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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 (API’s) as announced in the Concept paper on the revision of the guideline on the chemistry of active substances (11th of July 2022, EMA/CHMP/600383/2022).

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 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.

The Nitrosamine Implementation Oversight Group (NIOG) was set up by the European medicines regulatory network to oversee the harmonised implementation of the Article5 (3) Committee for Medicinal Products for Human Use (CHMP) opinion on nitrosamines in human medicinal products. The NIOG will be the main interface between regulators and industry to agree on topics requiring further scientific discussion. The NIOG discussed the approach on the risk of presence of nitrosamine in marketed medicines and also in new applications and line extensions and noted the approaching call for review deadline for human medicines with chemical active substances (26th of September 2022) and discussed approaches to facilitate companies to implement adequate remediation actions for products where presence of nitrosamine has been identified while ensuring adequate levels of patient protection and availability of critical medicines.