Revisit: EMA guideline on active substances - what changed at final adoption

In this follow-up to our January 2025 blog, Rachael O’Kane, Senior Manager at G&L, revisits the EMA guideline on the chemistry of active substances following its transition from draft to final adopted text.

This update confirms which anticipated changes have been retained and highlights where additional clarity has been introduced.

Background

In our January 2025 blog, Updates and impacts: Understanding the EMA’s revised guideline on active substances, we examined the draft guideline on the chemistry of active substances (EMA/321776/2024).

The consultation closed in January 2025, and the guideline was finalised in February 2026 following adoption by the EMA’s Quality Working Party (QWP) and CHMP.

Key procedural points for manufacturers are:

• Final reference: EMA/CHMP/QWP/49484/2026 (replacing draft EMA/321776/2024)
• Effective date: 1 September 2026
• Replaces: EMA/454576/2016

Encouragingly, most of the changes highlighted in our earlier analysis have been retained largely as anticipated. The continued focus on N-nitrosamines and “cohort of concern” impurities, enhanced Starting Material requirements, and the emphasis on control strategy under ICH Q11 remain central to the final text.

This is reflected in the guideline’s executive summary, which confirms that the revision introduces further recommendations on cohort of concern impurities (principally N-nitrosamines) and expands expectations relating to starting materials, recovery, and reprocessing.

The detailed nitrosamine control provisions discussed previously, including the LOQ standard and routine testing exemption, remain unchanged. This article therefore focuses on the additional clarifications and changes introduced in the final version.

What’s new in the final text

Legal basis: The final guideline now references only Directive 2001/83/EC (human medicinal products). The previous reference to the repealed veterinary Directive 2001/82/EC has been removed.

Scope – inclusion of ICH Q13: ICH Q13 (continuous manufacturing) is now explicitly included alongside ICH Q8–Q11, both in the general scope and in relation to the structure of sections 3.2.S.2.2 to 3.2.S.2.6. This provides a clear regulatory framework for companies adopting continuous manufacturing approaches.

Section 4.2.2 – schematic representation: Three notable updates are introduced:

• Processing aids must now be included in reaction schemes alongside reagents, catalysts, and solvents.
• Block flow diagrams shift from a preferred element to a default expectation, except for simple processes.
• Abbreviations for reagents and solvents must be explicitly defined, rather than simply avoiding non-standard terms.

Section 4.2.2 – procedural narrative: The sequential narrative must now explicitly describe additional physical treatments, such as micronisation, alongside each manufacturing step.

Section 4.2.2 – reprocessing: The final text introduces a clearer distinction between routine and occasional reprocessing. Where reprocessing is used for the majority of batches, it must be incorporated into the approved manufacturing process and aligned with ICH Q7 and EU GMP Part II. Only exceptional reprocessing should be justified case by case within the dossier.

Section 4.2.3 – Starting Material sites: The wording now refers to “starting material manufacturing sites” rather than “manufacturers,” clarifying that variations are triggered by site-level changes.

Section 4.2.3 – nitrosamine risk: Risk evaluation is expanded to include nitrosamine precursors, not just nitrosamines. Where a risk is identified in a Starting Material, the corresponding discussion in section 3.2.S.3.2 must also be updated, introducing a clear cross-referencing requirement.

Section 4.2.3 – origin of Starting Materials: For materials of animal, human, or herbal origin, information on geographical origin, extraction processes, and (for herbal materials) collection, cultivation, and post-harvest treatment now moves from optional to expected. This reflects a shift from discretionary to standard submission requirements.

Section 4.3.1 – reduced structure elucidation: The scope for reduced structure elucidation is narrowed from “existing active substances” to “pharmacopoeial active substances,” providing a more precise and objective criterion.

Section 4.3.2 – impurities: A new opening requirement has been introduced: the maximum daily dose (MDD), route of administration, and treatment duration must be stated and cross-referenced within the dossier. This provides assessors with a clear exposure context for evaluating impurity control strategies.

Implications for the pharmaceutical industry

Benefits:

• Regulatory certainty: Finalisation of the guideline and confirmation of the effective date enable structured planning against a fixed target.
• Clearer control strategy expectations: The combined emphasis on nitrosamines, reprocessing thresholds, and explicit MDD/route/duration requirements provides a more defined basis for justification.
• Support for continuous manufacturing: The inclusion of ICH Q13 establishes a clear regulatory reference point.
• Reduced ambiguity: Stronger wording on Starting Materials and precursor risk reduces reliance on interpretation.

Challenges:

• Fixed implementation timeline: The 1 September 2026 effective date sets a firm compliance deadline.
• Increased documentation requirements: Additional expectations around exposure parameters, precursor risk, and origin data will require updates to existing dossiers and templates.
• Process description updates: Manufacturers using routine reprocessing must formally integrate it into standard process descriptions rather than treating it as an exception.

Conclusion

The adoption of EMA/CHMP/QWP/49484/2026 confirms that the overall direction signalled during consultation has been maintained, while introducing greater clarity in several key areas.

Particular attention should be given to the clarified reprocessing expectations, the new requirement to define MDD, route, and treatment duration within impurity strategies, and the expanded requirements relating to nitrosamine precursors and Starting Material origin.

With the guideline coming into effect on 1 September 2026, manufacturers should already be aligning their documentation and control strategies.

This includes reviewing process descriptions against reprocessing expectations, ensuring exposure parameters are clearly defined and cross-referenced, and confirming that Starting Material risk assessments adequately address precursor risks. These steps will support both compliance and the robustness of active substance control strategies across the supply chain.

References

EMA - CHMP, 2026. Guideline on the chemistry of active substances EMA/CHMP/QWP/49484/2026, Amsterdam: EMA.

EMA - CHMP, 2024. (Draft) Guideline on the chemistry of active substances EMA/321776/2024, Amsterdam: EMA.

EMA-CHMP, ICH, 2021. ICH guideline Q13 on continuous manufacturing of drug substances and drug products EMA/CMP/ICH/427817/2021, Amsterdam: EMA.

EMA-CHMP, ICH, 2012. ICH guideline Q11 on development and manufacture of drug substance (chemical and biological entities) EMA/CHMP/ICH/425213/2011, Amsterdam: EMA.