Q&A Document on Nitrosamine Impurities Updated

At the end of June, the question and answer document of the EMA and the CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures - Human) was updated again and published as 4th revision on 29 June 2021. The updates affect questions 3 and 10 of the document.

Question 3 (analoguous wording): In the context of the referral procedure according to Article 5(3) of Regulation 726/2004 ("Call for Review"), marketing authorisation holders of chemically synthesised and biological medicinal products are required to report to their competent authorities. When and how should these reports be submitted?

The clarifications in the answer to this question refer to confirmatory testing and the submission of the results of confirmatory testing and the corresponding deadlines.

Confirmatory testing (Step 2)

This test must be performed if a potential risk of contamination with nitrosamines was previously identified during the risk assessment (Step 1). The following should be noted:

• Confirmatory testing must be performed irrespective of the marketing status.
• This requirement applies even if the manufacturers indicated in the registration documents are currently not actively manufacturing.
• If a finished product batch is not available from the inactive manufacturers for confirmatory testing, a written commitment must be submitted that when the product is available and/or prior to its marketing, testing will be performed.
• The results of the confirmatory testing (Step 2) and any variations (Step 3) must be submitted and approved before the product is marketed and before the inactive manufacturer resumes production.

Submission of results

The results of the confirmatory testing must be submitted to the regulatory authorities by the following deadlines:

• 26 September 2022 for medicinal products containing chemically-synthesised APIs.
• 1 July 2023 for biological medicinal products
• The authorities must be informed - irrespective of the content of the detected nitrosamine impurities. The appropriate reporting templates must be used.
• If nitrosamines are detected, the risk to the patient must be assessed using the ICH Q10 guideline as a basis.
• If nitrosamines are not detected in several different products, they may be grouped into one submission. Such a grouping consisting of all strengths and dosage forms of a marketing authorization is also possible for products with nitrosamine content, but only if the documentation of these products is completely identical. Otherwise, a separate submission is required.
• If the nitrosamine levels exceed the limits specified in ICH Q10, the documentation must include the following information:
• Test results in ng and ppm
• An interim investigation report consisting of an indication of the root cause of the contamination, a risk mitigation plan and a benefit/risk assessment.

Question 10: "What are the limits for nitrosamines in medicinal products?"

N-nitrosomorpholine (NMOR) was included at 127 ng/day in the list of different nitrosamines and their limits.