Nitrosamine Impurities

CHMP Article 5(3) Scientific Opinion

The EMA’s human medicines committee (CHMP) has requested as a matter of precaution that marketing authorisation holders (MAHs) for human medicines containing chemically synthesised active substances review their medicines for the possible presence of nitrosamines, test all products at risk, and submit variations to the marketing authorisation as required.

Although nitrosamines are not expected to form during the manufacture of the vast majority of medicines containing chemically synthesised active substances, it is important that all companies who have not already done so take appropriate precautionary measures, if necessary, in line with recommendations from the recently concluded review of sartans.

Information on the process to be followed for non-centrally authorised products and the deadlines to be adhered to has been published by CMDh.

MAHs are required to review the process and guidance as published by CMDh and to note the following additional national procedural requirements.

  • The responses outlined should be submitted in the agreed CMDh template format to nitrosamines@hpra.ie including the required email headings and details. Inclusion of several products in one template where the outcome is the same, as outlined by CMDh can be accepted.
  • Where the risk of a nitrosamine impurity is identified as part of Step 1, or nitrosamines are detected as part of Step 2, the relevant excel files as published by CMDh must also be completed and provided as part of the response.
  • Where nitrosamines are detected as part of step 2, and the quantity detected is above the agreed interim limits which have been established for specific nitrosamine impurities, the applicant should also copy qualitydefects@hpra.ie in the email when submitting the response.
    • In the above circumstance (i.e. limits exceeded) the applicant should also complete a Quality Defect report following the HPRA’s Guide to Reporting and initial Investigation of Quality Defects in Medicinal Products for Human and Veterinary use using the Quality Defect Report form SUR-F0180.
    • The excel file submitted as part of the response should specifically highlight the results where nitrosamine levels above the acceptable daily intake are detected.

In all instances the MAH is responsible for performing an independent review of the data prior to submission. In the event of further queries, please submit these to nitrosamines@hpra.ie.

Further information for companies in respect of centrally authorised medicines is available from the EMA website.