Nitrosamine impurities in medicinal products: updated requirements for risk assessments, data submission and parallel import products
Swissmedic supplements measures for the risk assessment of possible nitrosamine impurities in active substances and finished medicinal products
30.06.2025
Nitrosamine impurities in medicinal products first came to light in mid-2018. Swissmedic constantly adapts its risk minimisation measures to the latest scientific and technical findings. International exchanges have resulted, for example, in the establishment of the Carcinogenic Potency Categorisation Approach (CPCA) and the Enhanced Ames Test (EAT). These scientific methods are used to assess the carcinogenic potential of nitrosamines and define acceptable intakes (AIs) based on the results – they are also an important foundation for ensuring drug safety in Switzerland. The aim is to eliminate the risk of nitrosamine impurities as far as possible while also ensuring that patients have access to a reliable supply of medically important medicines. Meanwhile, the analytical tools for measuring Nitrosamine Drug Substance-Related Impurities (NDSRIs) have improved significantly. A risk-based approach depending on the measured quantity of NDSRIs and the respective published AI value is recommended. For parallel imports, importers must satisfy the same quality and safety requirements as those that apply to the holders of the original authorisation.
Submission of analytical data
Depending on the quantity of NDSRIs and the AIs defined and published on the basis of the CPCA, Swissmedic employs the following graduated procedure:
- All measured values below 10% of the AI are considered to be safe. No specific control strategy is required in such cases, provided the submitted analytical data are plausible and methodologically sound. The data are reviewed by the Market Monitoring of Medicines Division (see also Q&A 14 EMA/409815/2020).
- All measured values below the AI (between 10 % of the AI and the AI) require a formal variation of the authorisation. To this end, a suitable specification and a control strategy for monitoring the NDSRI content must be defined and submitted.
- Individual measured values above the AI are rated as Out of Specification (OOS), even if a specification has not yet been formally established.
In these cases, applicants / authorisation holders must contact the Market Monitoring of Medicines Division without delay in order to define appropriate corrective and preventive actions (CAPAs) and specify any required interim limits.
Adopted_Nitrosamines EMEA-H-A5(3)-1490 - QA Art. 5(3) - version 22)
Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products
Specification of limits (Acceptable Intakes)
- The basis for NDSRI limits is the Acceptable Intake (AI) as determined by the Carcinogenicity Potency Categorisation Approach (CPCA) (see EMA/451665/2023, Appendix 2).
- The internationally harmonised AIs published by the EMA are considered to be reference values (see EMA/165331/2025/Rev. 9).
- While deviating limits based on experimental data or read-across analyses are possible in principle, these must be coordinated at the international level. To this end, Swissmedic requires the applicant’s consent before it can share information with the Nitrosamine Technical Working Group (NITWG).
- The submitted data must enable conclusions to be drawn about the quality and conduct of studies, and should ideally include complete study reports on experimental data (particularly on the Ames test and in vivo mutagenicity studies).
- Although positive in vivo mutagenicity data cannot currently be used to derive higher AIs, they do provide relevant information in the context of an evidence-based risk assessment.
- For nitroso compounds that are not classed as nitrosamines and for which no acceptable intakes (AIs) have been published to date, risk assessments should be implemented according to the requirements of the ICH-M7 guideline.
Appendix 2 to Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products Carcinogenic Potency Categorisation Approach for N-nitrosamines
EMA Acceptable Intakes for established N-Nitrosamines
Regulatory requirements for parallel imports
Throughout the authorisation period, importers of medicinal products must fulfil the same quality and safety requirements as those of the authorisation holders of the original products (according to Art. 14 para. 2 let. b TPA). Even after market launch, parallel-imported medicinal products are subject to the same quality, safety and efficacy requirements as those that apply to the original product or an equivalent reference product.
If safety signals or quality defects are reported for the original product, such as elevated nitrosamine levels, Swissmedic may require the importers to implement risk minimisation measures in a similar manner for their products, for example batch-specific nitrosamine analyses. Further information on this subject can be found in the guidance document Import of a human medicinal product according to Art. 14 para. 2 and 3 TPA (parallel import).
Nitrosamine risk assessments for new authorisations
The requirements for submitting risk assessments on nitrosamines have been clarified and included in the guidance document Formal requirements. Risk assessments should be based on the current state of knowledge.
ZL000_00_020e_WL Guidance document Formal requirements (PDF, 1 MB, 01.06.2025)
Risk assessment for the active substance
- Mandatory for all new authorisations with chemical/synthetic active substances or active substances with synthetic components
- Non-submissions must be substantiated.
- Not required for:
- Veterinary medicinal products
- Co-marketing medicinal products
- Medicinal products for parallel import
- Radiopharmaceuticals
Risk assessment for the finished medicinal product
- Mandatory for all new authorisations.
- Non-submissions must be substantiated.
- Not required for:
- Veterinary medicinal products
- Co-marketing medicinal products
- Medicinal products for parallel import
- Radiopharmaceuticals
- Complementary medicinal products with no indication (notification procedure)
- Teas and lozenges under the notification procedure
The risk assessment documents should be submitted as Additional information, preferably in Module 1 as stated in EMA Q&A (Question 14).
Alternatively, it can also be placed in CTD section 3.2.P.5.6 (Justification of specification). In this case, the placement should be mentioned in the cover letter.