EMA adopted a revised Guideline on the chemistry of active substances (EMA/CHMP/QWP/49484/2026), published on 20 March 2026 and now the current effective version. It is the first substantive revision since the guideline was consolidated in 2016, and it lands on three areas that have caused more dossier deficiencies than almost anything else in the quality section: nitrosamines, starting materials, and recovery and reprocessing.
What the revision covers
According to EMA, the 2026 revision was made to include further recommendations on cohort-of-concern impurities — principally N-nitrosamines — and to expand the sections covering starting materials, recovery and re-processing. The guideline continues to describe the information required for the manufacture and control of active substances, whether existing or new chemical entities, in an application made under Directive 2001/83/EC.
The revised text followed a concept paper consulted on in 2022 and a draft released for public consultation between 25 July 2024 and 31 January 2025.
Why these three areas
Cohort-of-concern impurities. Nitrosamines have moved from crisis response to a permanent feature of active substance control. Bringing specific recommendations into the chemistry guideline — alongside ICH M7 on mutagenic impurities — means the expectation is now embedded in the dossier rather than handled through ad hoc requests for information.
Starting materials. The justification of the proposed starting material is one of the most persistently contested parts of a drug substance dossier. Where a company sets the boundary determines how much of the synthetic route sits under GMP and how much of it a regulator ever sees. Expanded guidance here reduces the room for optimistic interpretation.
Recovery and reprocessing. Recovering solvents and reagents, and reprocessing material that has failed to meet specification, are normal industrial practice. The problem has always been describing them honestly in the dossier. Where reprocessing is routine, it belongs in the process description, not in a deviation file.
What this means for dossiers in preparation
- Module 3.2.S sections on starting material justification should be reviewed against the revised text before submission, not after a first round of questions.
- Nitrosamine risk assessments should be traceable into the active substance control strategy, not held as a separate exercise.
- Where recovery or reprocessing occurs, the process description and the validation package need to match what the site actually does.
- Active Substance Master File holders should expect assessors to apply the revised expectations, which has knock-on effects for applicants relying on an ASMF they do not control.
- The Qualified Person declaration on GMP compliance of active substance manufacture should be consistent with the route as described.
The wider point about quality guidelines
Guidelines of this kind are not only submission documents. Inspectors read them. When a guideline expands its treatment of reprocessing, a site that treats reprocessing as an undocumented exception has both a dossier problem and a GMP problem — and the two are usually discovered together.
How PQRA helps
We review drug substance dossiers against current EU quality guidelines before submission, prepare and defend starting material justifications, build nitrosamine risk assessments that connect to the control strategy, and align the dossier description with what the manufacturing site actually does — so that the quality section survives both assessment and inspection.
If you are preparing or updating an active substance dossier, talk to our regulatory and quality teams.
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