Understanding EU GMP Part I, Part II, and Annexes: A Complete Introduction

The European Union’s Good Manufacturing Practice (EU GMP) guidelines form the foundation of quality assurance in pharmaceutical manufacturing across Europe. Developed by the European Medicines Agency (EMA) and aligned with PIC/S and ICH standards, these guidelines ensure consistent safety, efficacy, and quality of medicinal products. This article provides a structured introduction to EU GMP Part I, Part II, and the Annexes, helping professionals navigate regulatory expectations and implement best practices across GMP systems.

Regulatory Context of EU GMP Guidelines:

• Mandated under EU Directive 2003/94/EC for human medicines and EU Regulation 2019/6 for veterinary medicines
• Compliance is enforced by EU Member State inspectorates and EMA
• EU GMP aligns closely with WHO, PIC/S, and ICH Q10 frameworks
• Regular updates address technological evolution, globalization, and emerging risk factors

Structure of the EU GMP Guideline:

• Part I: GMP for medicinal products (finished dosage forms)
• Part II: GMP for active pharmaceutical ingredients (APIs) – aligned with ICH Q7
• Annexes: Supplementary GMP requirements for specific products or processes

Part I – GMP for Finished Medicinal Products:

Part I of EU GMP is primarily applicable to manufacturers of finished dosage forms such as tablets, capsules, injectables, and sterile products.

• Consists of 9 chapters that cover:
  • Quality Management
  • Personnel
  • Premises and Equipment
  • Documentation
  • Production
  • Quality Control
  • Outsourced Activities
  • Complaints and Product Recall
  • Self-Inspection
• Emphasizes cross-functional responsibility, deviation management, and risk-based decision-making
• Closely monitored during routine inspections and regulatory filings

Part II – GMP for Active Substances:

Part II reflects the principles of ICH Q7 and governs the manufacturing of APIs used in medicinal products.

• Applicable to chemical synthesis, fermentation, biotech, and purification processes
• Structured into 19 sections including:
  • Materials Management
  • Process Equipment
  • Documentation and Records
  • Laboratory Controls
  • Validation
  • Change Control
  • Product Complaints and Recalls
• Ensures APIs meet safety, purity, and quality requirements for finished drug manufacture
• Required for both EU-based and third-country API suppliers

Annexes – Tailored Requirements for Specialized Areas:

The Annexes to EU GMP provide specific guidance for unique dosage forms, technologies, and processes. Currently, there are 21 Annexes in total.

Key Annexes Include:

• Annex 1: Manufacture of Sterile Medicinal Products – updated to include Quality Risk Management (QRM), CCS, and environmental monitoring
• Annex 2: Biotechnological/Biological Products – covers manufacturing of vaccines, monoclonal antibodies, and gene therapies
• Annex 3: Radiopharmaceuticals
• Annex 11: Computerized Systems – Part 11 equivalent for electronic systems
• Annex 15: Qualification and Validation – critical for facility, process, and cleaning validation
• Annex 16: Certification by a Qualified Person (QP) and batch release
• Annex 19: Reference and Retention Samples

Recent Revisions and Their Impact:

• Annex 1 (2022 Update): Introduces Contamination Control Strategy (CCS) and visual inspection requirements
• Annex 21 (New): Covers importation of medicinal products, especially from non-EU countries
• Periodic updates to Annex 11, 15, and 16 reflect evolving technology and regulatory expectations

Comparison of EU GMP vs US FDA GMP:

• EU GMP requires QP certification of each batch before release
• EMA inspections may occur at both manufacturing and testing locations
• Documentation format and terminology differ slightly from 21 CFR Parts 210/211
• Annexes provide more prescriptive guidance on advanced technologies and sterile manufacturing

Compliance and Inspection Strategy in the EU:

• Inspections conducted by Member State inspectorates (e.g., MHRA, ANSM, BfArM)
• EMA coordinates GMP inspections for centralized marketing authorization applications
• EU maintains a publicly accessible EudraGMDP database of GMP certificates and non-compliance reports
• Non-EU sites must be audited by EU-authorized bodies for GMP equivalency

Best Practices for EU GMP Compliance:

1. Conduct a gap assessment against all three parts: Part I, II, and relevant Annexes
2. Develop a cross-referenced SOP matrix aligned with each GMP chapter
3. Train QA, QC, and production teams on annex-specific controls (e.g., Annex 1 for sterile areas)
4. Audit vendors and contract manufacturers for EU GMP readiness
5. Use internal inspections to monitor compliance with EU GMP inspection protocols

Conclusion:

EU GMP guidelines—comprising Part I for finished products, Part II for APIs, and detailed Annexes—offer a robust framework for pharmaceutical quality assurance. Understanding and implementing each section appropriately ensures compliance with EMA expectations and facilitates successful inspections across the EU. As regulatory science advances, manufacturers must continuously review and integrate EU GMP updates to remain competitive and compliant in the European pharmaceutical market.