New Updates of the Templates for Reporting Nitrosamine Contamination

Marketing authorisation holders of medicinal products containing chemically-synthesized and biological APIs are required to perform a confirmatory assessment (Step 2) of their products for nitrosamine impurities following the three-step "Call for Review" as part of the referral procedure under Article 5(3) of Regulation (EC) 726/2004, if a potential risk of impurities has been identified in a previous risk assessment (Step 1).

The reporting forms to be used for this confirmatory testing have been recently updated; as alread reported under "Updated Templates for Reporting Nitrosamine Contamination to Regulatory Authorities". The Nitrosamine detected response template has now been revised again by the EMA; the corresponding updated template from the CMDh was made available on the CMDh website shortly thereafter. In addition, question 10 was amended in the Q&A document by the EMA and CMDh.

Additions to the Nitrosamine Contamination Reporting Form

  • Change Notifications/Variations
    The template includes reference to a checkbox in the XML delivery file for variations in the eSubmission Portal to be used for reporting changes made to reduce nitrosamine impurities in the manufacturing process in accordance with Step 3 of the Call for Review.
  • Limit values of newly identified nitrosamines
    For reporting limits of new nitrosamines that were not considered in the CHMP statement on the Art. 5(3) procedure, the following two selection fields should be used as an alternative:
    - General class specific TTC (18 ng/day) in line with CHMP article 5(3) Q&A is being applied.
    - Substance specific AI limit (including SAR considerations) is being applied

Additions in the Q&A document from the EMA and CMDh

  • The table with daily limits of different nitrosamines in question 10 of the Q&A document (Which limits apply for nitrosamines in medicinal products?) has been extended by the compound N-nitroso-varenicline, NNV. Its limit of 37.0 ng/day was derived from structure-activity-relationship (SAR) estimations (original publication in the International Journal of Environmental Research and Public Health).

The confirmatory testing reporting template as well as the Q&A document can be found on the EMA website relating to nitrosamine contamination. The CMDh notification template can be accessed via the CMDh website.

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