Swissmedic updates Risk Assessment of Nitrosamines in Active Substances and finished Medicinal Products

Swissmedic has published new provisions for the assessment of possible nitrosamine impurities, taking into account international methods such as the Carcinogenic Potency Categorisation Approach (CPCA) and the Enhanced Ames Test (EAT). The aim is to assess the carcinogenic potential of nitrosamines on a sound basis and to define acceptable intake (AI) values that are also used in Switzerland.

The analytical detectability of so-called Nitrosamine Drug Substance-Related Impurities (NDSRI) has improved significantly. Depending on the amount of NDSRI determined and the AIs defined and published on the basis of the CPCA, Swissmedic describes the following graduated procedure

• <10% of the AI: no control strategy necessary if the data is traceable. 
• 10% - 100% of the AI: variation of the authorisation with specification and control strategy required. 
• >100% of the AI: categorised as Out of Specification (OOS) - contact with Swissmedic to define CAPA and possibly interim limits necessary.

Definition of limits (Acceptable Intakes - AIs)

• The basis for NDSRI limits is the Acceptable Intake (AI) according to the Carcinogenicity Potency Categorisation Approach (CPCA) (see EMA/451665/2023, Appendix 2). 
• The AIs published and harmonised by the EMA are regarded as reference values (see EMA/165331/2025/Rev. 9). 
• Deviating limit values based on experimental data are possible in principle, but require international harmonisation. 
• Positive in vivo mutagenicity data cannot currently be used to derive elevated AIs, but represent relevant information in the context of an evidence-based risk assessment. 
• For nitroso compounds that are not nitrosamines, risk assessments must be carried out in accordance with the requirements of the ICH M7 guideline.

Parallel imports are also subject to the same quality and safety requirements as original products for the entire authorisation period. In the event of incidents with the original product, Swissmedic can also order corresponding measures for parallel imports.

New registrations

The following requirements apply to new authorisations:

• Risk assessment for active substances is mandatory for chemically synthesised substances. 
• Risk assessment for finished medicinal products is generally required. 
• Exceptions include veterinary medicinal products, radiopharmaceuticals and medicinal products for parallel import.
  The submission should preferably be made in Module 1 as Additional Information; alternatively, Module 3.2.P.5.6 is also permissible, provided this is noted in the cover letter.

Read the Swissmedic communication on nitrosamines in detail.