Nitrosamine impurities

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

The European Medicines Agency (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 will work with marketing authorisation holders to find rapid solutions to address any adverse findings. 

Guidance to avoid nitrosamines in human medicines

In September 2019 EMA began a review under Article 5(3) of Regulation (EC) No 726/2004 to provide guidance to marketing authorisation holders on how to avoid the presence of nitrosamine impurities in human medicines. As part of this review, the CHMP has requested marketing authorisation holders for human medicines containing chemically synthesised active substances to review their medicines for the possible presence of nitrosamines and test all products at risk.

 

Marketing authorisation holders should follow these steps:

  • Step 1: conduct a risk evaluation to identify products at risk of N-nitrosamine formation or (cross-)contamination and report the outcome by 26 March 2020 at the latest.

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 appropiate.

  • 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.

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 appropiate.

  • 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 Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) website.

The European medicines regulatory network plans to complete this exercise by 26 September 2022. At all steps, timelines should be shortened and authorities immediately informed if findings indicate an immediate risk to public health.

Update: 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 will streamline the processes for handling new information on the presence of nitrosamines in medicines whilst the CHMP finalises its 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.

Review of ranitidine medicines

At the request of the European Commission, EMA is currently reviewing ranitidine medicines 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

On 6 December 2019, EMA confirmed that trace amounts of NDMA had been found in a small number of metformin-containing medicines outside the EU. There were no data indicating that EU medicines were affected.

EMA and national competent authorities are working closely with the official medicines control laboratories (OMCLs) and companies to test EU medicines. EMA will provide further updates as soon as possible.

EMA advised 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. 

For more information, see:

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