The European Medicines Agency (EMA) has assessed the risk of nitrosamine formation or presence during the manufacture of human medicines and is providing guidance to marketing authorisation holders (MAH) on how to avoid its presence. Nitrosamines, probable human carcinogens, were discovered in blood pressure medications ‘sartans’ in mid-2018, prompting EMA to review and advise MAH on avoidance measures. In June 2020, the EMA finalised review under Article 5(3) of Regulation (EC) No 726/2004, providing general guidance and recommendations on mitigating and preventing the presence of nitrosamines in human medicinal products.
The process involves reviewing all medicines and implementing appropriate control strategies to prevent or limit the presence of these impurities. Additionally, where necessary, improving the manufacturing processes is recommended. An implementation plan was agreed upon in February 2021 to execute these guidelines, specifying actions if nitrosamines are found.
EMA and national competent authorities continue to monitor the presence of nitrosamine impurities in medicines in co-operation with regulators from outside the European Union (EU), and work closely with MAH to find rapid solutions to address any adverse findings.
Regular updates for MAH are available, with the latest version of Q&A on nitrosamine impurities for marketing authorization holders released on October 12, 2023, just ten days after the previous update. With revision 19, Annexes 2 and 3 were removed from the document and are now available as separate Appendices.
In Version 19, Q&A 10 has been updated to allow referral to other sources for CPCA categorisation:
‘If the nitrosamine is not included in Appendix 1, MAH/MA applicants can also refer to a CPCA category from another source, e.g., CPCA categories published by other regulatory authorities, but this will need confirmation to allow control of the substance at the level corresponding to that category.’
Furthermore, Version 19 changed the reference from ICH M7(R1) to ICH M7(R2) guideline. The ICH M7(R2) guideline came into force on September 30, 2023, and addresses the evaluation of mutagenic impurities in pharmaceuticals.