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.

Scientific review on the risk of nitrosamine impurities in human medicines

EMA finalised a review under Article 5(3) of Regulation (EC) No 726/2004 in June 2020 to provide guidance to marketing authorisation holders on how to avoid the presence of nitrosamine impurities in human medicines.

The CHMP asked marketing authorisation holders to review all chemical and biological human medicines for the possible presence of nitrosamines and test products at risk by following the guidance on this page.

Companies are required to have appropriate control strategies to prevent or limit the presence of these impurities and, where necessary, to improve their manufacturing processes.

The CHMP's assessment report is available below.

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

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 CHMP's review.

This includes specific measures that the network will take if nitrosamines are detected in a medicine.

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.

European Medicines Regulatory Network approach for the implementation of the CHMP Opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 for nitrosamine impurities in human medicines

Nitrosamine Implementation Oversight Group

The Nitrosamine Implementation Oversight Group (NIOG) oversees the harmonised implementation of the CHMP's Article 5(3) opinion on nitrosamines.

It was set up by the European medicines regulatory network under the February 2021 implementation plan, and reports on progress to EMA's Management Board and the Heads of Medicines Agencies (HMA). 

The group contains representatives from the CHMP, CMDh, EMA working parties, EDQM and EMA staff. It also acts as the main interface for the pharmaceutical industry stakeholders to discuss regulatory and scientific developments on nitrosamines with EMA and the European medicines regulatory network. 

For details of meetings involving pharmaceutical industry stakeholders and supporting documents, see: 

More information on the group's mandate, activities and composition is available in the document below:

Nitrosamine Implementation Oversight Group Terms of Reference

Guidance for marketing authorisation holders

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 call for review was extended to biological active substances in July 2020, as an outcome of CHMP's Article 5(3) opinion. This complements the review of chemically synthetised active substances, which has been ongoing since September 2019. To allow marketing authorisation holders enough time to implement the Article 5(3) opinion, the European medicines regulatory network agreed new deadlines. Further details and guidance are available below.

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) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products 

      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 nitrosamines.review.cap@ema.europa.eu 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 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.

      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

      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 nitrosamines.review.cap@ema.europa.eu 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:

      • 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. 

      Update: 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.

      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 also need to adhere to the nitrosamines guidance outlined by the European medicines regulatory network.

      Marketing authorisation holders and manufacturers should work together and take precautionary measures to mitigate the risk of presence of nitrosamines during the manufacturing and storage of all authorised medicines.

      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. It covers the following:

      • Outcome of the Article 5(3) referral
      • Instructions, scope and timelines of the product review process
      • principles and methodology for confirmatory and release testing
      • 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
      • 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

      • Updated less than lifetime approach (LTL) to include authorised products for chronic use and define applicability, and the removal of the temporary AI (t-AI) approach in alignment with the CPCA and EAT protocol
      • Updated content (question 3) to provide information on the future of the call for review (new)

      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

      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.

      Sartan medicines

      The requirements that marketing authorisation holders for sartan medicines need to follow to avoid the presence of nitrosamine impurities in their products are the same as for all human medicines.

      The CHMP updated the requirements for sartans in November 2020, bringing them in line with the outcome of its Article 5(3) opinion. It first issued recommendations for sartans in January 2019.

      For more information see: 

      Lessons learned

      In June 2020, the European medicines regulatory network published the outcome of a lessons learned exercise on the presence of nitrosamines in sartan medicines (also known as angiotensin II receptor antagonists). This includes recommendations to help reduce the risk of impurities in medicines and ensure that regulators are better prepared to manage cases of unexpected impurities:

      The recommendations apply to all medicines. They include:

      • developing additional guidance on:
        • the roles and responsibilities of companies involved in the manufacture of medicines;
        • controlling impurities;
        • good manufacturing practice (GMP);
        • sampling and testing.
      • improving communication with patients and healthcare professionals;
      • expanding cooperation with international partners;
      • further developing information technology systems.

      An Lessons learnt from presence of N-nitrosamine impurities in sartan medicines - Implementation plan agreed in October 2020 sets out how the European medicines regulatory network intends to address each recommendation. It identifies lead responsibilities and indicative timelines. 

      The recommendations were relevant for the Article 5(3) procedure.

      A stakeholder consultationprocess fed into the lessons learned exercise, including a meeting with stakeholders in November 2019:

      Rifampicin medicines

      Authorities in the EU are investigating the presence of a nitrosamine impurity, 1-nitroso-4-methyl piperazine, in rifampicin),> medicines.),>

      The national competent authorities are working closely with companies and the official medicines control laboratories (OMCLs) in the ongoing investigation of EU medicines.

      As of February 2021, national competent authorities are asking marketing authorisation holders for rifampicin-containing medicines to test their medicines before releasing them onto the market. 

      This is a precautionary step to ensure patient safety while the investigation is ongoing. It is in line with the measures introduced by EMA's Article 5(3) review to limit the presence of nitrosamines in human medicines.

      The national competent authorities will carefully monitor responses to this request and take action if necessary.

      Rifampicin is a first-line treatment for tuberculosis. It is also used for management of other serious infections, including blood infections and leprosy.

      The risk to patients from not taking their rifampicin medicines far outweighs any potential risk from MeNP. Healthcare professionals should therefore continue to prescribe rifampicin medicines as normal in accordance with the product information.

      Authorities will provide updates as necessary.

      For more information, see the press release of the Co-ordination group for Mutual recognition and Decentralised procedures – human (CMDh).

      Ranitidine medicines

      EMA's review of ranitidine medicines led it to recommend their suspension after tests showed that some of these products contained NDMA. For more information, see:

      Metformin-containing medicines

      EMA and the national competent authorities are investigating the impact of tests which detected NDMA in some EU batches of metformin-containing medicines, used for the treatment of diabetes. This follows confirmation of NDMA in some batches outside the EU in late 2019.

      EMA and the national competent authorities are working closely with companies and the official medicines control laboratories (OMCLs) in the ongoing investigation of EU medicines.

      As of October 2020, EMA and the national competent authorities are asking marketing authorisation holders for metformin-containing medicines to test their medicines before releasing them onto the market. 

      This is a precautionary step to ensure patient safety while the investigation is ongoing. It is in line with the measures introduced by EMA's Article 5(3) review to limit the presence of nitrosamines in human medicines.

      EMA and the national competent authorities will carefully monitor responses to this request and take action if necessary.

      EMA advises patients in the EU to continue to take metformin medication as the risks from not treating diabetes far outweigh any possible effects of the low levels of NDMA seen in tests. 

      As metformin is considered a critical medicine, EMA and national authorities are cooperating closely to avoid possible shortages so patients can continue to get the treatments they need. 

      For more information, see:

      Champix

      EMA's CHMP has carried out a review of the presence of a nitrosamine impurity, N nitroso-varenicline, in Champix (varenicline), a smoking cessation medicine.

      The CHMP concluded that the marketing authorisation holder should make changes to Champix's authorisation to ensure that it conforms to acceptable nitrosamine intake limits for EU medicines, calculated in line with the ICH M7 guideline

      As a precaution, the marketing authorisation holder recalled several batches and paused distribution of Champix, as of June 2021.

      As a result, there are shortages of the medicine in the EU that are expected to continue. As Champix is not a critical medicine, the CHMP did not consider its temporary absence from the EU market to be a public health concern.

      EMA has issued advice for healthcare professionals, including not to start new patients on Champix. 

      Patients should not stop taking Champix without first consulting their healthcare professional and should talk to them if they have any questions or concerns. 

      More information: 

      Champix (varenicline) supply shortage

      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 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 (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.

      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.

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