Nitrosamine impurities – current update

Rapid implementation of the revised sartan monographs on 1 April 2021

Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies.

The review of sartans concerned candesartan, irbesartan, losartan, olmesartan and valsartan, which belong to a class of medicines called sartans (also known as angiotensin-II-receptor antagonists).

These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities. Other sartan medicines which do not have this ring, such as azilsartan, eprosartan and telmisartan, were not included in this review but are covered by the subsequent review of other medicines.

The five monographs on sartans with a tetrazole ring, namely Valsartan (2423), Losartan potassium (2232), Irbesartan (2465), Candesartan cilexetil (2573) and Olmesartan medoxomil (2600) have been revised to align them with the latest regulatory recommendations issued by the CHMP that were published on 13 November 2020 on the EMA’s website. The revision concerns a rewording of the “Production” section and deletion of the N-nitrosamines test section.

These revised monographs were not published in Pharmeuropa for public enquiry as the changes made are in line with the CHMP recommendations. In addition, to ensure that the implementation date for the Ph. Eur. requirements is aligned with regulatory decisions as much as possible, the Ph. Eur. Commission has decided to publish the monographs under the rapid-revision procedure. The implementation date for the five revised monographs has therefore been set as 1 April 2021. The PDF versions of these monographs can be downloaded from the EDQM website:

https://www.edqm.eu/sites/default/files/medias/fichiers/Monographie%20Candesartanum%20cilexetili.pdf

The revised monographs have been added to the online and downloadable versions of Supplements 10.4 and 10.5. They will be included in the printed version from Supplement 10.6.

If you need any clarification or support to help implement the responsibilities of a MAH with regard to Nitrosamines contact us and Ivowen will gladly assist you in a timely manner.

Written by Nanda Naik

Guidance to avoid Nitrosamines in Biological Medicines

Following the outcome of the Article 31 referral on sartans with a tetrazole ring and the knowledge acquired on N-nitrosamines in medicinal products, EMA together with the EU Network and international partners has continued the review to identify if there are any consequences for medicinal products outside the class of sartans.

Taking into account that N-nitrosamines have been found in sartans with a tetrazole ring but also in other API/medicinal products in September 2019 the CHMP’s opinion was sought by the EMA’s Executive Director in accordance with Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use.

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

The risk of presence of nitrosamines must be evaluated by the MAHs/Applicants. In case of risk, confirmatory testing must be performed.

  • A risk evaluation/risk assessment for the presence of nitrosamines must be submitted for new marketing authorization applications at the time of submission, and for already authorized medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) as per the ‘call for review’:

https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf

And for biological medicinal products in a similar exercise, as per instructions to be published in a ‘Questions and Answers document’:

https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-information-nitrosamines-marketing-authorisation_en.pdf

  • The approach for risk evaluation/risk assessment should cover manufacturing processes of active substance and finished product in consideration of the root-causes, and subsequent confirmatory testing in the finished product in case a risk is identified
  • Although the overall risk of presence of nitrosamines in biological medicinal products is considered very low, the following risk factors should be taken into consideration:
    • Biologicals containing chemically synthesized fragments, where risk factors similar to chemically synthesized active substances are present,
    • Biologicals using processes where nitrosating reagents are deliberately added,
    • or those packaged in certain primary packaging material, such as blister packs containing nitrocellulose.

For details see CHMP – Assessment Report: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf

If you need any clarification or support to help implement the responsibilities of an MAH with regard to Nitrosamines reporting contact us and Ivowen will gladly assist you in a timely manner.

Written by Nanda Naik