EudraLex Volume 4: What it is, Key annexes, and compliance tips

When your manufacturing line is running smoothly and your paperwork looks in order, you might think you’re “doing GMP”.
Although your pharmaceutical or biotech organization might be compliant, that doesn’t mean you’re not vulnerable.

That’s where one set of guidelines stands out. EudraLex Volume 4 isn’t just a regulatory badge of honour. Volume 4 shapes how medicinal products — human and veterinary — are manufactured, controlled, and delivered. It is the operational blueprint that EU auditors use to judge whether products are reliably safe and effective. However, Eudralex Volume 4 is not a static framework; it is constantly evolving.

In this article, I’ll walk through what Eudralex Volume 4 is, why it differs from other volumes in the EudraLex family, and how you can use it to bring your manufacturing, the supply chain for APIs and medicinal products,  and digital systems into sharper compliance focus.

Key takeaways

What is Eudralex Volume 4?

EudraLex Volume 4 is the EU’s detailed guidelines for Good Manufacturing Practice (GMP) relating to the manufacture of medicinal products for human and veterinary use.

Now that you know what is Eudralex Volume 4, let’s move on to the scope.

Scope of Eudralex Volume 4

Eudralex Volume 4 translates the requirements of EU legislation, specifically Commission Directive (EU) 2017/1572 (human). Commission Delegated Regulation (EU) 2017/1569 for investigational products, and Directive 91/412/EEC (veterinary), into operational expectations.

The volume applies provides the legal foundation for GMP inspections, authorizations, and certification within the EU/EEA. It aims to control the manufacturing risks that cannot be eliminated simply by testing the final product alone

Key differences between Volume 4 and other EudraLex volumes.

Among EudraLex's ten volumes, Volume 4 stands apart as the one entirely dedicated to manufacturing and quality assurance.

The other volumes serve different regulatory domains:

• Volumes 1 & 5 focus on legislative frameworks; human for Volume 1, veterinary for Volume 5.
• Volumes 2 & 6 cover regulatory submission processes
• Volumes 3 & 7 are scientific guideline topics.
• Volume 9 addresses pharmacovigilance (safety monitoring) and,
• Volume 10 outlines clinical-trial guidance.

Scilife Tip:

In contrast to those, Volume 4 is tailored for professionals working in production, quality-control, supply-chain, and manufacturing sites (both human and veterinary).  It concentrates on how products are manufactured and controlled, not just what must be evaluated or approved.

If your role touches manufacturing operations, contract manufacturing, or API supply chains, Volume 4 becomes your primary regulatory benchmark. The other volumes still matter, but they focus on adjacent areas of the pharmaceutical lifecycle.

Recommended learning:

EudraLex- Key FAQs every QA professional should know.

Why Eudralex Volume 4 matters to medicinal products and APIs

EudraLex Volume 4 remains a cornerstone of pharmaceutical regulatory compliance within the EU and EEA. For manufacturers of medicinal products, it serves as the reference framework ensuring uniform standards of quality, safety, and efficacy.

Its principles underpin GMP inspections, import/export authorisations, and batch certification procedures. Failure to comply can result in regulatory findings and the worst consequences that are neither theoretical nor rare.

In the context of active substances (APIs) and starting materials, Volume 4 takes a similarly comprehensive view. It places emphasis on ensuring GMP-equivalent conditions throughout the supply chain, particularly when these materials are destined for medicinal products entering the EU.

Inadequate oversight at the API level invariably introduces quality risks downstream, often with significant implications for patient safety and product integrity.

From a procedural standpoint, aligning internal documentation, training programs, SOPs, and electronic quality management systems with the structure of Volume 4 establishes a clear benchmark.

This alignment not only reinforces regulatory compliance but also enhances audit preparedness and operational consistency, which are critical factors in maintaining credibility with both regulators and clients.

Nowadays, the regulatory landscape is not static. Advances in digital technologies, the rise of AI, and increasingly complex computerised systems are prompting a revision of the framework. Public consultations are already underway concerning updates to Chapter 4 (Documentation), Annex 11 (Computerised Systems), and the proposed Annex 22 (Artificial Intelligence). These revisions reflect the evolving nature of pharmaceutical oversight in the digital age.

Structure of Eudralex Volume 4

EudraLex Volume 4 is divided into three principal sections, complemented by a comprehensive set of annexes that address specific product types and manufacturing practices.

• Part I outlines the foundational GMP requirements for medicinal products. It addresses key operational domains, including the pharmaceutical quality system, personnel responsibilities, facility and equipment standards, documentation protocols, production controls, quality assurance, outsourced activities, complaint handling, product recall procedures, and internal audits.
• Part II focuses specifically on the manufacture of active substances (APIs) used as starting materials. Its requirements are closely aligned with the ICH Q7 guideline, ensuring coherence with international expectations for API quality management.
• Part III serves as a repository for supplementary GMP-related documentation. This includes interpretative materials such as templates, guidance documents, and Q&A resources issued by the European Medicines Agency (EMA) and the European Commission. These documents aim to clarify expectations and support consistent implementation.

The annexes provide targeted guidance for specialised manufacturing contexts and technologies. For instance:

• Annex 1 addresses the manufacture of sterile medicinal products, encompassing contamination control strategies, facility design, cleanroom classification, aseptic processing, sterilisation methods, environmental monitoring, validation practices, and personnel qualifications.
• Annex 2 focuses on biological substances and medicinal products for human use, covering biotechnology-derived products as well as advanced therapies such as cell-based treatments.
• Other annexes explore a range of domains: radiopharmaceuticals (Annex 3), veterinary products (Annexes 4 and 5), medical gases (Annex 6), herbal products (Annex 7), sampling procedures (Annex 8), computerised systems (Annex 11), and qualification and validation (Annex 15), among others.

These annexes are subject to periodic revision, reflecting both technological progress and shifts in regulatory emphasis.

Importantly, Volume 4 is broadly harmonised with international GMP standards, particularly those established by the World Health Organization (WHO), the Pharmaceutical Inspection Co‑operation Scheme (PIC/S), and the International Council for Harmonisation (ICH).

Scilife Tip:

If you want to know what changes are coming in the following months at Eudralex Volume 4, check the 3-year work plan for the Inspectors Working Group from the EMA.

The most searched Eudralex Volume 4 annexes explained

Within EudraLex Volume 4, some annexes consistently attract more attention than others because they hit hard on high-risk areas, reflect major regulatory updates, evolving technologies, or cover complex supply-chain issues.

While hard search‑volume data is not publicly published, consulting and training enquiries suggest the following annexes drive the highest interest: Annex 1, Annex 11, New Annex 22,  and Annex 16.

Below is a walk-through of these high-interest annexes: what they cover, why they matter, and key implications for quality, training, and knowledge management.

Eudralex Volume 4 Annex 1 – Manufacture of Sterile Medicinal Products

Eudralex Volume 4 Annex 1 governs the manufacture of sterile products and has been recently revised to emphasise a formalised Contamination Control Strategy (CCS).

Why interest is high:

Sterile manufacturing remains one of the most challenging and inspection-sensitive areas. Manufacturers and suppliers are actively reviewing their processes and facilities against the updated Annex 1 requirements.

Implications:

• It is not enough to do end-product tests to formulate a contamination strategy across the manufacturing lifecycle. It must be made across the product lifecycle.
• The design and monitoring of facilities and utilities are being scrutinized more closely.
• Training modules should highlight the link between sterility assurance and regulatory expectations under Eudralex Volume 4 Annex 1.

How to prepare for EU GMP Annex 1

Eudralex Volume 4 Annex 11 computerized systems

Eudralex Volume 4 Annex 11 sets out the GMP expectations for computerised systems used in GMP operations. It addresses system validation, data integrity, audit trails, electronic records and signatures, lifecycle management, supplier oversight, and risk controls.

Why interest is high:

Digitalisation, cloud-based systems, hybrid workflows, and remote operations are now integral to pharmaceutical manufacturing. With draft revisions in consultation, companies are seeking clarity on compliance.

Implications:

• Systems must be validated throughout their lifecycle, and data integrity cannot be ignored.
• Audit trails, access controls, and supplier management are core to GMP compliance.
• Knowledge management should integrate digital-system governance training, linked to Volume 4 Annex 11 computerized systems.

Eudralex Volume 4 Annex 13 – Investigational Medicinal Products (IMPs)

Eudralex Volume 4 Annex 13 covers GMP requirements specifically for investigational medicinal products used in clinical trials.

Why interest is high:

With the growth in clinical development, outsourcing, and global supply chains for IMPs, organizations are checking whether their processes align with Annex 13’s expectations when moving from the “trial” stage to the “commercial” stage.

Implications:

• Processes for IMPs must reflect GMPs comparable to commercial product manufacture.
• Packaging, labelling, and supply chain logistics under trial conditions have additional constraints.

Eudralex Volume 4 Annex 15 – Qualification & Validation

Eudralex Volume 4 Annex 15 provides detailed guidance on the qualification of facilities, equipment, utilities, and systems, and validation of processes, cleaning procedures, computerized systems, and analytical methods. The revisions reinforce a risk-based lifecycle approach.

Why interest is high:

Effective validation and qualification underpin manufacturing quality. The need to align with newer technologies (continuous manufacturing, cleaning validation, hybrid systems) makes Annex 15 very relevant.

Implications:

• Qualification and validation must span the full lifecycle of facilities/systems, with re-qualification and re-validation when changes occur.
• Annex 15 cross-references Annex 11 for computerized systems, emphasising inter-linked compliance.
• Training modules should cover validation planning, change management, and documentation under Eudralex Volume 4 Annex 15.

Eudralex Volume 4 Annex 16 – QP Certification & Batch Release

Eudralex Volume 4 Annex 16 governs the role of the Qualified Person (QP) and the legal-scientific framework for batch certification and release in the EU/EEA. It addresses responsibilities, documentation, supply-chain oversight, and batch release from multiple sites or importation situations.

Why interest is high:

The QP sits at the final gate before a product hits the market. With global manufacturing and imports, Annex 16’s emphasis on the QP’s oversight of third parties and sites beyond direct control demands attention.

Implications:

• Each finished batch must be certified by a QP within the EU/EEA before release.
• The QP must be confident about manufacturing, testing, control, and supply-chain documentation.
• Training should emphasise the QP’s role in batch release, multi-site contracts, and import arrangements per Eudralex Volume 4 Annex 16.

Eudralex Volume 4 Annex 19 – Reference & Retention Samples

Eudralex Volume 4 Annex 19 deals with the requirements for taking, storing, and retaining reference samples and retention samples, and the associated storage duration and traceability.

Why interest is high:

Reference and retention samples are critical for investigations, complaints, stability challenges, recall readiness, and regulatory audits. Mistakes or gaps in this area raise red flags.

Implications:

• Reference samples of starting materials, packaging, and finished products must be retained for the shelf life or a defined period to support investigations.
• Traceability of the sample chain must be maintained.
• Training should include sample-management policies, retention times, and responsibilities mapped to Eudralex Volume 4 Annex 19.

Eudralex Volume 4 Annex 21 – Importation of Medicinal Products

Eudralex Volume 4 Annex 21 outlines GMP requirements for the importation of medicinal products into the EU/EEA. It addresses the role of the Manufacturing Import Authorisation (MIA) holder, documentation, QP oversight post-import, supply-chain controls, and documentation for imported goods.

Why interest is high:

With increasingly global supply chains, import operations often involve multiple jurisdictions, and Annex 21 clarifies what EU authorities expect under import scenarios.

Implications:

• Importation of products into the EU/EEA triggers full GMP expectations for the importer/MIA holder.
• The importer must ensure documents, batch records, and QP certification align with EU GMP.
• Training, SOPs, and quality systems for supply-chain staff should include import compliance under Eudralex Volume 4 Annex 21.

How to apply Eudralex Volume 4 in practice

Moving from what the rules say to how we actually implement them is where many organizations stumble.

The challenge for quality professionals is translating Eudralex Volume 4's text into daily operations, training, audits, and continuous improvement. Below are four key areas we have mastered and how to implement them.

Risk-management principles (ICH Q9)

Volume 4 explicitly references risk-based thinking as part of the pharmaceutical quality management environment. For example, it expects organizations to identify hazards, assess risks, control them, and review the outcomes.

For a practical insight:

• When you conduct a change of new equipment or a new process, apply a documented risk assessment (such as FMEA) to show how you considered potential impact on product quality and patient safety.
• Integrate this with your training materials. Teach operators and QAs how risk thinking links to GMP expectations. This is why auditors will ask for evidence

Pharmaceutical Quality Systems (PQS) (ICH Q10)

Volume 4’s Chapter 1 on the PQS reflects lifecycle-oriented, knowledge-driven models.

For a practical insight:

• Map your SOPs, WIs, training programs, documentation control, change control, deviation investigations, CAPAs, and management reviews into a coherent PQS.
• For example, suppose you have many individual SOPs for equipment cleaning, validation, operator training, and documentation. Rather than separate silos, show how they link under a PQS: cleaning validation leads to procedure, leads to training, leads to trending KPIs.

Audit preparation and inspection expectations

Auditors use Volume 4 as the benchmark. Understanding how they assess your site helps you prepare better.

For a practical insight:

• Create audit checklists aligned with Volume 4’s structure: Part I chapters (Personnel, Premises & Equipment, Documentation, Production, Quality Control), plus relevant annexes for your operations (e.g., Annex 11 for computerised systems).
• For example, before an inspection, run a “mock-audit” of your documentation control system: check revision history, signature authenticity, archival retrieval, and link that to Chapter 4 expectations.

Data integrity and digital compliance (Annex 11)

Digital systems are increasingly central to GMP regulatory and manufacturing environments.

For a practical insight:

• Create an inventory of all computerised systems used in your GMP operations (MES, LIMS, ERP, eQMS). Classify them by risk (high/medium/low) according to how they impact product quality or data integrity.
• For example, imagine your organisation uses a validated electronic Quality Management System (eQMS) such as Scilife. This platform centralises all quality workflows-document control, training records, CAPA,  audit, etc. -  in a compliant digital ecosystem. In practice, you would:
  • Classify the system as “GMP-relevant” because it handles documented information, records, deviation logs, or audit trails.
  • Ensure that user access controls, electronic signatures, and audit-trail logging meet the requirements of EudraLex Volume 4 Annex 11 (Computerised Systems).
  • Validate the system lifecycle: Installation Qualification (IQ), Operational Qualification (OQ),  Performance Qualification (PQ), and periodic review, linked to change-control workflows.
  • Automate training modules in the eQMS so that staff using the system have documented competence, supporting data integrity and system validation.

This example helps turn the regulation’s language about computerised systems controlled under GMP into concrete action. The tool becomes not just a piece of software, but a quality-system component aligned with regulatory expectations.

Conclusion

At the end of the day, alignment with EudraLex Volume 4 doesn’t happen in silos. It happens through integrated systems, trained teams, and documented workflows.

That’s where Scilife can help. With modules like Document Control, Change Control, and Training Management, Scilife brings your QMS into one unified platform, so you’re not chasing audit trails with spreadsheets; you’re owning them with clarity.

The result is less time spent repairing compliance gaps and more time confidently demonstrating traceability, data integrity, and operational readiness.

Reduce compliance risk by design through connected processes, audit-ready records, and a strong quality culture.