Renewed Revision of the Q&A Document on Nitrosamine Impurities: temporary acceptable intakes no longer need to be set

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Only three weeks after the publication of Revision 16 of the EMA/CMDh question and answer document on nitrosamine impurities in medicinal products for human use, the newly revised version of this document (Rev. 17) was issued on the EMA's "Nitrosamine Impurities" website. The reason for the further update is the now obsolete requirement to define temporary acceptable intakes (t-AI) for nitrosamines with the introduction of the Carcinogenic Potency Categorization Approach (CPCA) (also see our news The New Annex to EMA's Question and Answer Document on the Determination of Acceptable Intake Levels of Nitrosamines). The answer to question 21 ("What is the approach to control the presence of nitrosamines until a substance specific AI is established?") has been adapted accordingly (meaning: With the application of the CPCA and the extended AMES test, the establishment of a temporary AI [t-AI] is no longer necessary) and the part of the sentence regarding the t-AI in question 20 ("What are the regulatory steps taken by authorities following the identification of an N-nitrosamine exceeding the AI?") has been deleted.

In the answer to question 22 ("What is the approach to control presence of N-nitrosamines exceeding the AI during CAPA implementation?"), the previous restriction to a 10-year treatment period with the medicinal product in question was removed and extended to products with an undetermined duration of intake (e.g. in chronic diseases). The regulation for the nitrosamine limit value of 1.5 µg/day was supplemented as follows: exceeding this value is also possible if the nitrosamine falls into category 5 according to the CPCA and shows a negative result in the extended AMES test.

The template for the notification according to step 2, the nitrosamine detected response template, was also updated.

Information of the German BfArM for marketing authorisation holders on the submission of Step 2 - "Nitrosamines detected".

In a notification dated 7 August 2023 on its risk information website, the German BfArM (Bundesinstitut für Arzneimittel und Medizinproduke) advises all marketing authorisation holders that Step 2 submissions for medicinal products for which impurities with nitrosamines have been detected are to be resubmitted to the BfArM via the PharmNet.Bund portal using the updated feedback template. The newly established function structure number 6364 is to be used for this purpose. This submission is not considered a notification of change and is therefore free of charge.

Instructions for feedback via PharmNetBund are also available on the BfArM website.

Guidance of the MHRA applicable in the United Kingdom

On 24 August 2023 the Medicines and Healthcare products Regulatory Agency (MHRA) published a Guidance entitled Nitrosamines impurities in medicines. In this document the MHRA confirms a harmonised approach to establish acceptable intake levels (AIs) based on ICH M7 guidelines. The Guidance contains relevant information for marketing authorisation holders. E.g. the section Common mistakes in nitrosamine submissions provides a list of frequently issues the MHRA has to deal with.