Over the last four years Marketing Authorization Holders (MAHs) have been responding to critical directives from global regulators in addressing the safety risk of nitrosamine impurities in chemical and biological human medicines. In previous blogs, ProductLife Group (PLG) has summarised the three-step process proposed by the European Medicines Authority (EMA) for MAHs to review their manufacturing processes for products containing chemically synthesised or biological active substances to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities.

In July, The Committee for Human Medicinal Products (CHMP) and The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) extended the deadline for step 3 of this process. The extension specifically and exclusively relates to the final stages of the process, which involve the necessary updating of the marketing authorization following confirmatory testing of the presence of nitrosamines at step 2. The deadline for submitting variation applications for chemical medicines has been extended from 26 September 2022 to 1 October 2023 as outlined in the EMA’s revision of the guidance document, EMA, Questions and Answers for Marketing Authorisation Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 Referral on Nitrosamine Impurities in Human Medicinal Products (July 29, 2022).

The authorities believe the extension of just over 12 months will enable companies to perform a thorough investigation and establish any necessary risk mitigating actions in context of new scientific developments made since the EMA completed its original review in June 2020; in particular those concerning active substance-derived nitrosamines. Despite this extra time, the European medicines regulatory network is encouraging MAHs to submit variation applications as soon as they have finalised their investigations, and to do so before the extended deadline.

It is important to note this extension does not affect the deadline for completing step 2 confirmatory testing for chemical medicines, which passed on 26 September 2022.

PLG has experience in supporting MAHs fulfill their responsibilities in submitting timely and accurate information with regard to updating Marketing Authorization Variations at step 3. PLG has expertise in compilation, format, content, evaluation, and review of the step 3 report, including:

Step 3 Update of Marketing Authorization – Variation

  • Evaluation of a nitrosamines control strategy by variation
  • Classification of the changes involved (updated API or finished product specification and/or updated API or finished product manufacturing process)
  • Recommendation of a suitable variation submission strategy (individual variations or appropriate groupings)
  • Co-ordination between the MAH and the API and/or finished product manufacturer or CMO, to obtain the technical information for presentation of the change
  • For changes involving APIs authorized via certificate of suitability (CEP) applications or through the active substance master file procedure
  • Preparation of the variation package, module 1 and Module 3, eCTD compilation and submission
  • Follow-up of the variation procedure and integration with the step 3 report.

Step 3 Update of Marketing Authorization – Referral

If the N-nitrosamine presence is confirmed to be intrinsic to the API (e.g., a structural feature or a metabolic formation) and/or if additional root causes for the presence of nitrosamines are reported and require further extensive assessment, then the regulatory authority may initiate a referral procedure, and ProductLife Group can also assist MAHs with this procedure.

If you have completed your confirmatory testing investigations at step 2, please contact us to find out how we can help you manage the final steps of the nitrosamine risk management and control procedure, in compliance with your regulatory responsibilities.

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EMA Gives Extra Time to Marketing Authorization Holders to Manage Nitrosamine Risk