Nitrosamine impurities: guidance for marketing authorisation holders

The European Medicines Agency (EMA) has assessed the risk of nitrosamine formation or presence during the manufacture and storage of human medicines. EMA has also provided guidance to marketing authorisation holders to avoid or minimise the presence of nitrosamine impurities. 

Regulators in the European Union (EU) first became aware of nitrosamines in medicines in mid-2018. 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. For more information, see Scientific review on the risk of nitrosamine impurities in human medicines. 

The resulting Article 5(3) opinion of EMA's CHMP provides guidance for managing, detecting, and preventing nitrosamine impurities.

EMA reminds marketing authorisation holders (MAHs) of their obligation to comply with CHMP's opinion as applied to chemical and biological medicines. 

MAHs should also uphold their responsibilities to ensure quality, safety and efficacy of medicines. This includes risk evaluation, confirmatory testing and updating marketing authorisations.

• Scientific review on the risk of nitrosamine impurities in human medicines
• Nitrosamine impurities in specific medicines

Ongoing responsibilities of marketing authorisation holders and applicants

Compliance with CHMP opinion: Call for review

EMA reminds marketing authorisation holders (MAHs) of their responsibility to comply with the Article 5(3) opinion on nitrosamines of EMA's CHMP. 

This came via a call for review that covered chemical and biological medicines. 

The call for review framework includes three steps: 

• Step 1 - risk evaluation
• Step 2 - confirmatory testing
• Step 3 - update marketing authorisations  

These steps aim to help MAHs meet their responsibility to ensure the quality, safety and efficacy of their medicines. 

MAHs should follow the nitrosamines guidance that the European medicines regulatory network provided.

The related deadlines have passed but the reporting responsibilities still apply.

Nitrosamine impurities risk evaluation

Any MAH that has not yet reported on their nitrosamine impurities risk assessment, or evaluation, should do so as a mater of priority. This applies also to those needing to provide updates to previous notifications. 

For this, they should use the call for review's response templates and reporting mechanisms. They are described in the 'Review and reporting mechanism' section on this page.

MAHs have an obligation to monitor and mitigate nitrosamine risk throughout the lifecycle of their medicines. MAHs should review their manufacturing processes to ensure they are compliant with the latest scientific and technical processes.

MAHs should work with manufacturers. Together, they need to take precautionary measures to mitigate the risk of nitrosamine presence in authorised medicines during manufacturing and storage.

Confirmatory testing

If tests detect N-nitrosamines, MAHs must inform the relevant national competent authorities (for nationally authorised products) or EMA (for centrally authorised products) as soon as possible. For more information, see the 'Questions and answers' section on this page.

Importance of timely compliance 

MAHs should implement corrective and preventative actions and submit a response to the call for review step 3 (update marketing authorisations).

MAHs are expected to implement corrective and preventative action within 3 years from when acceptable intake limits are established and published.

If MAHs predict their medicine could not be in compliance within the 3-year-period, they should inform the relevant authorities with a detailed justification.

Surveillance

EMA reminds marketing authorisation holders of the importance to assess the immediate risk to patients and take appropriate action to avoid or minimise patient exposure to nitrosamines.

At all steps, they should promptly inform authorities if findings indicate an immediate risk to public health.

EU competent authorities may check compliance with the expectations on nitrosamines through routine inspections and marker surveillance activities.

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.

Questions and answers

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

The European medicines regulatory network published the first version of this question-and-answer document in August 2020. It replaces document EMA/CHMP/428592/2019 which was first published in September 2019 and updated in March 2020. 

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.

Nitrosamines EMEA-H-A5(3)-1490 - 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

Reference Number: EMA/409815/2020 Rev.23

Appendix 1: Acceptable intakes established for N-nitrosamines

Reference Number: EMA/245074/2025 Rev. 10

Appendix 2 : Carcinogenic Potency Categorisation Approach for N-nitrosamines

Appendix 3 : Enhanced Ames Test Conditions for N-nitrosamines

Reference Number: EMA/120337/2024

Review and reporting mechanism

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 together products with the same risk evaluation outcome (step 1). 

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

Step 1 - No risk identified response template

Step 1 - Risk identified response template

Step 1 - Risk identified response template

Marketing authorisation holders for centrally authorised products should send the completed template(s) only to [e-mail] using the subject 'Risk evaluation outcome/Risk identified or No risk identified/Marketing authorisation holder's name/Product name', as appropriate.

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 the questions and answers above.

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 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.

Step 2 - No nitrosamine detected response template

Step 2 - Nitrosamine detected response template

Step 2 - Nitrosamine detected above acceptable intake or new nitrosamine detected response template

Marketing authorisation holders for centrally authorised products should send the completed template(s) to [e-mail] using the subject 'Confirmatory testing outcome/Risk confirmed or Risk not confirmed/Marketing authorisation holder's name/Product name', as appropriate.

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.

The European medicines regulatory network encourages marketing authorisation holders to submit variation applications as soon as they conclude their investigations.

Marketing authorisation holders for nationally authorised products should refer to the information on nitrosamines for marketing authorisation holders published on the CMDh website.

The deadlines of the call for review - including steps 1, 2 and 3 - for medicines containing chemically synthesised and biological active substances have passed.

Any marketing authorisation holder for such products that has not yet notified the relevant national competent authority about any nitrosamine impurities they have identified should do so as a matter of priority, in line with the CHMP's Article 5(3) opinion. 

Marketing authorisation holders should also update any previous notifications if needed, using the response templates and reporting mechanisms previously established.