The EU GMP Part IV ATMP revision — the update of the GMP guidelines specific to advanced therapy medicinal products — is officially under way: with concept paper EMA/INS/GMP/48771/2025, EMA's GMP/GDP Inspectors Working Group has started aligning Part IV with the 2022 Annex 1, introducing the Contamination Control Strategy, ICH Q9 and Q10 and updated requirements for closed systems and new technologies. For anyone manufacturing cell therapies, gene therapies or tissue-engineered products, it is the most significant regulatory change since 2018: it pays to understand now what will change and what to prepare before the draft arrives.
Why the EU GMP Part IV ATMP revision is coming
Part IV of EudraLex Volume 4 ("Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products") was adopted by the European Commission in November 2017 and has applied since 2018. It was conceived as a standalone, risk-based framework built around ATMP specificities: individual batches, starting materials of human origin, manual manipulations, very short shelf lives.
Since then, however, the reference framework for sterile manufacturing has changed radically. The revised Annex 1, in operation since August 2023, redefined requirements and inspection expectations on the Contamination Control Strategy (CCS), cleanroom qualification, barrier technologies (isolators and RABS), environmental monitoring and Aseptic Process Simulation. Part IV, frozen in 2017, does not reflect these concepts, does not incorporate ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System), and does not adequately cover technologies now common in advanced therapy manufacturing. The practical result: manufacturers and inspectors currently navigate between two misaligned texts, with diverging interpretations on the points most critical to sterility.
The affected audience is wider than it looks: not only ATMP manufacturing authorisation holders, but also CDMOs manufacturing on behalf of clients, hospital and academic facilities producing under exemption, and suppliers of human-origin starting materials. QPs certifying ATMP batches will also need to realign their release criteria with the new text, because sterility rationales acceptable today may no longer be tomorrow.
What the EMA concept paper proposes
The concept paper, under public consultation from 8 May to 8 July 2025, sets a precise scope: the revision concerns the sterile manufacturing sections, not the whole of Part IV. The announced areas of intervention are these:
| Revision area | What changes in practice |
|---|---|
| Annex 1 alignment | Sterile manufacturing requirements harmonised with the 2022 text, while keeping flexibility for ATMP specificities |
| Contamination Control Strategy | Formal introduction of the CCS as the document summarising the site's contamination controls |
| ICH Q9 and Q10 | Integration of Quality Risk Management and the Pharmaceutical Quality System into the text |
| Cleanrooms and barrier systems | Clarified expectations on qualification and management of cleanrooms, isolators and RABS; biosafety cabinets remain permitted for the manual manipulations of individual batches |
| New technologies | Automated systems, closed single-use systems and rapid microbiological methods |
| Human-origin materials | Legal references and definitions updated to the SoHO Regulation (EU) 2024/1938, applicable from 7 August 2027 |
Two messages in the concept paper deserve attention. First: Annex 1 alignment will not be a mechanical transposition, because EMA recognises that ATMP manufacturing requires a flexible approach. Second: the confirmation of biosafety cabinets is a deliberate choice, justified by the manual, individualised nature of many cell-based operations, and clearly distinguishes Part IV from Annex 1's barrier-first philosophy.
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The expected timeline
The timeline indicated in the concept paper includes these steps:
- 11 March 2025 — publication of the concept paper (agreed by the GMP/GDP IWG on 15 April 2025).
- 8 May – 8 July 2025 — public consultation on the concept paper.
- September 2026 — planned release of the draft revised guideline.
- December 2026 — expected deadline for stakeholder comments on the draft.
- March 2027 — planned adoption by the GMP/GDP IWG.
The dates after the concept paper are planned and may slip, as often happens in EudraLex revision processes. The operational point stands: between draft, consultation and adoption, the useful window to prepare is now, not when the final text is published. Remember also the parallel track of the SoHO Regulation: from 7 August 2027, blood, tissues and cells used as starting materials will be governed by Regulation (EU) 2024/1938, which replaces Directives 2002/98/EC and 2004/23/EC, and the revised Part IV will incorporate its definitions and references.
What to prepare today: 5 concrete actions
- Part IV vs Annex 1 gap assessment. Compare your sterile manufacturing procedures with the 2022 Annex 1 requirements: area classification and qualification, environmental monitoring, APS, gowning. Document where current practice relies on Part IV flexibility and with what risk rationale.
- A formalised CCS. If your site does not yet have a documented Contamination Control Strategy, it is the highest-return investment: it will be explicitly required and is already an established inspection expectation today.
- Rationales for biosafety cabinets and open systems. The BSC remains permitted, but expect more pointed questions on risk justification, first air, airflows and monitoring: strengthen your documented rationales now.
- A dossier for closed and single-use systems. Inventory closed systems, single-use and automation: integrity, extractables/leachables, validation of sterile connections. These will be explicit chapters of the new text.
- Mapping of human-origin materials. Review agreements and qualifications with tissue establishments and blood centres from a SoHO perspective: ownership of activities, donor-to-batch traceability, import requirements.
GuideGxP recommendation
Treat the Part IV revision as a regulatory change control project, not as news to monitor: open an assessment now with owners and deadlines, using the concept paper as the index of the chapters that will change. Also plan your participation in the consultation on the expected draft: commenting at draft stage is the only moment when your process specificities can still make it into the text, and it is an activity QA and Regulatory should budget for already. Those who have implemented Annex 1 well have most of the work done; those manufacturing ATMPs relying on the flexibility of the 2017 Part IV must demonstrate, with data in hand, that this flexibility survives the new text. In both cases, the CCS is the document that holds everything together.
To set the work on solid foundations, GuideGxP's Operational Guide to GMP Annexes 1, 15, 16 and 20 – With Best Practices covers precisely the Annex 1 requirements (CCS, qualification, APS) that Part IV is aligning with, including ready-to-use checklists and tools.
Official sources
- EMA – Concept paper on the revision of Part IV GMP Guidelines specific to ATMPs (EMA/INS/GMP/48771/2025)
- European Commission – EudraLex Volume 4 (Part IV: GMP for ATMPs)
- European Commission – EU GMP Annex 1: Manufacture of Sterile Medicinal Products (2022)
- Regulation (EU) 2024/1938 on substances of human origin (SoHO)
