WHO Site Master File Requirements for GMP Prequalification

The Site Master File (SMF) is a foundational document required during the WHO GMP prequalification process. It provides a comprehensive overview of a pharmaceutical manufacturing site’s quality system, infrastructure, operations, and compliance framework. As a core submission component under the WHO Prequalification Programme (PQP), the SMF serves as a roadmap for inspectors and significantly influences inspection readiness. This guide outlines the detailed structure, expectations, and best practices for preparing a WHO-compliant SMF.

What Is a WHO Site Master File?

The WHO SMF is a written description of the GMP-related activities of a manufacturing site, including facilities, equipment, personnel, quality assurance systems, and production operations. It helps WHO inspectors understand the site layout and quality controls before and during GMP inspections.

Reference Guidance for SMF Submission:

WHO TRS 961, Annex 14: “Guidance for drafting a Site Master File”
WHO TRS 986: “GMP for pharmaceutical products”
ICH Q7/Q10: Complementary expectations for API and quality system management

When Is the SMF Required?

During WHO PQP applications for finished pharmaceutical products (FPPs), APIs, or vaccines
Before a WHO on-site GMP inspection
As part of collaborative registration with national regulatory authorities
For WHO post-approval requalification and variation assessments

Also Read: WHO PQP for Finished Pharmaceutical Products (FPPs): A Complete Guide

WHO SMF Standard Structure:

The Site Master File should be structured according to the WHO format, typically with the following 10 main sections:

1. General Information

Site name, address, and contact details
Organization structure (ownership, legal status)
Activities carried out at the site (manufacturing, packaging, QC, etc.)

2. Personnel

Organogram with reporting lines for QA, QC, Production
Qualifications and responsibilities of key staff
Training systems and frequency

3. Premises and Equipment

Facility layout with product and personnel flows
HVAC, water, compressed air systems
Cleaning and maintenance procedures

4. Documentation

Document control system (SOPs, batch records, logbooks)
Data retention and archival policies
Version control and electronic documentation details

5. Production Activities

Types of dosage forms produced
Process flow diagrams and in-process controls
Equipment lists and cleaning validation status

6. Quality Control

Laboratory overview and organization
Analytical methods used and equipment inventory
Stability testing program and ICH Q1A(R2) alignment
OOS/OOT investigation procedures

Also Read: Importance of Transparency in International Inspection Findings

7. Contract Activities

Details of outsourced testing or manufacturing
Vendor qualification and technical agreements

8. Distribution, Complaints, and Recalls

Warehouse and dispatch procedures
Complaint handling system and product recall process

9. Self-Inspection and Quality Audits

Internal audit frequency and scope
CAPA tracking system and follow-up mechanisms

10. Appendices

Site layout plans
Process flow diagrams
Equipment lists and calibration status
Organization charts and key SOP index

Key Formatting Requirements:

Typed and formatted in clear, logical sections
Page-numbered with revision date and document control
Preferably 25–30 pages excluding annexes
Include a document history and approval signature page

Common Deficiencies in WHO SMF Submissions:

Outdated site plans or equipment lists
Incomplete batch record traceability descriptions
Lack of integration between SOPs and described activities
Discrepancies between SMF and actual site operations
Missing discussion on computerized systems and data integrity

Best Practices for a WHO-Compliant SMF:

Keep the SMF updated annually or after major changes
Involve cross-functional teams (QA, Engineering, QC, HR)
Use flowcharts and diagrams for visual clarity
Map content against WHO Annex 14 checklist
Link SMF content to relevant SOPs and controlled documents

Also Read: Understanding WHO’s Risk-Based Inspection Model

How WHO Uses the SMF During Inspections:

Plan the scope and focus of the audit
Verify consistency between declared and actual operations
Determine traceability and risk-prone areas (e.g., storage, stability, validation)
Assess systemic compliance before facility walkthroughs

Role of the SMF in Regulatory Reliance:

As part of WHO’s Collaborative Registration Procedure (CRP), the SMF is shared with national regulatory agencies. A clear and robust SMF improves the likelihood of expedited product registration across LMICs and enhances trust in the site’s GMP maturity.

Conclusion:

The Site Master File is more than a technical document—it’s a strategic asset for GMP credibility and WHO prequalification. It allows regulators to assess risk, verify consistency, and streamline audit planning. For pharmaceutical manufacturers, investing time and quality into preparing a WHO-compliant SMF lays a strong foundation for successful inspection outcomes, sustained global compliance, and broader access to international procurement channels.