The European Pharmacopoeia (Ph. Eur.) published its new general chapter on the analysis of N-nitrosamine impurities inactive substances (2.4.36) for a 3-month public consultation in Pharmeuropa 32.2. The closing date for public comments was 30th June 2020. Given the exceptional circumstances due to the COVID-19 pandemic, would like to remind stakeholders to provide comments before the end of June to contact their respective national pharmacopeia Authority (NPA) or the EDQM as soon as possible so as to announce their intent to comment. The general chapter on the analysis of N-nitrosamine impurities inactive substances (2.4.36) will remain available in the Pharmeuropa archives issue 32.2 and comments to be sent no later than 31st August 2020, comments after this date will be too late for consideration.
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-dibutyl amine (NDBA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-diisopropylamine (NDiPA), N-nitroso-ethyl-isopropylamine (NEiPA) and N-nitroso-diisopropylamine (NDPA). The three procedures have been validated as limit tests with a target concentration of 30 ppb, forgiven 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. In addition, given the global use of the medicines which have been found to contain nitrosamine impurities, the European Pharmacopoeia and the United States Pharmacopeia will work on convergence and ensure that their public quality standards are harmonized.
Recently USP has announced the release of six new Reference standards to support manufacturers and regulators in analyzing and monitoring potentially harmful nitrosamine impurities in the drug supply chain:
N-Nitrosodimethylamine (NDMA) (1 mg/mL in methanol);
N-Nitrosodiethylamine (NDEA) (1 mg/mL in methanol);
N-Nitrosodibutylamine (NDBA) (1 mg/mL in methanol);
N-Nitrosomethylaminobutyric acid (NMBA) (1 mg/mL in acetonitrile).
In September 2020, USP will also propose for public comment a new United States Pharmacopeia—National Formulary general chapter standard to provide guidance on assessing materials for nitrosamine presence, establishing control strategies for these impurities, and ensuring the performance of analytical procedures to monitor nitrosamine levels in drug products. It’s important for manufacturers to develop validated methods and predictive approaches for wherein the supply chain impurities can emerge and establish risk-based strategies so that patient safety remains protected. With these six reference standards as well as the forthcoming general chapter, they confident in providing modern and useful tools to address this critical issue. Focused on predictive tools and approaches, USP established a body of volunteer experts to develop the nitrosamines general chapter. Comprised primarily of industry experts with extensive experience in impurities and drug manufacturing, the USP Nitrosamines Joint Subcommittee represents a wide range of scientific perspectives. The subcommittee also includes representatives from the U.S. Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines & HealthCare, which is responsible for drug quality standards in the European Pharmacopeia. Given the widespread global use of the medicines which have been found to contain nitrosamine impurities, the USP and the European Pharmacopoeia will continue to work on convergence and to ensure that their public quality standards for regulators and industry are harmonized.
USP’s new nitrosamine Reference Standards can be used by manufacturers to test their own materials against methods in USP’s general chapter. The Reference Standards may also be used with methods provided by U.S. FDA and other regulators as well as those developed by manufacturers in-house. As with all USP Reference Standards, the nitrosamine Reference Standards are highly-characterized and have been rigorously evaluated by USP’s collaborative process across multiple laboratories.