Nitrosamine impurities

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.

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.

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.

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:

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:

    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 should use the templates below in their responses:

      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  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’.
       

      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:

      In order to meet these deadlines, it is necessary to perform the step 2 confirmatory testing activities sufficiently in advance.

      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:

      • outcome of the Article 5(3) referral;
      • instructions, scope and timelines of the product review process;
      • principles and methodology for confirmatory and release testing;
      • approaches for determining limits for nitrosamines;
      • 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.

      The European medicines regulatory network published this question-and-answer document in August 2020.

      This document replaces the question-and-answer document (EMA/CHMP/428592/2019 Rev. 3) published by the network in September 2019.

      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 PDF icon 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 consultation process 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 treating several 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: 

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