[co-author: Grégoire Paquet]

1. Introduction

In late October 2019, the Co-ordination Group for Mutual Recognition and Decentralised procedures – Human (CMDh) of the Heads of Medicines Agencies (HMA) published a practical guidance on nitrosamines. The guidance is addressed to marketing authorisations holders (MAHs) of products medicinal products authorised nationally in the EU Member States and through the mutual recognition and decentralised procedures. The guidance provides the steps to be followed to evaluate the risk of the presence of nitrosamine impurities in human medicinal products. The guidance includes the contact details of the competent authorities of the individual EU Member States and their published guidance in Annex.

2. Request to evaluate the risk of the presence of nitrosamine impurities

The practical guidance is a follow-up to an information document in which the CMDh requested MAHs to evaluate the risk of the presence of nitrosamine impurities in their human medicinal products. The guidance also adds to an opinion of the European Medicines Agency’s human medicines committee (CHMP) making the same request to MAHs as a matter of precaution.

The steps are a result of discovery of the presence of nitrosamines in sartans supplied by active pharmaceutical ingredients manufacturers. Nitrosamines are classified as probable human carcinogens. As their presence in sartans was unexpected, the CMDh decided to set strict limits for nitrosamines in these products. In addition, the CMDh recommended that manufacturers review and make necessary changes to their manufacturing processes to minimise nitrosamine impurities.

The CMDh recalled that MAHs are responsible for ensuring that their medicinal products are manufactured in accordance with the requirements laid down in Directive 2001/83/EC. This includes the quality of the active pharmaceutical ingredients regarding potential formation of nitrosamine impurities and the potential for cross contamination. The practical guidance provides the steps to be followed to complete the requested risk assessment.

3. Sequential steps to follow

The practical guidance includes three sequential steps following which the evaluation should be performed.

In the first step, MAHs should perform risk assessments. MAHs are required to submit the conclusions of these risk assessments for all of their products before 26 March 2020. Related templates are provided by the HMA. These documents must be sent to:

• the concerned national competent authorities where the product was authorised at the national level;
• the reference EU Member State for products authorised through the mutual recognition or decentralised procedures; and
• the European Medicines Agency for products authorised under the centralised procedure.

As a second step, MAHs are requested to perform confirmatory testing if the risk assessment indicates a potential risk of formation of, or contamination with nitrosamines. Where a high risk is identified, MAHs should initiate a confirmatory testing procedure immediately. The guidance provides that confirmatory testing should be finalised by 26 September 2022 at the latest.

As a third step, where the results of testing so require the guidance provides that MAHs should submit the necessary variations for amendment of the quality dossier within three years, i.e. 26 September 2022.

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