EMA’s Updated Guideline on the Chemistry of Active Substances: What API Makers Should Check
On September 1, 2026, a revised European Medicines Agency (EMA) quality guideline began to apply to chemical active substances. If you manufacture, buy or register APIs for the EU market, the EMA guideline chemistry of active substances sets out what the dossier is expected to say about how an API is made and controlled. This update puts more emphasis on starting materials, reprocessing and recovery, and N-nitrosamine impurities. This guide summarises the points that matter most to API makers and buyers, and what to check with your regulatory team.
This is a plain-English summary of the EMA guideline and trade-press coverage. It is not regulatory advice. Always read the guideline itself and confirm how it applies to your products and dossiers.
The Quick Answer
- What it is: The EMA “Guideline on the chemistry of active substances” (EMA/CHMP/QWP/49484/2026), which sets out the information needed on the manufacture and control of chemical active substances in a medicinal product dossier.
- When it applies: From September 1, 2026. It was adopted by the CHMP on February 16, 2026 and replaces the 2016 version (EMA/454576/2016).
- What stands out: Clearer expectations on how starting materials are chosen and justified, how reprocessing and recovery are described, and how nitrosamine and other mutagenic impurity risks are assessed and controlled.
- Who it touches: Marketing authorisation applicants, and the API manufacturers who supply the data, including through an Active Substance Master File (ASMF) or a Certificate of Suitability (CEP).
The Basics
| Item | What the guideline states |
|---|---|
| Title and reference | Guideline on the chemistry of active substances, EMA/CHMP/QWP/49484/2026 |
| Adopted | CHMP, February 16, 2026 (agreed by the Quality Working Party on January 20, 2026) |
| Applies from | September 1, 2026 |
| Replaces | The 2016 guideline, EMA/454576/2016 |
| Covers | Existing and new chemical active substances used in medicinal products |
| Excludes | Herbal, biological and biotechnological products, radiopharmaceuticals and radiolabelled products |
| Dossier routes | The marketing authorisation application. An ASMF or a CEP can be used as an alternative route for active substance data, with the same requirements |
| Structure | Follows CTD module 3.2.S (general information, manufacture, characterisation, control, reference standards, container closure, stability) |
What Is New or Emphasised
Trade-press summaries (RAPS, March 2026, and ECA, April 2026) describe the final guideline as largely similar to the 2024 draft, with the update originating from a 2022 EMA proposal prompted by nitrosamine findings in sartans and other APIs. The areas that API makers are likely to focus on:
| Area | What the guideline says (summarised) |
|---|---|
| Starting materials | The applicant must propose and justify the starting material. Non-isolated compounds are not considered appropriate. Impurity carry-over, including mutagenic impurities, must be discussed, and nitrosamine formation or carry-over risk in starting material synthesis must be evaluated |
| Reprocessing | Must follow ICH Q7 or EU GMP Part II. If used for most batches, it should be part of the standard process. Occasional reprocessing must be described and justified |
| Recovery of materials and solvents | Acceptable under ICH Q7 or EU GMP Part II. Recovered materials should be shown clearly in the process description. Use in the same process, preferably the same step, is recommended, and use in the final step needs justification |
| Re-working | The guideline states that re-working procedures should not be included in the dossier |
| Impurities | The maximum daily dose, route of administration and treatment duration used to develop the control strategy and specification should be presented. Potential mutagenic impurities, including nitrosamines, must be discussed |
| Nitrosamine analysis | The limit of quantification should be at or sufficiently below the toxicologically required limit |
Starting Materials: Where Questions Start
Starting materials are where the API’s regulatory story begins, so the guideline’s wording here matters to both API makers and dossier owners. In practice, expect questions on:
- Why this compound was chosen as the starting material, and how it relates to the API’s structure.
- Whether it is isolated. The guideline says non-isolated compounds are not appropriate.
- What impurities could carry through the process, and how they are controlled.
- Whether any step in the starting material’s own synthesis creates nitrosamine risk.
If you want a refresher on why tracing materials upstream matters, see our post on API supply chain fragility.
Reprocessing and Recovery: Be Precise in the Description
The guideline distinguishes routine from occasional reprocessing. If reprocessing happens for most batches, it belongs in the standard process description. If it is occasional, the dossier should describe it and the criteria for when it can be done. Recovered solvents, reactants and intermediates should be clearly shown in the process description or block flow diagram, with their impurity risk assessed.
Impurities and Nitrosamines
The guideline asks for a specific discussion of potential mutagenic impurities, including nitrosamines, with control strategies following ICH M7 where a mutagenic impurity is likely. It also asks applicants to show the maximum daily dose, route and duration used to develop the control strategy. For nitrosamines, analytical methods need to be sensitive enough relative to the required limit. For background on the topic, see our post on nitrosamine impurities in APIs.
EMA Guideline Chemistry of Active Substances: A Checklist for API Makers
Use this as a conversation starter with your regulatory team. It is a general checklist, not a statement of what the guideline requires for any one product.
- Map your dossiers. List which products have an ASMF, a CEP or data supplied directly to applicants for the EU market.
- Check how the guideline applies to your submissions. Ask your regulatory team how the September 1, 2026 date and the guideline’s scope apply to your existing and new submissions. We did not find transition details in the sources we reviewed.
- Review starting material justifications. Confirm each is isolated, well characterised and justified, and that impurity carry-over has been assessed.
- Review nitrosamine risk at starting-material level. Check whether any step in the supply chain creates a risk.
- Review process descriptions for reprocessing and recovery. Make sure routine and occasional steps are described accurately, and that recovered materials are shown.
- Check analytical methods. Confirm that LOQ for nitrosamines is at or below the relevant limit.
- Align the control strategy. Check that the process description, impurity discussion and specification tell one consistent story.
- Set a change-control routine. Agree how you will notify customers of process, site or material changes.
What Buyers Can Ask Their API Supplier
- Which dossier route (ASMF, CEP or other) supports your product for the EU, and what is its status?
- How are starting materials selected and justified, and where do they come from?
- Is reprocessing or solvent recovery used, and how is it described and controlled?
- What has been done to assess nitrosamine risk across the process, including starting materials?
- What method sensitivity is used for nitrosamine testing?
- How do you notify customers of changes?
Chemox Pharma’s Perspective
Chemox Pharma is a WHO-GMP certified manufacturer of APIs and intermediates, with its own facility and in-house R&D centre in Dahej, Gujarat. If you are preparing or updating an EU dossier, our team can discuss the documentation available for the specific API you need and answer questions about our manufacturing steps. Documentation and regulatory status vary by product, so please confirm the details for your product with us directly.
Request a Quote and Documentation
If you are sourcing an API or intermediate for an EU-bound product and want to discuss documentation, contact Chemox Pharma for a quote and documentation review.
FAQs
Q: What is the EMA guideline on the chemistry of active substances?
It is an EMA quality guideline (EMA/CHMP/QWP/49484/2026) that sets out the information needed on the manufacture and control of chemical active substances in a medicinal product dossier. It applies from September 1, 2026 and replaces the 2016 version.
Q: When does the EMA guideline chemistry of active substances apply?
It applies from September 1, 2026. The CHMP adopted it on February 16, 2026.
Q: Does it apply to existing active substances as well as new ones?
The guideline states that it covers information for existing and new chemical active substances. We did not find transition details in the sources we reviewed, so check with your regulatory team how it applies to existing submissions.
Q: What does it say about nitrosamines?
It asks for a specific discussion of potential mutagenic impurities, including nitrosamines, evaluation of nitrosamine risk in starting material synthesis, and analytical methods with a limit of quantification at or sufficiently below the toxicologically required limit.
Q: Does it affect ASMF and CEP holders?
The guideline says an ASMF or a CEP can be used as an alternative route for active substance data, with the same requirements. API manufacturers who hold or supply data through those routes should review the guideline with their regulatory team.
