Understanding WHO PQP Inspection Criteria for Active Pharmaceutical Ingredients (APIs)

The quality of an Active Pharmaceutical Ingredient (API) is fundamental to the safety and efficacy of a finished pharmaceutical product (FPP). As part of the WHO Prequalification Programme (PQP), API manufacturers may undergo direct evaluation and inspection to ensure compliance with international GMP standards and data integrity practices. This article explores the key inspection criteria for APIs under WHO PQP, covering dossier submission, site inspection scope, and regulatory expectations.

When Is an API Subject to WHO PQP Inspection?

• When an API is submitted independently for prequalification (stand-alone API PQ)
• When the API is included in a finished product dossier and the supplier is not WHO-prequalified
• When requested by WHO based on risk or lack of SRA/API Master File access

Applicable Guidelines and References:

• WHO TRS 957: Annex 1 – Guidelines on submission of documentation for API evaluation
• WHO TRS 986 & 961: GMP for API manufacturers
• ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

WHO PQP API Evaluation Process:

1. Submission of API Master File (APIMF)

The API manufacturer submits an APIMF, which is confidential and contains critical quality and manufacturing information including:

• Manufacturing process flow and description
• In-process controls and critical quality attributes
• Stability data aligned with ICH Q1A
• Control of impurities, residual solvents, and heavy metals
• Specifications, analytical methods, and validation data

2. Quality Assessment by WHO

WHO PQT (Prequalification Team) reviews the submitted documentation for completeness, consistency, and adherence to GMP and pharmacopoeial standards.

3. Site Inspection Planning

• Triggered when API site is not prequalified or SRA-inspected
• Based on risk: sterile APIs, complex synthesis, or critical excipient handling
• Inspector selection based on API type and region

Key Inspection Criteria for API Manufacturing Sites:

1. Quality Management System (QMS)

• Documented QA structure and procedures
• Self-inspection programs and internal audits
• Deviation management and CAPA tracking

2. Raw Material and Starting Material Control

• Vendor qualification and audits
• Traceability and receipt verification logs
• Cross-contamination controls for shared facilities

3. Manufacturing Process and Facility Design

• Detailed batch records and process flow alignment
• Cleaning validation and campaign manufacturing strategies
• Dedicated vs. multipurpose equipment setup

4. Laboratory Controls and Data Integrity

• Analytical method validation and transfer protocols
• Raw data retention and audit trail reviews
• Chromatographic integrity, especially for impurity profiles

5. Stability Program and Retention Samples

API sites must provide:

• Accelerated and long-term stability data in compliance with ICH Q1A(R2)
• Packaging and container interaction studies
• Retention samples and storage conditions verification

6. Data Transparency and Access

• Availability of executed batch records during inspection
• Cross-checking of batch data against COAs submitted in the FPP dossier
• Inspector access to lab notebooks and audit trails of software systems

Common Deficiencies Observed During WHO API Inspections:

• Inadequate impurity control strategy or failure to justify limits
• Repeat OOS results not properly investigated or trended
• Non-compliant cleaning validation (especially in shared facilities)
• Missing or incomplete raw data sets for analytical testing
• Expired analytical standards and improper documentation

How to Prepare for a WHO API Site Audit:

1. Conduct a mock audit using WHO and ICH Q7 checklists
2. Prepare cross-functional SMEs from QA, QC, and production teams
3. Review and reconcile all batch documentation and analytical reports
4. Ensure system audit trails are enabled and reviewed periodically
5. Align your SOPs with WHO GMP clauses and update change control records

Role of APIs in FPP Prequalification:

If the API fails to meet WHO PQ criteria, the entire FPP application may be delayed or rejected. Therefore, many FPP applicants prefer using WHO-prequalified APIs or those manufactured at sites previously inspected by WHO or Stringent Regulatory Authorities (SRAs).

Post-Inspection Follow-Up:

• Submission of CAPA plan typically within 30 days
• Follow-up documentation including SOP updates, retraining logs, and revised validation reports
• Possible re-inspection if critical deficiencies are noted

Conclusion:

API manufacturers play a critical role in the WHO PQP ecosystem. Understanding and adhering to WHO’s inspection criteria—covering GMP systems, documentation integrity, and data transparency—ensures that their APIs contribute to high-quality finished products eligible for global health procurement. With regulatory scrutiny increasing and international harmonization accelerating, investing in WHO audit readiness is no longer optional—it is a strategic imperative.