Updated Templates for Reporting Nitrosamine Contamination to Regulatory Authorities

Within the framework of the referral procedure according to Art. 5(3) of Regulation (EC) 726/2004 ("Call for Review"), marketing authorisation holders of medicinal products containing chemically synthesissed and biological APIs are requested to perform a confirmatory testing of their products for nitrosamine content (step 2) after a risk of contamination with nitrosamines has been identified in a previous assessment of the manufacturing process (step 1) (see our news on the update of the question and answer document on nitrosamine contamination).
Two of the reporting templates (response templates) for this were revised and published on the EMA website on July 2. The two updated response templates should now be used as follows:

Nitrosamine detected response template

This template is to be used whenever one or more nitrosamine species have been analytically detected, regardless of concentration.

Nitrosamines detected above acceptable intake or new nitrosamine detected response template

This template (xlsx format) is to be used in addition to the "Nitrosamines detected response template" when at least one of the following scenarios applies:

  • The acceptable intake level (AI; acceptable intake) is exceeded.
  • The 1:100 000 life-time risk is exceeded. This limit comes from the ICH M7(R1) guideline and reduces the increased risk of cancer caused by nitrosamines for people taking the medicinal product for life. 
  • A new type of nitrosamine was detected that was not described in the CHMP final report on the referral process (CHMP article 5(3) opinion). The concentration of the nitrosamine does not matter.

If none of these three points apply, only the nitrosamine detected response template needs to be submitted.

If no nitrosamine contamination was detected, this must be confirmed with the No Nitrosamine detected response template.

Shortly after publication by the EMA, the updated templates also appeared on the CMDh website. The Nitrosamine detected response template additionally contains the request to the marketing authorisation holder to indicate, in case of a purely national marketing authorisation, if the acceptable intake value or the 1:100 000 life-time risk limit is exceeded, whether and in which EU Member States the medicinal product is still authorised and whether the respective data apply in each case. Furthermore, after submitting the variations (step 3), the national authorities in the case of a purely national marketing authorisation and the reference Member State in the case of a decentralised marketing authorisation/mutual recognition procedure (MRP/DCP) should be informed about the details of the marketing authorisation and the date of submission of the variations (indication of the marketing authorisation number). The worksharing procedure is recommended for this procedure.

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