EMA: Reflection Paper on Non-Mutagenic Impurities published

The 'Reflection paper on the qualification of non-mutagenic impurities' was published on the EMA website at the beginning of February 2026. It is intended to supplement the existing guidelines for non-mutagenic impurities (NMI) with regard to qualification and safety assessments and also discusses animal-free methods for more specific determination of impurities.

In addition to a list of common abbreviations, the 'Reflection Paper' includes the following table of contents:

1. Executive summary
2. Introduction
3. Scope
4. Legal basis and relevant guidelines
5. Key considerations
5.1. General outline for risk assessment of NMIs
5.2. Metabolites
5.3. Read across
5.3.1. Surrogate approach
5.3.2. API-like vs. non-API-like impurities
5.3.3. Grouping approach
5.4. Level of concern considerations
5.4.1. Key Factors for Each Step
5.4.2. Exposure level considerations
5.4.3. Clinical considerations
5.5. Acceptable Level calculation
5.6. New approach methodologies
5.6.1. Computational toxicology
5.6.2. In vitro approaches
5.6.3. Adverse Outcome Pathways (AOPs)
5.6.4. Hazard characterisation and quantitative risk estimation
5.7. In vivo qualification studies
5.7.1. Design of in vivo studies
5.7.2. Setting limits based on in vivo data
5.8. Products under clinical development
6. Conclusion
7. References
Annex 1
Annex 2

The 'Reflection paper on the qualification of non-mutagenic impurities' and further information on this topic can be found on the EMA website.