In the article "Potential nitrosamine contamination: request to perform a risk evaluation" published in the Swissmedic Journal 11/2019 and, as a communication, on the Swissmedic website on 3 April 2020, the authorisation holders of all medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) were asked to take precautions in order to minimise the risk of contamination with nitrosamines. This applies both to authorised medicinal products that are already on the market and medicinal products that are currently notified, or scheduled to be notified, for new authorisation. The requirements concerning the documentation for the new authorisation of all medicinal products containing chemically synthesised APIs are detailed below. These requirements are based on the following current EMA publications:
- Guideline "Questions and answers on Information on nitrosamines for marketing authorisation holders" (EMA/CHMP/428592/2019 Rev.3; Question 13. "What is the approach for new and ongoing marketing authorisation applications (MAA)?")
- Guideline "Information on nitrosamines for marketing authorisation holders: Request to evaluate the risk of the presence of nitrosamine impurities in human medicinal products containing chemically synthesised active pharmaceutical ingredients" (EMA/189634/2019; 19 September 2019)
Medicinal products to be submitted for new authorisation
The submitted documents should be accompanied by a risk evaluation on the formation and occurrence of potential nitrosamines in the medicinal product. If the risk evaluation identifies a potential risk in one or more manufacturing steps or in the stability behaviour, a comprehensive risk assessment should also be submitted. This should also include an assessment of the impact on the benefit/risk profile, a risk minimisation strategy and a testing plan for confirmatory analytical investigations and/or confirmatory analytical test results (confirmatory tests).
Medicinal products that are already notified for new authorisation
Missing risk evaluation or risk assessment documents in connection with the review of submitted authorisation documents are always requested in the "List of Questions". If sufficient information and/or an assessment of the risk/benefit profile are still not available at this time, the corresponding documents will need to be submitted at a later phase.
The presence of these documents is a precondition for the subsequent authorisation of the medicinal product.
Scope of a risk evaluation/risk assessment
The risk evaluation and risk assessment must cover the whole manufacturing chain of the medicinal product with all steps of the manufacturing process. The manufacture of a medicinal product as a sum of all the individual steps comprises the synthesis of the active pharmaceutical ingredient, including the starting materials and reagents used, the pharmaceutical formulation of the API with the pharmaceutical excipients and the materials used in this process, as well as the primary and secondary packaging process. The stability behaviour of the medicinal product should also be considered.
Risk evaluation/risk assessment documentation
Active substance: The documentation on the risk evaluation and/or risk assessment of the formation and occurrence of potential nitrosamines in the active substance should preferably be incorporated in the CTD sections 3.2.S.2.6 Manufacturing process development, 3.2.S.3.2 Impurities and/or 3.2.S.4.5 Justification of specification. Other CTD sections may be involved depending on the result (e.g. 3.2.S.2.3 Control of Materials, 3.2.S.2.4 Control of Critical Steps and Intermediates).
Medicinal product: The documentation on the risk evaluation and/or the risk assessment of the overall formation and occurrence of potential nitrosamines in themedicinal product should preferably be presented in the CTD section 3.2.P.5.6 Justification of specification. Other CTD sections may be involved depending on the result (e.g. 3.2.P.3.4 Control of Critical Steps and Intermediates).
The new requirements enter into force immediately.