Nitrosamine impurities overview

In 2018, nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were found in a number of blood pressure medicines known as 'sartans'. This lead 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.

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.

EMA plans to complete this exercise by 26 September 2022. This timeline should be shortened in case of findings indicating higher risk to public health and that may require further risk minimisation measures.

EMA has published a 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 document lists potential sources of nitrosamine contamination that have been identified to date. This information can support companies in their ongoing review of their manufacturing processes:

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:

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