8 July 2025
EMA/144509/2025
European Medicines Agency
This report provides an overview of the response of the European Medicines Regulatory Network (EMRN) to the presence of nitrosamine impurities in human medicines.
Following the discovery in 2018 of these potentially carcinogenic impurities in a group of medicines used to treat cardiovascular diseases, known as ‘sartans’, and later in other medicines, the EMRN initiated a number of regulatory and scientific reviews. These include Article 31 reviews of sartans and ranitidine and an Article 5(3) review for all human medicines as well as, a lessons learnt on the experience from the sartans.
Through these procedures, the EMRN established acceptable intake (AI) limits in collaboration with international regulatory partners to ensure that exposure to nitrosamine impurities remained at or below safe levels.
The network issued a call for review (CFR) for all marketing authorisation holders (MAHs) for authorised human medicines containing chemical active substances. The CFR required MAHs to institute a stepwise evaluation process to identify, assess and mitigate any risks of nitrosamines potentially present in their medicines. The CFR was later extended to medicines containing biological active substances.
In addition, for marketing authorisation applications (MAAs), a requirement for applicants to submit risk assessments on the potential presence of nitrosamines was also introduced.
The EMRN also established the Nitrosamine Implementation Oversight Group (NIOG) to oversee the implementation of recommendations from the Article 5(3) review. There were also regular interactions with international partners as well as industry associations to discuss regulatory requirements and scientific information concerning nitrosamines.
These elements of the EMRN response were crucial in developing a harmonised approach in the EU for protecting patients while maintaining availability of medicines. The development of this harmonised regulatory approach for nitrosamines, as described in this report, has also supported the management and assessment of individual cases where nitrosamines have been detected in human medicines within the EU.
In terms of future developments to the regulatory framework, the latest scientific knowledge on toxicology, safety and quality aspects of nitrosamines will be reflected in an addendum to the ICH M7 guideline on the assessment and control of mutagenic impurities in order to harmonise guidance on nitrosamines across ICH members, which was initiated in June 2024.
Nitrosamine impurities in human medicines
The response of the European Medicines Regulatory Network