Nitrosamine Impurities: Extension of the Deadline for the Submission of Variations

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EMA's Question and Answer document for marketing authorisation holders regarding nitrosamine impurities has been updated again. In the 11th revision of the document published on 29 July 2022, the deadline for submission of variations has been extended from 26 September 2022 to 1 October 2023.

Background

In September 2019, the EMA started a call for review to all marketing authorisation holders of medicinal products containing chemically-synthesised and biological APIs to review their manufacturing processes with regard to contamination with nitrosamines. This 'call for review' consists of 3 steps:

• Step 1: Marketing authorisation holders assess the potential risk of contamination with nitrosamines at the level of the API and/or the finished medicinal product by means of a risk analysis.
• Step 2: If a risk is identified, a confirmatory test is carried out with the aim of confirming and quantifying the nitrosamine contamination or excluding it.
• Step 3: Following confirmation of nitrosamine contamination by confirmatory testing, the marketing authorisation holder must take effective measures to reduce the risk, which need to be submitted using the appropriate variation(s).

Further details on the procedures for steps 1 - 3 can be found in our news "Question and answer document on nitrosamine contamination updated" dated 19 July 2021.

The deadline for conducting the confirmatory review - 26 September 2022 for medicinal products with chemically-synthesised APIs and 1 July 2023 for those with biological APIs - remains unchanged. This gives pharmaceutical companies an extended timeframe of 12 months to take measures to reduce the risk of nitrosamine contamination and to submit the relevant variations to their competent authority. In doing so, the submission of incomplete data of the confirmatory examination should be avoided.

Shortly after the publication of the Q&A document on the EMA website, the notification addressed to all CEP holders was published in the EDQM newsroom regarding this extension of the deadline. Here, the EDQM explicitly points out the obligation of CEP holders to provide their customers with all information related to risk assessments of their products with regard to nitrosamines, so that they in turn can fulfil their obligations as marketing authorisation holders towards the authority. There is also a Guidance Document of the EDQM on this information obligation of CEP holders, which was published earlier this year.

Another update relates to the form for step 2, which has been amended to include a checkbox for confirming that the result of the risk analysis after step 1 is to be changed from "risk" to "no risk". This option for a subsequent change can be used if relevant information was still missing at the time of submission of the risk assessment and only became available after the deadline for step 1 (31 March 2021 for chemically-synthesised substances and 1 July 2021 for biological substances). A subsequent change vice versa, from "no risk" to "risk", cannot be made with this form.