Information on nitrosamines for marketing authorisation holders

CALL FOR REVIW FOR CHEMICALLY SYNTHESISED AND BIOLOGICAL MEDICINAL PRODUCTS

Marketing authorisation holders should review their manufacturing processes for all products containing chemically synthesised or biological active substances to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities.

The European medicines regulatory network encourages marketing authorisation holders to submit the outcome of step 1 before the deadlines if they complete the risk evaluation or identify a risk in their products. 

Marketing authorisation holders should inform the national competent authorities for nationally authorised products or EMA for centrally authorised products as soon as possible if tests confirm the presence of nitrosamine, irrespective of the amount detected. 

They should also assess the immediate risk to patients and take appropriate action to avoid or minimise the exposure of patients to nitrosamines.

At all steps, timelines should be shortened and marketing authorisation holders should immediately inform authorities if findings indicate an immediate risk to public health.

Step 1: Risk evaluation

Conduct a risk evaluation to identify active substances and finished products at risk of N-nitrosamine formation or (cross-)contamination and report the outcome by:

  • 31 March 2021 for chemical medicines;
  • 1 July 2021 for biological medicines.

If a risk is identified for an active substance, marketing authorisation holders should submit the step 1 response template and proceed with step 2 confirmatory testing of the finished product.

If no risk is identified for an active substance, marketing authorisation holders should conduct a risk evaluation of the finished product and submit the outcome of step 1 only when they reach a final conclusion on the active substance and finished product.

Marketing authorisation holders can submit a single email notification grouping products with identical outcome of step 1. For more information, see Questions and answers for marketing authorisation holders / applicants on the CHMP opinion for the Article 5(3) referral .

Marketing authorisation holders should use the templates below in their responses:

Step 2: Confirmatory testing

Perform further confirmatory testing on the products identified to be at risk of N-nitrosamine formation or (cross-)contamination and report confirmed presence of nitrosamines as soon as possible.

For more information on the development of analytical methods, see  Questions and answers for marketing authorisation holders / applicants on the CHMP opinion for the Article 5(3) referral .

Marketing authorisation holders should use the templates below in their responses:

Step 3: Update marketing authorisations

Apply for any necessary changes to the manufacturing process resulting from this review,  by requesting a variation to the marketing authorisation via standard regulatory procedures.

Marketing authorisation holders should complete the confirmatory testing and submit their variation applications by:

  •  26 September 2022 for chemical medicines 
  • 1 July 2023 for biological medicines.

In order to meet these deadlines, it is necessary to perform the step 2 confirmatory testing activities sufficiently in advance.

Questions and answers

A question-and-answer document is available for marketing authorisation holders on implementing the Article 5(3) CHMP opinion. It covers the:

  • outcome of the Article 5(3) referral;
  • instructions, scope and timelines of the product review process;
  • principles and methodology for confirmatory and release testing;
  • approaches for determining limits for nitrosamines;
  • changes to marketing authorisations and requirements for new applications;
  • outcome of the Article 5(3) referral and its relation to the recently published report on lessons learnt exercise from presence of nitrosamines in sartans.

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

For additional specific information related to nationally authorised products (including MRP/DCP), the CMDh has drafted a practical guidance document

CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines (September 2020) [Tracked]