Human medicinal product licences to be reviewed for the presence of Nitrosamine Impurities

On 26 September 2019 the European Medicines Agency requested that, as a matter of precaution, all Marketing Authorisation Holders (MAH) should perform a risk evaluation for all of their medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) to assess the possible presence of nitrosamines.

Nitrosamines refer to any molecule containing the nitroso functional group and are classified as probable human carcinogens on the basis of animal studies. Long-term exposure above certain levels may increase the risk of cancer in humans.

In December 2019, the CMDh also released an updated practical guidance for MAHs of nationally authorised products in order to explain the necessary steps for fulfilling the requested risk assessment.

Both EMA and CMDh specify that the conclusions of the risk evaluations by all MAH should be submitted to the relevant regulatory authorities where products are authorized by 26 March 2020; if the potential for nitrosamine contamination is identified for any human medicine, this must be reported to the relevant regulatory authorities promptly so that appropriate regulatory actions can be taken.

How can S-cubed help you?

S-cubed is working with client companies, both MAHs and API manufacturers, to review their licensed medicines and manage the required risk evaluation process. We can help with liaising with contract manufacturers, and obtaining information to complete risk evaluations.

The Background

Why did the EMA release this advice?

In 2018, nitrosamines (N-nitrosodimethylamine and N-nitrosodiethylamine) were detected in some blood pressure medicines known as sartans. Their presence was unexpected and led to a recall of several products.

An Article 31 review, conducted by EMA/CHMP, of sartans at risk of containing nitrosamine impurities (i.e. sartans with a tetrazole ring; including candesartan, irbesartan, losartan, olmesartan and valsartan) concluded that manufacturers must review and make necessary changes to their manufacturing processes to minimise nitrosamine impurities as much as possible. As a result, strict limits were set for nitrosamines in these products.

The findings of the review indicated that depending on the API and the process used to manufacture the finished product, there is a potential for nitrosamines to be present in the APIs for medicines other than sartans.

Since then, a nitrosamine impurity has been detected in batches of pioglitazone from one company and more recently in batches of ranitidine, triggering an EU-wide review of these products.

It is not expected that nitrosamines can be formed during the manufacture of the vast majority of APIs outside the class of sartans with a tetrazole ring. However, under certain conditions and when certain solvents, reagents and other raw materials are used, it is now known that nitrosamines impurities can form during production and can also be carried over during the manufacturing process when using already-contaminated equipment or reagents. The EMA has therefore requested that, despite the low risk of nitrosamines being present, MAHs should take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicinal products containing chemically synthesised APIs.

The Ph. Eur. monographs for the sartan APIs with a tetrazole ring have been revised as a consequence of the presence of nitrosamines in these substances. The Ph. Eur. general monograph on Substances for pharmaceutical use (2034) is also to be revised. It is currently out for public consultation (January to March 2020).

Which products to be reviewed by the MAH?

All authorised human medicinal products containing chemically synthesised APIs regardless of marketing status are to be reviewed, including generics and over-the counter products.

EMA have advised that MAHs should prioritise products on the basis of principles defined within ICH M7 and ICH Q9 in order to establish the sequence in which their products are to be evaluated. Prioritisation should be based on certain factors such as the maximum daily dose taken, duration of treatment, therapeutic indication or number of patients treated and medicinal products more likely to be at risk of containing nitrosamines should be evaluated immediately.

What are the responsibilities of MAHs?

MAHs are responsible for ensuring that the quality of each batch of their finished product is fully satisfactory, including the quality of the APIs, excipients and raw materials used to manufacture them.

MAHs should therefore work with their API (including ASMF or CEP holders) and finished product manufacturers to access the relevant information concerning the potential formation of nitrosamine impurities and the potential for cross-contamination.

How to perform the risk evaluation?

As stated in the EMA Q&A document, the MAH should take the following sequential steps for their medicinal products:

Step 1 – Risk evaluation:MAHs should perform an evaluation of their medicinal products containing chemically synthetized API using a risk-based approach.

The risk assessments for all their human medicinal products should be concluded by 26 March 2020 and the relevant competent authorities (CAs) informed of the conclusion. The associated risk evaluation documents do not need to be submitted but should be made available upon request.
Step 2 – Confirmatory testing:Confirmatory testing should be performed as soon as step 1 identifies a potential risk of the presence of nitrosamines to confirm the presence of any nitrosamine impurities.

Confirmatory testing should be completed by 26 September 2022 and the results of the testing (irrespective of the amount the of impurity detected) and investigation report including the risk assessment and any proposed CAPAs should be immediately sent to the relevant CA(s).

The relevant CA(s) will evaluate the information and inform of any necessary measures that should be undertaken.
Step 3 – Changes to the marketing authorisation:If required and identified by carrying out the above steps, MAHs should apply for the necessary variations for amendments to the Quality dossier (i.e. changes to the manufacturing process, formulation or specifications) in a timely manner.

EMA and CMDh have released predefined templates for submitting the outcomes of steps 1-3 to the CAs.

Action required by CEP Holders

Although it is not expected that this issue impacts many substances, EDQM has expanded the review to all other APIs manufactured from chemical synthesis for which CEPs have been granted (which is a similar stepwise approach to that for MAH).

CEP holders are not required to confirm to EDQM that the risk assessment (step 1) has been completed where no risk is identified. However, where a risk is identified, EDQM should be immediately informed and the company should progress to step 2.

Any Questions?

If you have any questions on this topic, please don’t hesitate to ask! You can contact us through our website (, via email (, and telephone (S-cubed Ltd: +44 1235 77 22 60).


  • EMA – EMA/511347/2019 (26 September 2019) ‘EMA advises companies on steps to take to avoid nitrosamines in human medicines’
  • EMA – EMA/189634/2019 (19 September 2019) ‘Information on nitrosamines for marketing authorisation holders’
  • CMDh – CMDh/412/2019, Rev.2 (December 2019) ‘CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines’
  • CMDh – CMDh/405/2019, Rev.2 (December 2019) ‘Questions and answers on “Information on nitrosamines for marketing authorisation holders”’