EU GMP Part IV Revision: What ATMP Manufacturers Should Expect

The European Medicines Agency (EMA) has started to revise Part IV of the EU GMP guide, the standalone set of Good Manufacturing Practice rules that applies specifically to Advanced Therapy Medicinal Products (ATMPs). A concept paper agreed by the GMP and GDP Inspectors Working Group in April 2025 sets out why the revision is needed and what it will cover. The short version is that Part IV has stood still while the sterile manufacturing rules around it moved, and the revision will bring it back into line.

For cell and gene therapy developers and their contract manufacturers, this is not a distant academic exercise. The revision will pull the contamination control strategy thinking that reshaped sterile manufacturing into ATMP production, and it will clarify expectations for cleanrooms, closed systems and new technologies. Manufacturers that start aligning now will face a smaller gap when the draft guideline arrives.

Executive summary

EU GMP Part IV is the standalone GMP guideline for ATMPs, adopted in 2017 under the ATMP Regulation. Since then the revised Annex 1 for sterile products came into operation in August 2023, introducing formal quality risk management, the pharmaceutical quality system and the contamination control strategy (CCS). The Part IV revision, described in EMA concept paper EMA/INS/GMP/48771/2025, will align the sterile-manufacture sections of Part IV with Annex 1, clarify how to qualify and control cleanrooms and closed systems such as isolators and restricted access barrier systems, embrace new manufacturing technologies, and update definitions for starting material of human origin. The concept paper proposes a draft guideline in September 2026, a comment period to December 2026, and adoption in March 2027. This article explains the change and how to prepare, including what it means for Canadian sites.

What is changing, and why

What it is: a revision of EU GMP Part IV, the ATMP-specific GMP guideline, to align it with the revised Annex 1. Why it matters: the current Part IV does not reflect the quality risk management, pharmaceutical quality system and contamination control strategy concepts that Annex 1 introduced, or recent manufacturing technology. What to do: read the revision as an alignment exercise, and begin mapping your ATMP quality system to Annex 1 concepts now. How it affects compliance: once the revised guideline is adopted, inspectors will expect ATMP sites to show the same contamination control discipline that sterile manufacturers already apply.

The trigger is the revised Annex 1, which came into operation in August 2023 and made the contamination control strategy a central expectation for sterile products. Because the current ATMP guideline predates that shift, the concept paper concludes that Part IV should be revised so the ATMP sector applies the same modern principles, while keeping the flexibility that individualised, small-batch cell and gene therapy manufacture requires.

What Part IV is and where it sits

What it is: Part IV of EudraLex Volume 4 is a standalone GMP guideline written specifically for ATMPs, which are gene therapy, somatic cell therapy and tissue-engineered products. Why it matters: it is a self-contained reference, so ATMP manufacturers rely on it rather than on the general GMP chapters and annexes. What to do: know that Part IV, not the general Part I, is your primary GMP standard if you make ATMPs.

Part IV was developed under the initiative of the European Commission according to Article 5 of Regulation (EC) No 1394/2007 and was adopted on 22 November 2017. The intent was to bring all requirements for ATMP manufacture into a single guideline, moving away from the former Annex 2 on biological products and the various chapters of Volume 4, so that academia, developers and manufacturers could produce high-quality ATMPs consistently across the European Union. That consolidation was helpful, but it also meant Part IV sat apart from later revisions to the general guide, including Annex 1.

The Annex 1 alignment: what it pulls into ATMP GMP

What it is: the revision will bring the concepts introduced by the revised Annex 1 into the ATMP guideline. Why it matters: these are the same concepts that reshaped sterile manufacturing, so ATMP sites should expect the expectations to rise accordingly. What to do: use the table below to see which Annex 1 concepts are coming and what each means in an ATMP context.

The concept paper is explicit that the revision will keep a flexible approach for ATMP production. It notes that biosafety cabinets remain acceptable because of the many manual manipulations associated with individualised batches, even as the guideline gives clearer expectations for isolators and RABS. The scope is deliberately narrow: the revision focuses on the sterile-manufacture sections that relate to the updated Annex 1, not a wholesale rewrite of every ATMP topic.

Timeline: the concept paper and what comes next

What it is: the schedule set out in the concept paper for producing the revised guideline. Why it matters: it tells you when to expect a draft to review and when the new expectations are likely to land. What to do: treat the dates as the concept paper proposes them, and plan your gap work against the draft rather than the final.

These dates are the concept paper's proposed timetable, not fixed regulatory deadlines, and they can move. The Part IV revision is one item in a broader EU GMP revision programme that also touches Chapter 1, Annex 11, Annex 22 and veterinary GMP. Watching the whole programme, not just Part IV, helps a manufacturer plan quality-system changes once rather than repeatedly.

What ATMP manufacturers should expect in the revised guideline

What it is: the specific changes the concept paper signals. Why it matters: knowing them lets you prepare the right parts of your quality system. What to do: expect the following, and check each against your current documentation.

• A contamination control strategy expectation adapted to individualised ATMP batches, tying together facility, process and personnel controls into one documented strategy.
• Explicit use of quality risk management (ICH Q9) and the pharmaceutical quality system (ICH Q10), rather than a general reference to a risk-based approach.
• Clearer expectations for qualifying, controlling and managing cleanrooms and closed systems, including isolators and RABS, to prevent detrimental impact on product, while keeping biosafety cabinets available for manual manipulations.
• Recognition of new technologies not covered in the current version, such as automated advanced technology, closed single-use systems and rapid microbiological testing methods.
• Updated legal references and definitions for starting material of human origin, following the new regulation on the quality and safety of substances of human origin.

Why this matters for Canadian sites

What it is: EU GMP expectations reach Canadian manufacturers through export and through Health Canada's participation in international GMP cooperation. Why it matters: a Canadian ATMP or biologics site that supplies, partners with, or wants to reach the EU market will be measured against these expectations. What to do: if the EU is in your plans, align to Annex 1 thinking now, the same way sites pursuing EU-GMP certification already do.

The contamination control discipline behind Annex 1 is already where many otherwise compliant sterile sites stumble in inspection, which is exactly why compliant sites fail Annex 1 inspections. ATMP manufacturers that have not yet built a formal CCS will feel that same pressure once the Part IV revision lands. Building the strategy before it is mandatory turns a future finding into current good practice.

How to prepare now

What it is: the practical steps that reduce your gap before the draft guideline arrives. Why it matters: preparation done against Annex 1 concepts will carry over almost entirely into the revised Part IV. What to do: work through the steps below.

• Build or mature a contamination control strategy. Document how facility, equipment, process, personnel and monitoring controls work together to prevent contamination of your ATMP.
• Requalify cleanrooms and closed systems. Confirm your isolators, RABS and single-use systems are qualified and controlled, and that qualification and validation documentation reflects current expectations.
• Strengthen aseptic controls. Review your aseptic processing, including aseptic process simulation, against the risk of the many manual manipulations in ATMP manufacture.
• Formalise QRM and the PQS. Make sure quality risk management drives real decisions and your pharmaceutical quality system maintains a state of control across the life cycle.
• Review starting material controls. Check that your controls and documentation for starting material of human origin will meet updated definitions and legal references.
• Comment on the draft. When the draft guideline is released, submit comments during the consultation so your operational reality is reflected in the final text.

ATMP GMP readiness checklist

• Do you have a documented contamination control strategy covering your ATMP process end to end?
• Are your cleanrooms, isolators and RABS qualified and controlled, with current documentation?
• Does quality risk management (ICH Q9) drive documented decisions, not just a general statement?
• Does your pharmaceutical quality system (ICH Q10) maintain a state of control across the life cycle?
• Are new technologies such as closed single-use systems and rapid microbiological methods validated and controlled?
• Do your starting material controls and definitions align with the regulation on substances of human origin?
• Is someone assigned to review the draft guideline and submit consultation comments when it is released?

Common mistakes

• Waiting for the final guideline. The concepts come from Annex 1, which is already in force, so there is no reason to delay building a contamination control strategy.
• Treating a risk-based statement as quality risk management. A sentence saying you use a risk-based approach is not the systematic ICH Q9 process inspectors will expect.
• Assuming ATMP flexibility means lower expectations. The revision keeps flexibility for manual, individualised batches, but it raises the contamination control bar at the same time.
• Closing contamination investigations without effective CAPA. A CAPA that never proves effectiveness leaves the same root cause to resurface at the next inspection.

Frequently asked questions

What is EU GMP Part IV?

Part IV of EudraLex Volume 4 is the standalone GMP guideline that applies specifically to Advanced Therapy Medicinal Products: gene therapy, somatic cell therapy and tissue-engineered products. It was adopted in 2017 under the ATMP Regulation, Regulation (EC) No 1394/2007.

Why is Part IV being revised?

Because the revised Annex 1 for sterile products, in operation since August 2023, introduced quality risk management, the pharmaceutical quality system and the contamination control strategy. Part IV predates these concepts, so the EMA is revising it to align the ATMP sterile-manufacture sections with Annex 1.

When will the revised Part IV guideline be published?

The concept paper proposes releasing a draft guideline in September 2026, with a comment deadline in December 2026 and adoption in March 2027. These are proposed dates in the concept paper, not fixed regulatory deadlines, and they may change.

What is a contamination control strategy for an ATMP?

It is a documented, facility-wide strategy that ties together every control preventing microbial, particulate and pyrogen contamination, adapted to the manual, individualised nature of ATMP batches. It is the same CCS concept Annex 1 requires for sterile products.

Will biosafety cabinets still be allowed?

Yes. The concept paper states the revision will keep biosafety cabinets available because of the many manual manipulations in individualised ATMP manufacture, while giving clearer expectations for isolators and restricted access barrier systems.

Does this affect Canadian ATMP manufacturers?

Yes, if they supply or plan to reach the EU market or partner with EU sponsors. EU GMP expectations reach Canadian sites through export and international GMP cooperation, so aligning to Annex 1 concepts now is prudent for any Canadian ATMP or biologics manufacturer with EU ambitions.

How MFLRC can help

MFLRC helps cell and gene therapy manufacturers get ahead of the Part IV revision. We run ATMP GMP gap assessments against the revised Annex 1 concepts, develop contamination control strategies for individualised batches, write and update qualification and validation documentation for cleanrooms and closed systems, build quality risk management and pharmaceutical quality system frameworks, prepare GMP inspection readiness assessments, and support sites pursuing EU-GMP certification. We also draft consultation submissions so your operational reality is reflected in the final guideline.

If you manufacture ATMPs or plan to, the Part IV revision is a chance to build good contamination control now rather than under inspection pressure later. Contact MFLRC at info@mflrc.com or +1-647-492-5301 for an ATMP GMP gap assessment.

Conclusion

The EU GMP Part IV revision is an alignment exercise, but not a minor one. It will bring the contamination control strategy, quality risk management and pharmaceutical quality system thinking of the revised Annex 1 into ATMP manufacture, along with clearer cleanroom and closed-system expectations and recognition of new technologies. The concepts are already in force through Annex 1, so the manufacturers that prepare now will meet the draft guideline from a position of strength rather than scrambling to close a gap under inspection.

Sources and references

• EMA, Concept paper on the revision of Part IV Guidelines on GMP specific to ATMPs (EMA/INS/GMP/48771/2025)
• European Commission, EudraLex Volume 4, Annex 1 Manufacture of Sterile Medicinal Products (2022)
• Regulation (EC) No 1394/2007 on advanced therapy medicinal products, EUR-Lex
• ICH Quality Guidelines (including Q9 Quality Risk Management and Q10 Pharmaceutical Quality System)