EMA GMP Requirements for Contract Manufacturing and Testing Operations

Outsourcing of manufacturing and analytical activities has become a strategic norm in the pharmaceutical industry. However, with this trend comes the responsibility of ensuring regulatory compliance across all contracted operations. The European Medicines Agency (EMA), through its GMP framework, imposes stringent expectations on Marketing Authorization Holders (MAHs) and manufacturers engaging contract manufacturing and testing. This article explores EMA GMP requirements for contract manufacturing and testing, focusing on legal obligations, quality agreements, and operational oversight under EU GMP guidelines.

Regulatory Basis for Outsourcing Under EU GMP

• Outlined in EU GMP Chapter 7 – Outsourced Activities
• Reinforced through Annex 16 for batch release and Directive 2001/83/EC
• EMA expects the same level of GMP compliance from contract sites as in-house operations
• Responsibility for product quality remains with the MAH and the designated Qualified Person (QP)

Key Responsibilities in Contracted GMP Operations

• Contract Giver: The entity outsourcing the activity (e.g., MAH or manufacturer)
• Contract Acceptor: The third-party entity performing manufacturing or testing
• Qualified Person (QP): Must certify the batch, taking into account all contracted work

Mandatory Elements of a Quality/Technical Agreement

• Clearly defined roles and responsibilities for both parties
• Details of GMP activities to be performed (e.g., packaging, QC, storage)
• Change control and deviation reporting mechanisms
• Audit and inspection rights
• Documentation and data ownership protocols
• Responsibilities for recall, complaints, and batch release information flow

Contractor Qualification Requirements

1. Perform initial GMP audit before engaging the contractor
2. Evaluate regulatory inspection history and GMP certificates on EudraGMDP
3. Verify compliance with EU GMP Part I or Part II, as applicable
4. Assess technical capabilities, documentation systems, and training records
5. Conduct periodic requalification based on risk level and performance

Risk-Based Oversight Model

• Use a risk-based approach to determine audit frequency and documentation depth
• Factors include:
  • Criticality of the process (e.g., sterile manufacturing vs. secondary packaging)
  • Compliance history and regulatory standing
  • Volume of product processed at the site
• EMA supports reliance on Mutual Recognition Agreements (MRAs) for low-risk third-country contractors

Responsibilities of the MAH and Manufacturing Site

• MAHs must ensure that all sites listed in the dossier are compliant and auditable
• All manufacturing and testing locations must be declared in the Marketing Authorization Application (MAA)
• MAHs and manufacturers must maintain visibility over all subcontracted activities
• Final product release remains the QP’s responsibility regardless of outsourcing

Common EMA Inspection Observations in Contract Operations

• Lack of a signed and detailed quality agreement
• Contract sites not audited or inadequately qualified
• Gaps in change control communication between parties
• Deviation investigations performed only by the contractor, with no involvement from the contract giver
• Non-disclosure of subcontractors (e.g., transport, secondary packaging)

Batch Certification and Annex 16 Compliance

• QP must review all documentation from contract sites before certifying a batch
• Annex 16 mandates that QPs have full visibility and control over outsourced GMP activities
• Batch records, deviations, CAPAs, and test results must be readily available for review
• Site visits and audits are strongly encouraged, especially for critical processes

Best Practices for Managing Contract Manufacturing and Testing

1. Develop a contractor approval SOP outlining selection, audit, and monitoring
2. Use a standardized technical agreement template across all vendors
3. Schedule annual or risk-based reviews of contractor performance and compliance
4. Maintain a central repository of all contract-related GMP documentation
5. Ensure deviation and change control systems allow for real-time collaboration

Document Types Inspectors May Request

• Signed quality/technical agreements
• Contractor audit reports and CAPA follow-ups
• Training and qualification logs for contractor staff
• Batch records involving outsourced steps
• Communication logs between QP and contractor

Integrating Contract Oversight into QMS

• Incorporate contract partner management into internal audit schedules
• Align contractor training and data systems with internal practices
• Include contractor-related KPIs in management reviews
• Document the flow of goods and responsibilities from raw material to finished product

Conclusion

Contract manufacturing and testing offer scalability and specialization but come with high regulatory scrutiny. The EMA expects MAHs and manufacturers to retain full responsibility for the quality and compliance of outsourced activities. Through thorough qualification, robust technical agreements, and real-time oversight, companies can meet EMA GMP expectations and build strong, audit-ready partnerships. In an increasingly complex supply chain landscape, contract control is not optional—it’s fundamental to maintaining regulatory confidence and product integrity.