Complying with EU GMP Requirements for Active Substances and Excipients

In the EU regulatory framework, ensuring the quality of both active substances (APIs) and excipients is a critical component of pharmaceutical compliance. The European Medicines Agency (EMA), through its Good Manufacturing Practice (GMP) guidelines, imposes clear requirements on manufacturers, importers, and marketing authorization holders (MAHs) to manage and control the sourcing, testing, and qualification of these raw materials. This article outlines the current EU GMP requirements for active substances and excipients, with a focus on GMP Part II, supplier qualification, and risk-based compliance strategies.

GMP Applicability to APIs and Excipients

• Active Substances (APIs): Must be manufactured in accordance with EU GMP Part II (ICH Q7 equivalent)
• Excipients: Subject to risk-based GMP oversight as per EU Guidelines 2015/C 95/02
• Importers must verify GMP compliance before release for manufacturing
• MAHs are ultimately responsible for compliance of all materials used in their products

GMP Requirements for Active Substances (APIs)

• Manufacturing must follow EU GMP Part II (adapted from ICH Q7)
• Applies to all APIs used in human medicinal products, including biological and synthetic materials
• GMP compliance must be demonstrated through:
  • GMP certificates listed in EudraGMDP
  • Written confirmation from third-country authorities
  • On-site GMP audit reports by MAH or manufacturer
• Batch release sites must perform identity testing and maintain full traceability

Key Areas of GMP Focus for API Manufacturers

• Contamination and cross-contamination control
• Cleaning validation, especially for multipurpose equipment
• Change control and deviation management
• Process validation and cleaning hold time studies
• Traceability from raw materials to finished APIs
• Document control, including master batch records and laboratory notebooks

Requirements for Excipients under EU Risk-Based GMP

• No mandatory GMP standard for all excipients—risk-based model applies
• MAHs must perform a formal risk assessment for each excipient based on:
  • Function in the formulation (e.g., preservative, filler)
  • Route of administration (e.g., injectable vs. oral)
  • Patient population (e.g., pediatric, immunocompromised)
  • Historical quality issues or recalls
• Based on the outcome, appropriate GMP guidelines must be applied (e.g., ISO 9001, EXCiPACT, IPEC-PQG)

Supplier Qualification for APIs and Excipients

1. Maintain an approved supplier list with full documentation history
2. Conduct initial and periodic supplier audits based on material criticality
3. Verify source of API manufacturing (not just the distributor)
4. For excipients, ensure qualification of both manufacturers and brokers
5. Retain signed quality agreements defining roles, responsibilities, and documentation flow

Documentation and Certificates Required

• APIs:
  • Certificate of GMP Compliance
  • Written confirmation (for imports from third countries)
  • DMF or CEP with cross-referenced manufacturing details
• Excipients:
  • Certificate of Analysis (CoA)
  • Risk assessment justification file
  • Quality agreement outlining GMP expectations

EMA Inspection Considerations for Raw Material Oversight

• Inspectors may request:
  • Supplier audit reports and requalification cycles
  • Material specifications and CoAs
  • Raw material release records and quarantine status
  • Excipient risk assessments and rationale for applied standards
• Sites must be ready to demonstrate full control over supply chain traceability
• Failure to audit critical suppliers is a frequent observation in EU GMP inspections

Stability and Compatibility Considerations

• Stability of APIs and excipients must be supported with appropriate stability studies
• Compatibility between APIs and excipients should be demonstrated during formulation development
• Storage conditions, retest dates, and shelf life must be defined and justified

Importation Requirements for APIs into the EU

• Importers must verify GMP compliance of API manufacturers before release
• Written confirmation must be issued by the competent authority of the exporting country
• EMA maintains a list of authorized API sites and importing authorizations in EudraGMDP
• Importers are subject to routine inspections focused on supplier qualification, testing, and documentation

Best Practices for Ensuring Compliance

1. Perform gap assessments against EU GMP Part II for APIs and Annex 21 for importation
2. Maintain a centralized supplier qualification tracker with audit status, CoAs, and GMP certificates
3. Integrate excipient risk assessments into formulation and QMS documentation
4. Establish a recall traceability matrix from raw material to finished dosage
5. Engage in industry-recognized excipient GMP certification schemes (e.g., EXCiPACT)

Conclusion

Compliance with EMA GMP requirements for active substances and excipients is essential to ensure the safety, efficacy, and quality of pharmaceutical products. While APIs must meet the rigorous standards of EU GMP Part II, excipients require a risk-based approach tailored to their criticality. Companies that implement robust supplier qualification processes, maintain documentation integrity, and proactively monitor raw material quality will be best positioned to meet regulatory expectations and support global product approvals.