EudraLex Volume 4 guide to EU GMP parts, annexes and US cGMP

EudraLex Volume 4, the EU GMP guide explained

EudraLex Volume 4 is the European Commission's GMP guide for human and veterinary medicines, formally the EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. National competent authorities use it when they assess manufacturing-authorisation applications and when they inspect manufacturers. It has four parts, numbered annexes and a glossary.

It is part of the Commission's collection, "The Rules Governing Medicinal Products in the European Union". The Volume 4 page lists the GMP legislation and the guidelines. Its latest update is dated 21 October 2026.

What the EudraLex EU GMP guidelines are for

The guide applies to operations that need a manufacturing authorisation, and it is relevant to manufacturing in hospitals. Worker safety is out of scope (Commission).

Other methods are acceptable if they reach at least an equivalent level of quality management. But GMP compliance is mandatory for a manufacturing or import authorisation (EMA). The word "should" does not make compliance optional.

The legal basis behind the guide

Binding GMP principles sit in EU law. Volume 4 interprets them. Older copies of the Introduction still name Directive 2003/94/EC. For human medicines, Directive (EU) 2017/1572 repealed that directive. The current basis is:

• Human medicines: Directive (EU) 2017/1572.
• Investigational medicinal products: Delegated Regulation (EU) 2017/1569, under the Clinical Trials Regulation (EU) No 536/2014.
• Active substances for human medicines: Delegated Regulation (EU) No 1252/2014.
• Veterinary medicines: Regulation (EU) 2019/6, with GMP set by Implementing Regulation (EU) 2025/2091 for finished products and Implementing Regulation (EU) 2025/2154 for active substances. Both are dated 17 October 2025, and both have applied since 16 July 2026. The Commission describes veterinary GMP as "aligned with" human GMP.

Implementing Regulation (EU) 2026/857 amends 2025/2091 on retention samples for products repackaged for parallel trade. It has applied since 16 July 2026.

The four parts of EU GMP Volume 4

The guide first appeared in 1989 and reached its four-part shape with Part IV in 2017 (Commission).

Part I for medicinal products

Part I has nine chapters. Each opens with a principle, then gives detailed guidance (Commission):

1. Pharmaceutical Quality System
2. Personnel
3. Premises and Equipment
4. Documentation
5. Production
6. Quality Control
7. Outsourced Activities
8. Complaints, Quality Defects and Product Recalls
9. Self Inspection

Part II for active substances

Part II covers active substances used as starting materials. It is based on ICH Q7. The former Annex 18 became the basis of Part II, and the current text has been in operation since 1 September 2014.

Part III for GMP-related documents

Part III clarifies regulatory expectations rather than setting detailed guidelines under the directives. It includes the Site Master File, ICH Q9(R1) on quality risk management (effective 26 July 2023) and ICH Q10. Other documents cover MRA batch certificates, written confirmation for active substances exported to the EU, shared-facility exposure limits, excipient risk assessment and investigational-medicine templates.

Part IV for advanced therapy medicinal products

Part IV was adopted on 22 November 2017 and has applied since 22 May 2018. Other Volume 4 documents apply to ATMPs only where Part IV refers to them. Annex 2 no longer applies to ATMPs.

The EU GMP annexes

The annexes cover specific activities. More than one can apply to the same process: sterile radiopharmaceutical manufacture falls under both Annex 1 and Annex 3. The Commission page currently lists these texts:

The revised Annex 1 applied from 25 August 2023, except point 8.123, which applied from 25 August 2024. The Annex 13 slot now holds the Commission guideline of 8 December 2017 under the Clinical Trials Regulation. Annex 21 covers human, investigational and veterinary imports.

Annex 19 was revised by C(2026) 4135 and applies since 24 September 2026. It now covers samples for parallel imported, distributed and traded products. It also allows controlled use of photographic or digital retention samples, with the competent authority's agreement.

The numbering has gaps, which is a nuisance if an old procedure still cites Annex 4 or 5. Annexes 4, 5, 18, 20 and 22 are absent from the current EU list. Annexes 4 and 5 were the veterinary annexes, and they still appear in the PIC/S GMP Guide. Annex 18 became Part II.

Revisions in progress

Several revisions remain unfinished as of 25 October 2026. A joint consultation ran from 7 July to 7 October 2025 on Chapter 4, Annex 11 and a new Annex 22 on artificial intelligence. No final text has been posted. The January 2011 Chapter 4 and Annex 11 still apply (Commission).

A revised Chapter 1 went to consultation from 3 September to 3 December 2025 and remains a draft. A concept paper for revising Annex 15 went to consultation in 2026. The 2015 Annex 15 remains in force (Commission).

Who applies the EU GMP guide

National competent authorities inspect sites on their own territory. Outside the EU, the authority of the importer's Member State inspects, unless a mutual recognition agreement applies. EMA coordinates inspections for centrally authorised products and chairs the GMP/GDP Inspectors Working Group (EMA). EudraGMDP has been public since 2011. It holds manufacturing, import and wholesale authorisations, GMP and GDP certificates, non-compliance statements and active substance registrations.

PIC/S describes its GMP requirements and EU GMP requirements as practically identical. Its current edition, PE 009-18, entered into force on 24 September 2026 and includes revised Annex 19.

For UK readers, the Windsor Framework explainer says EU GMP applies in Northern Ireland. In Great Britain, it applies as modified by Schedule 2A of the Human Medicines Regulations 2012. GB uses the EU guidance as it stood at the end of the transition period. Don't assume a later EU revision applies there on its own.

The MHRA GMP and GDP page points manufacturers to EU Volume 4 and the Orange Guide. A manufacturer's licence holder must have at least one Qualified Person (regulation 41).

EU GMP guidelines vs US cGMP guidelines

Both systems require GMP compliance. In the US, 21 CFR 210.1 sets the minimum current good manufacturing practice in Parts 210, 211, 213, 225 and 226. Non-compliance makes a drug adulterated under section 501(a)(2)(B) of the FD&C Act. The FDA overview also lists the Part 600s for biologics and Part 11 for electronic records.

Phase 1 investigational drugs are exempt from Part 211 (21 CFR 210.2(c)). In the EU, investigational products follow Delegated Regulation 2017/1569 and the Annex 13 guideline on the Commission page.

A practical difference is batch release for human medicines. In the EU, a Qualified Person certifies every batch under Article 51 of Directive 2001/83/EC. The QP records certification in a register or equivalent document kept for at least five years. Batches from third countries get a full qualitative and quantitative analysis in the EU unless an MRA applies (Article 51). Annex 16 sets out the process. In the US, the quality control unit has authority to approve or reject drug products.

The EU-US mutual recognition agreement has been in force since 1 November 2017. For most human medicines it has been fully operational since 11 July 2019. The EU can waive batch re-testing on import for covered products, but QP certification still applies. Blood and plasma, tissues and organs, veterinary immunologicals and ATMPs are outside the scope. Human vaccines and plasma-derived products are not yet included, and no date is set. The veterinary agreement has been in force since 30 May 2023 and fully operational since 29 May 2026.

RegAffairs AI's answer on EudraLex Volume 4 covers the parts, annexes and US comparison with citations to stored source documents.