Information on nitrosamines for marketing authorisation holders
Scientific review on the risk of nitrosamine impurities in human medicines
Regulators in the European Union (EU) first became aware of nitrosamines in medicines in mid-2018 when nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were detected in blood pressure medicines known as 'sartans'.
Following this discovery, scientific experts in the EU reviewed nitrosamine impurities in human EU medicines under Article 5(3) of Regulation (EC) No 726/2004.
The resulting Article 5(3) opinion of EMA's CHMP provides guidance for managing, detecting, and preventing impurities like nitrosamines.
Marketing authorisation holders were required to take action to comply with the CHMP's opinion, based on a call for review by EMA that covered chemical and biological medicines.
Although the deadlines for the call for review (including steps 1, 2 and 3 described below) have passed, the review and reporting mechanisms remain relevant.
Any marketing authorisation holder that has not yet reported any nitrosamine impurities or that have to provide updates to previously reported nitrosamines should do that as a matter of priority.
Authorities in the EU will continue to take all necessary measures to protect patients and ensure that medicines in the EU meet the required quality standards.
Ongoing responsibilities of marketing authorisation holders and applicants
National competent authorities, together with EMA, are reminding marketing authorisation holders of their responsibility for ensuring the quality, safety and efficacy of their medicines.
They should follow the nitrosamines guidance provided by the European medicines regulatory network.
Marketing authorisation holders should review their manufacturing processes for all products containing chemically synthesised or biological active substances to identify and mitigate the risk of nitrosamine impurities.
The European medicines regulatory network encourages marketing authorisation holders to submit as a matter of priority the outcome of step 1, 2 and 3, as applicable.
Any marketing authorisation holder (MAH) that has not notified the relevant competent authority about any nitrosamine impurities they have identified should do as a matter of priority, in line with the CHMP's Article 5(3) opinion.
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.
MAHs should also assess the immediate risk to patients and take appropriate action to avoid or minimise the exposure of patients to nitrosamines.
Marketing authorisation holders should also update any previous notifications as needed, using the step response templates and reporting mechanisms established under the call for review, as described below.
At all steps, timelines should be shortened where possible and marketing authorisation holders should immediately inform relevant national authorities if findings indicate an immediate risk to public health.
MAHs together with API and FP manufacturers are expected to maintain the quality of their product throughout its lifecycle. MAHs are expected to continue to review and re-visit the outcome of the risk evaluation as and when new information becomes available. MAHs are advised to routinely check this Q&A document and in particular Q&A 4 which will be kept up to date as regards newly identified risk factors for formation of nitrosamines, and also Q&A 10 concerning limits for nitrosamines.
Marketing authorisation holders and manufacturers should work together and take precautionary measures to mitigate the risk of nitrosamine presence in authorised medicines during manufacturing and storage.
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 to the relevant competent authorities.
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 requirements 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 (scenario a);
it exceeds the lifetime excess cancer risk of 1:100,000 (scenario a);
it is a newly identified nitrosamine that is not published in EMA Appendix 1 or is in line with question 10 of the questions and answers below, 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’.
Marketing authorisation holders should use the templates below in their responses.
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 dossier (e.g. the manufacturing process, controls and specification, product formulation, raw materials and packaging) resulting from this review, by submission of appropriate variation(s) to the marketing authorisation via standard regulatory procedures in accordance with the guideline on classification of variations.
Marketing authorisation holders should submit their variation applications as soon as they conclude their investigations.
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 following:
Outcome of the Article 5(3) referral and its relation to lessons learned exercise from nitrosamines detected in sartans
Principles, methodology and scope for nitrosamine management in human authorised products
Guidance for establishing and reporting acceptable intake limits derived from implemented approaches: carcinogenic potency categorisation approach (CPCA), read across (SAR) and in vitro (EAT) / in vivo studies.
Changes to marketing authorisations and requirements for new applications
New approaches for setting nitrosamines limits based on robust scientific knowledge about carcinogenic potency, including the Appendix 1 on acceptable intakes established for N-nitrosamines, Appendix 2 on the carcinogenic potency categorisation approach (CPCA), and Appendix 3 on the enhanced AMES test (EAT) protocol.
Appendix 1: Acceptable intakes established for N-nitrosamines
Appendix 2 : Carcinogenic Potency Categorisation Approach for N-nitrosamines
Appendix 3 : Enhanced Ames Test Conditions for N-nitrosamines
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.