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’.
The deadline for completing confirmatory testing for chemical medicines is 26 September 2022.
- Step 2 - No nitrosamine detected response template
- Step 2 - Nitrosamine detected response template (docx)
- 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” (April 2023)
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:
- 1 October 2023 for chemical medicines
- 1 July 2023 for biological medicines.
The CHMP and CMDh extended the deadline for submitting variation applications for chemical medicines from 26 September 2022 to 1 October 2023 in July 2022.
The extension aims to enable companies to perform a thorough investigation and to establish any required risk mitigating actions in light of new scientific developments since 2020, in particular those concerning active substance-derived nitrosamines.
This extension does not affect the deadline for completing the step 2 confirmatory testing for chemical medicines, which remains 26 September 2022. Marketing authorisation holders should submit complete step 2 outcomes by this deadline.
The European medicines regulatory network encourages marketing authorisation holders to submit variation applications as soon as they conclude their investigations, and before the extended deadline.
Active substance-derived nitrosamines
Authorities in the EU are aware that some active substances are at a higher risk of formation of active substance derived nitrosamine impurities.
Such active substances contain vulnerable amine functional groups that can undergo a reaction called nitrosation (often a secondary amine). Nitrosamines are thought to form when the nitrosatable amine group in the active substances and trace nitrite impurities in the inactive ingredients (excipients) react.
Active substances that contain secondary amines appear particularly vulnerable to this reaction, although some cases involving active substances with tertiary amines have also been observed.
More information on the root causes of nitrosamine impurities is available in Question-and-answer document on the Article 5(3) CHMP opinion (Question 4).
All marketing authorisation holders for EU medicines should consider this risk factor in their risk evaluations as a matter of priority, if they have not already done so.
If a risk is confirmed, they should prioritise confirmatory testing. If testing confirms the presence of nitrosamines, companies should immediately report their findings to the relevant competent authority.
Guidance for marketing authorisation holders on confirmatory testing is available (see above).
This is a precautionary step to ensure early detection of any potential risk, and to enable prompt regulatory action if necessary.
There is no immediate risk to patients who are taking these medicines. Patients who have any questions about their treatment should speak to their doctor.
Authorities will provide updates as necessary.
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):
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.