Nitrosamine impurities

Nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were found in a number of blood pressure medicines known as 'sartans' in 2018. This led to some product recalls and to a regulatory review, which set strict new manufacturing requirements for these medicines. Subsequently, a nitrosamine impurity was detected in batches of ranitidine, a medicine used to treat heartburn and stomach ulcers, and the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) carried out a review.

Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies. However, there is a very low risk that nitrosamine impurities at the levels found could cause cancer in humans.

EMA has asked marketing authorisation holders to take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicines containing chemically synthesised active substances.

EMA and national competent authorities continue to monitor the presence of nitrosamine impurities in medicines, in co-operation with regulators from outside the European Union (EU), and to work with marketing authorisation holders to find rapid solutions to address any adverse findings. 

Guidance to avoid nitrosamines in human medicines

EMA carried out a review under Article 5(3) of Regulation (EC) No 726/2004 from September 2019 to 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 their medicines for the possible presence of nitrosamines and test all products at risk, by following the guidance on this page.

Update: The CHMP adopted a scientific opinion in June 2020, which recommended reviewing biological medicines in addition to medicines containing chemically synthesised active substances:

Updated instructions for marketing authorisation holders will be available soon, based on the CHMP opinion. Until then, companies involved in the current call for review should continue to follow the current instructions and timelines. 

Marketing authorisation holders should review their manufacturing processes to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities in three steps.

The European medicines regulatory network has agreed to extend the deadline to complete step 1 (risk evaluation) of the review of manufacturing processes as described in PDF iconinformation on nitrosamines for marketing authorisation holders  to 1 October 2020

This follows reports of the challenges encountered in meeting the original deadline of 26 March 2020, and the impact of the severe restrictions in place to combat the COVID-19 pandemic. 

The European medicines regulatory network encourages marketing authorisation holders to submit the outcome of step 1 before 1 October 2020 if they complete the risk evaluation or identify a risk in their products. 

Marketing authorisation holders should inform the national competent authorities 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.

The European medicines regulatory network plans to complete this exercise by 26 September 2022. 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

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 1 October 2020 at the latest.

Marketing authorisation holders can submit a single email notification grouping products with identical outcome of step 1. For more information, see question 5 of  PDF iconQuestions and answers on 'Information on nitrosamines for marketing authorisation holders '.

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

    Marketing authorisation holders for centrally authorised products should send the completed template(s) 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

    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 question 4 of  PDF iconQuestions and answers on 'Information on nitrosamines for marketing authorisation holders '

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

    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

    Apply for any necessary changes to the manufacturing process resulting from this review using the established 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.

    Question-and-answer guidance

    On 20 December 2019, the European medicines regulatory network updated the questions-and-answers document for marketing authorisation holders who are currently reviewing their medicines for the possible presence of nitrosamines and testing products at risk. 

    The update follows the European medicines regulatory network's agreement to reinforce the use of interim limits for the evaluation of cases where nitrosamines are identified, in line with EMA's report on the review of sartans and the principles of ICH M7. This streamlines the processes for handling new information on the presence of nitrosamines until the outcome of the CHMP's scientific review under the Article 5(3) procedure. Cases where interim limits are exceeded will be handled through the EU network’s existing rapid alert systems.

    The updated document covers potential sources of nitrosamine contamination that have been identified to date, information on the methodology to calculate interim limits for exposure to nitrosamines and guidance for applicants of marketing authorisations. Marketing authorisation holders of sartans with a tetrazole ring should also consult question 1 of this document.

    Lessons learned with sartan medicines and recommendations

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

    The recommendations 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.

    These recommendations apply to all medicines.

    They are also relevant for other nitrosamine-related initiatives, such as the Article 5(3) procedure, which will provide the key scientific opinion on the presence of nitrosamine impurities in human medicines.

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

    Review of ranitidine medicines

    EMA has completed its review of ranitidine medicines and recommended their suspension after tests showed that some of these products contained NDMA.

    For more information, see:

    Review of sartans (angiotensin II receptor antagonists)

    EMA has completed its review of sartan blood pressure medicines (also known as angiotensin II receptor anatgonists). Manufacturers of sartan medicines must review their manufacturing processes to ensure they do not produce nitrosamine impurities.

    For more information, see:

    Metformin-containing medicines

    EMA and the national competent authorities are assessing the impact of tests which showed 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 awaiting further test results of EU medicines. They are working closely with companies and the official medicines control laboratories (OMCLs). EMA will provide further updates as soon as possible.

    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:

    How useful was this page?

    Add your rating
    Average
    32 ratings
    1 rating
    1 rating