Nitrosamine impurities – are you ready to fulfil your legal obligations as a MAH by March 26th, 2020?

During the summer 2018, authorities become aware of the presence of some nitrosamines in API – ( – presence of N- nitrosodimethylamine (NDMA) - other sartans – presence of N-nitrosodiethylamine NDEA).  Nitrosamines are chemical compounds classified as probable human carcinogens based on animal studies. However, risk is very low that nitrosamine impurities at the levels found in APIs so far could cause cancer in humans.

Article 31 review findings indicate that there is a potential for nitrosamines to be present in APIs for other medicines (i.e. non-sartans APIs), depending on the API and the finished product manufacturing processes. Subsequently, a nitrosamine impurity was detected in batches of ranitidine, batches of pioglitazone, and recently batches of metformin. An EU-wide review has been initiated.

The EMA requested MAHs to take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicines containing chemically synthetized APIs.  

In September 2019, EMA began a review under Article 5(3) of Reg (EC) 726/2004 to provide guidance to MAHs on how to avoid the presence of nitrosamine impurities in human medicines.

As part of this review, the CHMP has requested MAHs for human medicines (all products including generics and OTC) containing chemically synthetized APIs to review their medicines for the possible presence of nitrosamines and test all products at risk - and report the outcome by 26 March 2020 at the latest for Step 1 Risk evaluation.

• Step 1 :  Risk evaluation

The risk evaluation of all products should be concluded at the latest within 6 months of the publication of the notification. MAHs should inform the concerned competent authority when the risk evaluation is concluded. Risk evaluation document do not need to be submitted but should be made available upon request.

• Step 2 : if risk of presence of nitrosamines is identified as result of evaluation

- Confirmatory testing using validated and sensitive methods

- Products identified as high priority should be tested as soon as possible.

- MAHs should inform HC immediately if tests confirm the presence of a nitrosamine impurity irrespective of the amount detected.

• Step 3 : MAA changes= MAHs should apply for a variation within 3 years

Other regulatory agencies have also issued statements or precautions on this issue such as the FDA or Health Canada.

Our CMC, Quality and Regulatory Affairs experts at BlueReg will provide you guidance on the risk assessment and flexible solutions to address your obligations as a MAH in order to navigate this evolving challenge.