Nitrosamine impurities: guidance for marketing authorisation holders

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

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. 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 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.

See also:

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

Ongoing responsibilities of marketing authorisation holders and applicants

EMA, together with the national competent authorities, is 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.

If tests confirm the presence of nitrosamines, irrespective of the amount detected, they 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 below.

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. 

Marketing authorisation holders should also assess the immediate risk to patients and take appropriate action to avoid or minimise patient exposure to 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.

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

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.21

Appendix 1: Acceptable intakes established for N-nitrosamines

Reference Number: EMA/562717/2024/Rev. 8

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.