Potential nitrosamine contamination – harmonised implementation (update)

Regulatory and scientific developments regarding nitrosamines/Update September 2022

14.09.2022

Swissmedic is harmonising the requirements for dealing with nitrosamine contamination in medicinal products with those in the European environment as far as this is scientifically reasonable and is possible within the provisions of Swiss therapeutic products legislation.

As already detailed in previous publications, Swissmedic is aiming to harmonise requirements with those of the European environment. Since Swissmedic's publication of 16 April 2021 on nitrosamines, the EMA has published a number of updates to its questions and answers document. Swissmedic is therefore also updating its requirements based on the latest version of this document and adopting major revisions published by the EMA.

Implementation will be carried out within the valid provisions of therapeutic products legislation. Specific requirements of Swiss healthcare may entail deviations from the EMA’s approach. Such deviations or clarifications Swissmedic deems necessary are published in the following table and will be updated on an ongoing basis.

Regulatory and scientific developments regarding nitrosamines

As at 14 September 2022

Reference: EMA Q&A

SMC approach

Published on

Question 2:
Medicinal products containing biotechnological / biological active substances

For biological medicinal products already authorised at the time of this publication, Swissmedic only expects in-depth investigations if risk factors arise from the ingredients or as a consequence of the manufacturing conditions.

16 April 2021

Question 3:
Documentation to be submitted for authorised medicinal products

If no risk was identified, a "No risk identified template" does not need to be submitted.

16 April 2021

Question 3:
Timelines

On completion of step 1, and in contrast with the EU practice, documents do not need to be submitted to Swissmedic if no risks were identified.

16 April 2021

Question 3:
Amendment of deadlines

The deadline extension to 1 October 2023 regarding “Step 3 – submission of variations” for chemical medicines that was published by the EMA has been adopted by Swissmedic. The existing deadline (1 July 2023) continues to apply for biological medicines, as in the EU.

14 September 2022

Question 4:
Risk factors regarding the finished product (no. 8)

In the case of vulnerable active substances, particularly those with a secondary amine group, N-nitroso derivatives of the active substance can form in finished products with traces of nitrosylating substance contamination, e.g. from excipients or packaging materials, including over the shelf life. This should be taken into account in the risk assessment and if necessary protected against with analytical tests. Nitrocellulose-free blister components are recommended for packaging materials.

14 September 2022

Question 9, 10:
Analysis methods, acceptable intakes

For metformin products, the requirements stipulated by the Agency remain in effect until further notice.

16 April 2021

Question 10:
Ames test

We refer to the EMA's clarification that the in vitro bacterial reverse mutation test (Ames test) forms part of a comprehensive, evidence-based assessment and is not sufficient as a sole criterion for classification as a Class 5 impurity according to ICH M7.

14 September 2022

Question 10:
Acceptable intakes

Swissmedic has adopted the acceptable intakes defined by the EU (see Table 1, EMA Q&A document) and the basic approach for determining these.
The table in the update of April 2021 (below) is therefore obsolete.

14 September 2022