opportunity and stay tuned for more information!
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