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. Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies. 

EU regulators 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'.

There is a very low risk that nitrosamine impurities at the levels found in medicines could cause cancer in humans.

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:

The deadline has passed for submitting step 1 risk evaluations for medicines containing chemically synthesised active substances. Any marketing authorisation holder for such products that has not yet submitted a step 1 risk evaluation should do so as a matter of priority, in line with the CHMP's Article 5(3) opinion. Marketing authorisation holders for medicines containing biological active substances should respect the step 1 submission deadline of 1 July 2021.

The European medicines regulatory network is not currently considering any regulatory actions with regards to marketing authorisations or product distribution, but reminds marketing authorisation holders of their responsibility to ensure the quality, safety and efficacy of their 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 PDF icon Questions and answers for marketing authorisation holders / applicants on the CHMP opinion for the Article 5(3) referral .Marketing authorisation holders for centrally authorised products should send the completed template(s) only to [email protected] 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  PDF icon 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.Marketing authorisation holders for centrally authorised products should send the completed template(s) to [email protected] 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.

Marketing authorisation holders for nationally authorised products should refer to the information on nitrosamines for marketing authorisation holders published on the CMDh website.Marketing authorisation holders should complete the confirmatory testing and submit their variation applications by: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. 

EMA-Nitrosamine impurities