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Update on the EDQM review of CEP applications for sartans and next steps (June 2019)

18 June 2019
Strasbourg, France

The EDQM has now finalised the review and update of the vast majority of CEP dossiers for sartans containing a tetrazole ring structure. The CEP dossiers have been assessed following a risk- and science-based approach. When sufficient data was given to demonstrate that there were no risks of presence of nitrosamines and a limit in the specification of the active substance was not necessary (based on the process and an appropriate control strategy), the CEP was not revised but a letter of approval was sent to the CEP holder instead.

As part of this review, the EDQM had suspended a number of CEPs for sources of sartans containing levels of nitrosamines above the temporary limits. Three of these CEPs have been restored in the meantime, after appropriate corrective actions have been taken by manufacturers and the results have been positively evaluated by the EDQM.

On 2 April 2019, the European Commission has issued its final legally binding decision for medicines containing valsartan, candesartan, irbesartan, losartan and olmesartan. It defines a transition period of 2 years. The five sartans concerned by this Decision are each covered by an individual monograph in the Ph. Eur., and the monographs have been revised to align the Ph. Eur. requirements with this decision for the transitional period of 2 years by including a mandatory test for NDMA and NDEA. The revised monographs will be published in Ph. Eur. 10th edition, and will be implemented on 1 January 2020. More information on the revised monographs for sartans can be found here.

This has an impact on CEP dossiers for these substances, in particular where the current CEPs do not carry limits for NDMA and NDEA. The EDQM will soon contact CEP holders and request them to align their respective CEP dossiers with the revised monographs. As a result, the EDQM will revise the relevant CEPs to include limits for NDMA and NDEA, regardless if they may be present or not. This exercise will be completed by January 2020.

After the transition period (from April 2021) sartans with a tetrazole ring must not contain quantifiable levels of NDMA and NDEA (corresponding to less than 0.03 ppm). CEP holders may decide to apply already a limit of less than 0.03 ppm for NDMA and NDEA immediately, to avoid a new revision of their CEP in the future. The CEP dossiers which will not be in compliance with these requirements at the end of the transition period will have to be again updated accordingly. Manufacturers of sartans are requested to verify as soon as possible if changes to their manufacturing process and/or control strategy are necessary to meet these requirements, in which case an appropriate request for revision will have to be submitted with the relevant supportive data.

In addition, as precautionary measure, the absence of formation of nitrosamines is verified for any active substance covered by a CEP during the renewal process.

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