Information on nitrosamines for marketing authorisation holders
Call for review 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 1 - No risk identified response template
- Step 1 - Risk identified response template (doc)
- Step 1 - Risk identified response template (xls)
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 below 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.
Marketing authorisation holders should only use the ''Step 2 - Nitrosamine detected above acceptable intake or new nitrosamine detected response template' if they have detected a nitrosamine in their product and it meets at least one of the following criteria:
- it exceeds the acceptable intake limit;
- it exceeds the lifetime excess cancer risk of 1:100,000;
- it is a newly identified nitrosamine that is not covered in CHMP article 5 (3) opinion, irrespective of the amount detected.
In these cases, they should submit this template in addition to the ‘Step 2 - Nitrosamine detected response template’.
If they have detected a nitrosamine, but it does not meet any of the above criteria, they should only use the ‘Step 2 Nitrosamine detected response template’.
- Step 2 - No nitrosamine detected response template
- Step 2 - Nitrosamine detected response template (doc)
- Step 2 - Nitrosamine detected above acceptable intake or new nitrosamine detected response template (xls)
For more information on the response template(s) to be used, see below CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines
- Assessment report template for the nitrosamine risk assessment for the outcome of step 2 – “nitrosamine detected” (May 2021)
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.
For additional specific information related to nationally authorised products (including MRP/DCP), the CMDh has drafted a practical guidance document
European Medicines Regulatory Network approach for the implementation of the CHMP Opinion pursuant to Article 5(3)
An implementation plan agreed in February 2021 sets out how the European medicines regulatory network, together with the European Directorate for the Quality of Medicines & HealthCare (EDQM), will be implementing the outcome of the Art. 5(3) referral.
This includes specific measures that the network will take if nitrosamines are detected in a medicine.
CMDh, EMA and national competent authorities will continue to monitor the presence of nitrosamine impurities in medicines, in co-operation with regulators from outside the European Union (EU), and will work with marketing authorisation holders to find rapid solutions to address any adverse findings.