Quality & use of medicines
The EDQM’s response to nitrosamine contamination
Certain types of nitrosamines, such as N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), are known as possible carcinogens for humans and only very low amounts are acceptable according to current regulatory requirements. Since their detection in a number of active substances in 2018, the EDQM has been working actively at various levels to address this issue, co-operating continually with regulatory authorities at international and EU level. Full information on this matter can be found on the EDQM’s dedicated web page.
Ph. Eur. strategy
The European Pharmacopoeia Commission (EPC) continued to roll out its comprehensive nitrosamines action plan in 2023 after having adopted revised versions of two legally binding core general monographs, Substances for pharmaceutical use (2034) and Pharmaceutical preparations (2619), which now include a paragraph explaining the Ph. Eur. approach to N-nitrosamine impurities. This approach was defined based on the comments received on these texts during the last round of public consultation in Pharmeuropa, together with recent feedback from the Heads of Medicine Agencies (HMA) and European Medicines Agency (EMA) groups and from the NCAs of non-EU Ph. Eur. member states.
The new paragraph, added to the Production section of each of these major texts, states that manufacturers are now expected to evaluate the potential risk of N-nitrosamine formation and contamination occurring throughout their manufacturing process and during storage (2034) or shelf life (2619). If confirmed, manufacturers should mitigate as far as possible the risk of N-nitrosamines being present – for example by modifying their manufacturing process – and implement a control strategy to detect and control them.
The revised monographs were published in Ph. Eur. Supplement 11.3 (July 2023) and implemented on 1 January 2024.
Building on this, the next step in the action plan aimed at defining how to address the issue of nitrosamine control in individual monographs.
After consulting its stakeholders over the course of 2023, the EPC approved the strategy for N-nitrosamine impurities in individual monographs at its 177th session in November 2023. This strategy is detailed below.
Regarding active substances
The general requirement for N-nitrosamine impurities given in revised general monograph 2034 applies to all the substances for pharmaceutical use within the given scope. The EPC therefore agreed to remove existing statements about these impurities from the Production sections of individual monographs on active substances and to no longer include such statements in new monographs in the future.
In addition, the EPC defined clear rules on when specifications on N-nitrosamine impurities should be added to the Tests section of an active substance monograph. They will therefore only be included when the N-nitrosamine is a process-related impurity, i.e. generated during synthesis of the substance, or a degradation impurity arising from its storage. The test and limit will be included in an individual monograph if the impurity has been detected in several sources of the substance and once a limit approved by competent authorities becomes available.
The EPC also agreed not to address the following types of potential N-nitrosamine contamination in individual monographs, as they are assumed to be covered elsewhere:
- impurities resulting from manufacturing practices during synthesis of the API (recovered or recycled materials, cross-contamination);
- impurities potentially generated during the manufacture or storage of the medicinal product;
- potential risk of future transformation into a nitrosamine (e.g. secondary amines).
Regarding medicinal products
Where monographs on medicinal products are concerned, the EPC agreed that it was not appropriate to introduce a specification in the Tests section or a statement in the Production section, except in specific and justified cases, since the risk of N-nitrosamine formation depends to a great extent on the composition of the medicinal product and the conditions under which it is manufactured. The N-nitrosamines section of the general monograph Pharmaceutical preparations (2619) is considered to fully address this risk.
Actions on CEPs
By the end of 2023, the EDQM Certification Department had reviewed all the applications for which an N-nitrosamine risk had been identified. However, CEP holders regularly inform the EDQM about either a new risk of formation of N-nitrosamines or about their detection – mainly nitrosamine drug substance-related impurities (NDSRIs) – in their active substance. Avenues for regular contact are in place for such notifications.
An evaluation of the potential presence of N-nitrosamines is conducted routinely for all new CEP applications and at the time of renewal, as well as for revisions that are likely to impact the level of risk, based on data to be submitted by applicants.
In July 2023, the EDQM began implementing the new scientific approaches for the categorisation of N-nitrosamines, as well as the established acceptable intakes (AIs). The Carcinogenic Potency Categorisation Approach (CPCA) and enhanced Ames test (EAT) described in the EMA Q&As should now be used to determine the potency category and associated AI to be considered in the risk assessment and the related control strategy.
Collaboration with European and international partners
The EDQM maintains ongoing co-operation with regulatory authorities at national, EU and global level on this issue – for example, via the Nitrosamines International Strategic Group (NISG) and its technical working group (NITWG) – and will continue to do so to ensure a co-ordinated, harmonised approach to making and implementing decisions.
Sampling strategies and testing methods with OMCLs
Members of the GEON have been involved in various activities related to the detection of nitrosamines in APIs and medicinal products since mid-2018. A dedicated OMCL testing group has met 16 times since then and has extended its scope beyond the nitrosamine group (including NDSRIs) to the determination of mutagenic impurities at trace levels (e.g. azido impurities reported in tetrazole sartans).
The OMCL Mutagenic Contaminants Testing Group met once, in October 2023, to share the latest developments concerning the approaches discussed by international regulatory authorities to set up acceptance limits for NDSRIs, to discuss current and planned testing activities in the network at national level, and to decide on future testing strategies.
A hands-on training programme for OMCLs on nitrosamine testing was organised by the Swissmedic OMCL in Bern. In the context of the CAP Sampling and Testing co-operation programme with the EMA, a dedicated nitrosamine testing programme for centrally authorised products will be conducted in the future.
Publications
Three OMCLs and the EDQM, together with labs from Australia, Canada and the US FDA group members, authored a scientific paper in the Journal of Pharmaceutical Science entitled “Performance Characteristics of Mass Spectrometry-Based Analytical Procedures for the Quantitation of Nitrosamines in Pharmaceuticals: Insights from an inter-laboratory Study” (Yang et al. 2023).
