EMA Publishes a New Question and Answer Document for Marketing Authorisation Holders on the CHMP Opinion for the Article 5(3) referral on Nitrosamine Impurities in Human Medicinal Products (EMA/409815/2020)

The European Medicines Agency (EMA) have published a new ‘question and answer’ document for Marketing Authorisation Holders (MAHs) regarding the Article 5(3) referral for nitrosamine impurities in human medicinal products (EMEA/409815/2020). This follows the conclusion of the Article 5(3) review and the publication of the CHMP (Committee for Medicinal Products for Human Use) assessment report on nitrosamine impurities at the end of June 2020 (EMA/369136/2020), as well as the publication of other related guidance on the EMA’s website, which collectively replace the previous Q&A document (Questions and answers onInformation on nitrosamines for marketing authorisation holders’ – EMA/CHMP/428592/2019 Rev. 3).

EU regulatory authorities first called on all MAHs to undertake a review of their medicinal products in September 2019, with specific focus on those products containing chemically synthesised Active Pharmaceutical Ingredients (APIs). MAHs were requested to perform an initial risk evaluation of these medicinal products to determine if nitrosamines may be present and to submit a declaration of their findings to the relevant European Regulatory Agencies (step 1), followed (as required) by the performance of a risk assessment and confirmatory testing (step 2), and the introduction of any necessary risk mitigation measures to minimise the possibility of nitrosamines being present (step 3). Guidance and deadlines for submission of the initial risk evaluations continued to be revised, with the publication of the new Q&A document providing the latest update.

So, what’s new?

  • Following the issue of the CHMP’s Article 5(3) opinion, the requirement for the 3-step review is extended to include medicinal products that contain biological APIs
  • The deadlines for completion of each step have changed:
    Step 1: The risk evaluation exercise should now be completed by 31st March 2021 for chemical medicines and 1st July 2021 for biological medicines.  As before, if a risk is identified in step 1, the MAH should submit the appropriate response template to the regulatory authorities and proceed to step 2, as soon as possible.
    Step 2 & 3: As required, the MAH should complete confirmatory testing and submit their variation applications to the relevant regulatory authorities by 26th September 2022 for chemical medicines, and 1st July 2023 for biological medicines.
  • The new Q&A document comes into force, taking into account the outcome of the CHMP opinion on the Article 5(3) referral, and replacing the previous Q&A document.

What does the new Q&A document cover

The new Q&A document aims to support MAHs in understanding and fulfilling their obligations and represents a significant re-write of the previous document, providing both new and updated guidance on the following topics:

  • The outcome and changes introduced as a result of the Article 5(3) referral
  • The instructions, scope, and timelines of the required product review process, including conducting the risk evaluation
  • The identified root causes for the presence of nitrosamines
  • The principles and methodology for confirmatory and release testing
  • Approaches to be used for determining acceptable limits for nitrosamines, including changes and additions to the permissible limits
  • Actions to be taken in the event that nitrosamines are detected in a medicinal product
  • Measures to mitigate the risk of the presence of nitrosamines
  • Changes to marketing authorisations and new data requirements
  • MAH responsibilities for products which use an API with a CEP (Certificate of Suitability) or ASMF (Active Substance Master File)
  • The outcome of the Article 5(3) referral and its relation to the ‘lessons learnt’ exercise from the presence of nitrosamines in sartans
  • Regulatory requirements in other regions including USA, Canada, Japan, Singapore, Switzerland and Australia.

 A copy of the full Q&A document can be found here.

Any Questions

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