Nitrosamines are chemical compounds classified as probable human carcinogens.
Since September 2019, marketing authorisation holders of human medicinal products have been required to evaluate their manufacturing processes for all products containing chemically synthesised active substances to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities. The call for review was extended also to biological active substances in July 2020.
So, if you are dealing with human medicinal products, you have to perform a risk evaluation for all of your products.
Risk evaluation is conducted in order to identify active substances and finished products at risk of N-nitrosamine formation or contamination. Preparing the risk evaluation requires close co-operation between API manufacturers and/or ASMF/CEP holders, finished product manufacturers and marketing authorisation holders, since input is needed from all of them. The risk evaluations themselves do not need to be submitted but the outcome (risk identified or no risk identified) should be reported to competent authorities by
- 31 March 2021 for chemical medicines
- 1 July 2021 for biological medicines.
In case no risk to expect nitrosamine contamination is identified, risk evaluation is the only thing you will need to do.
However, if your risk evaluation identifies a risk for nitrosamine contamination, you have to perform further confirmatory testing on the products identified to be at risk. Confirmed presence of nitrosamines should be reported to competent authorities as soon as possible.
In the worst case scenario, you might have to make changes to the manufacturing process of the active substance or the finished product, the controls or the raw materials to mitigate the risk of having nitrosamines present in the product. In such cases, the necessary changes to the marketing authorisation are to be applied for via standard regulatory procedures. The deadlines for such variations depend on the type of product concerned:
- 26 September 2022 for chemical medicines
- 1 July 2023 for biological medicines.
What about new marketing authorisation applications then? If you are considering submitting a new marketing authorisation application in the near future, make sure that nitrosamine risk evaluation has been done.
Risk evaluation should be submitted as an attachment to Module 1 with a corresponding reference in Module 3.2 of the marketing authorisation dossier. Risk evaluation will have to be adequately documented and, if applicable, supported by confirmatory testing, in case a possible risk of nitrosamine presence has been identified.
If a risk of presence of nitrosamines in the medicinal product is identified, applicants are required to provide a risk assessment outlining the impact on the benefit-risk balance of the product as well as a risk mitigation strategy.
When a nitrosamine is identified after confirmatory testing, a limit will usually have to be included in the specifications of the finished product.
Testing is usually expected to be carried out on the finished product, however, if the source of the nitrosamine impurity is identified in the active substance (or excipient) manufacturing process, the control point can be on the active substance (or excipient) level, when properly justified.
Even if the control point for the nitrosamine is not at the finished product level, a limit has to be included in the finished product specification, and any batches should comply with it, if tested. Testing of raw materials (e.g. excipients) should also be considered if these are potential sources of nitrosamine impurities.
The EMA Q&A document provides up-to-date information about risk assessments, analytical development and acceptance limits related to nitrosamine impurities in human medicinal products.
Watch our video to learn what kind of actions related to nitrosamine impurities are needed from MAHs.
Our experts are happy to help you with the risk evaluations. For further information, please contact Ulla Orava.