On 20 March 2026, the EMA published a revision to the 2016 Guideline on the Chemistry of Active Substances, following public consultation in 2025, which will be effective from 01 September 2026.
The guideline details the information required for the manufacture and control of active substances used in a medicinal product, covering existing or new chemical entities.
The revisions are mainly centred on the manufacture of the drug substance, control of materials and the characterisation of impurities. They also reflect recent developments and improved understanding of the formation of N-nitrosamines and the implementation of adequate risk mitigation measures to reduce their potential presence. The updated guidance is also applicable to compounds within the ‘cohort of concern’, mutagens that display extremely high carcinogenic potency according to ICH M7, and more generally to other potent toxins.
Manufacture
A more comprehensive description of the manufacturing process of the active substance should be included:
- Schematic representation should cover the entire manufacturing process and each intermediary process stage/step.
- Molecular weights of starting materials, intermediates and the active substance should be stated.
- All materials used in the process should be disclosed, including depletion agents, recovered materials and materials used for quenching or work-up.
In addition, more stringent requirements are provided for the reprocessing and recovery of materials, which must be conducted in line with ICH Q7 guideline or Part II of the EU Good Manufacturing Practice Guide:
- Distinction is made between routine and occasional reprocessing, with routine reprocessing now required to be stated in the manufacturing process.
- Impact of the use of recovered materials should form part of the overall risk assessment, and a discussion regarding impurities focussing on potential impurities of concern should be included.
- Use of recovered materials in the final stages of manufacture should be avoided unless justified.
Significant updates have also been made on how the development of the manufacturing process should be detailed, which aids understanding of the control strategy of the active substance:
- Justification for the selected manufacturing process and parameters for each manufacturing step and for each sub-step in telescoped processes with non-isolated intermediates must be provided.
- Presence of potentially mutagenic impurities, particularly ‘cohort of concern’ compounds, and other potent toxins originating from intermediates and intentionally introduced materials should be discussed.
- Detailed description of the individual elements of the control strategy and a summary of the overall active substance control strategy, as detailed in ICH Q11, should be included.
- Efforts to minimise the risk of nitrosamine formation in the process should be guided by the European Q&A document, in which the risk factors together with the measures for risk mitigation and principles of control strategies are listed.
Control of Materials
More clarity is provided on how materials used in the manufacture of the active substance should be controlled and greater emphasis is placed on justifying the selection of the starting material(s):
- All materials used in the manufacture of the active substance should be stated with their intended function.
- The risk of formation and carry-over of nitrosamines and/or their precursors during the starting material synthesis should be evaluated during selection.
- Distinction is made regarding the origin of the starting materials. Different requirements are provided for starting materials of animal or human origin, herbal origin or for semi-synthetic active substances.
Characterisation of Impurities
More comprehensive guidance on the risk of presence of mutagenic impurities and how these should be controlled is provided:
- The maximum daily dose (MDD), route of administration and treatment duration considered during the development of the control strategy should be stated.
- Potential mutagenic impurities including nitrosamines and, where applicable, the risk of presence of compounds within the ‘cohort of concern’ or other potent toxins should be specifically discussed.
- Control strategy must be demonstrated to be in compliance with ICH M7.
- Analytical methods should be suitably sensitive to be able to adequately detect and quantify impurities.
- Limit of Quantitation (LOQ) for nitrosamines should be set at or sufficiently below the toxicologically required limit.
Conclusion
Overall, the revisions to the guideline focus on prevention, risk mitigation and control of N-nitrosamines, and other mutagenic impurities. Marketing Authorisation Holder’s are required to develop their control strategy for these impurities in full compliance with ICH M7 so that the risk of formation of mutagenic impurities is adequately considered during development, manufacture and evaluation of the active substance.
How can S-cubed help you?
S-cubed can provide regulatory support for Module 3 dossier content, including gap analysis and authoring modules from source data. We can also prepare and submit Active Substance Master Files (ASMFs) and Certificates of Suitability to the Monographs of the European Pharmacopoeia (CEPs) to the relevant authorities.
Any Questions?
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