EMA: Updated Guideline on Active Substance Chemistry
The EMA has updated guidance on the information required for the manufacture and control of active substances used in medicinal products, with a 1 September 2026 date of application.
The Guideline on the chemistry of active substances was revised to include further recommendations on cohort of concern impurities, principally N-nitrosamines, and expand the sections covering starting materials, recovery and re-processing.
What’s new compared to the 2016 guideline?
1. Strong focus on nitrosamines & mutagenic
impurities
The new guideline explicitly requires:
- Assessment of nitrosamine risks across the entire process
- Consideration of “cohort of concern” impurities (ICH M7)
- Implementation of robust control strategies
2. Much deeper process understanding expected
Compared to the previous version, companies now need to provide:
- Full process transparency, including all materials (e.g. gases, quenching agents, depletion agents)
- Quantitative information (e.g. molar equivalents, excess reagents)
- Clear process flow diagrams and step-by-step descriptions
3. Expanded requirements for starting materials
- Stronger justification of starting material selection
- Mandatory evaluation of impurity carry-over, especially mutagenic impurities
- Nitrosamine risk assessment already at starting material level
- Increased regulatory scrutiny of supplier and manufacturing changes
4. Tightened rules for reprocessing & recovery
- Clear distinction between routine vs. occasional reprocessing
- Reprocessing must be part of the validated process if frequently used
- Recovery of materials must be risk-assessed
- Use in late stages (e.g. final step) is discouraged unless justified
5. Explicit control strategy required (aligns with ICH
Q11)
The new guideline introduces a clear expectation to:
- Describe the overall control strategy (not just individual controls)
- Link process understanding, impurity risks, and specifications
- Justify decisions based on scientific rationale and risk assessment
6. Analytical expectations increased
- Methods must be sensitive enough for toxicologically relevant limits
- Specific expectations for nitrosamine detection (Limit of Quantitation, LOQ)
- Stronger link between analytics and control strategy
Source:
EMA: Chemistry of active substances (chemistry of new active substances) - Scientific guideline
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