EMA to address nitrosamine impurities in upcoming revision of active substances guidance
The European Medicines Agency (EMA) will be updating its guideline on active substances to incorporate strategies for controlling and preventing nitrosamines in drug products and active pharmaceutical ingredients (APIs), the agency announced in a new concept paper.The revised guideline is meant to address risk factors for formation of nitrosamines in medicinal products and strategies for preventing their formation and presence.
EMA and other regulators have been investigating the presence of nitrosamine impurities since they were first detected in valsartan medicines in 2018 and subsequently recalled by EU authorities. Though nitrosamines occur naturally in very small quantities, they are a potential carcinogen.
“The revision will clarify the requirements for all applications regarding active substances and will bring the guidance up to date with recent development and knowledge gained on formation of N-nitrosamines and implementation of adequate risk mitigation measures,” the paper states.
The concept paper drew from a June 2020 report called “Lessons learnt from presence of N-nitrosamine impurities in sartan medicines (LLE),” prepared by European regulators which recommended ways to reduce the presence of N-nitrosamines in human medicines and help manage future cases of unexpected impurities. (RELATED: EU Regulatory Roundup: Regulators propose 40 actions to cut risk of medicine impurities, Regulatory Focus 25 June 2020)
The report suggested EMA’s 2016 guideline on active substances be revised to incorporate some of its learnings with respect to nitrosamine contamination risks.
The revised guideline addresses topics such as process development strategies to mitigate the presence of N-nitrosamines or other impurities; the need to provide clear information on the use of raw materials, starting materials and intermediates in relation to their function in manufacturing steps, and their potential contamination risks; required discussions regarding the presence or formation of nitrosamines; the use of recycled materials; specific control options for nitrosamines; the need to consider nitrosamine impurities or other compounds and potential toxins arising during storage.
EMA’s Quality Working Party (QWP) has appointed two rapporteurs as well as experts from different member states with expertise in the field to serve on the drafting group. The group will be supported by an observer from the European Directorate for the Quality of Medicines (EDQM), which will work closely with the QWP expert group on nitrosamines.
The deadline to comment is 31 October.
Concept paper
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