WHO Prequalification: Process, Requirements, and Benefits for Drug Manufacturers

WHO Prequalification: Process, Requirements, and Benefits for Drug Manufacturers

Key Takeaways

What Is WHO Prequalification?

Program Overview

The WHO Prequalification Programme evaluates medicines to determine whether they meet acceptable standards of quality, safety, and efficacy. WHO PQ is not a regulatory approval in the traditional sense. WHO is not a regulatory authority and does not issue marketing authorizations. Instead, WHO PQ provides an independent assessment that procurement agencies use to make purchasing decisions.

Key distinctions:

Eligible Product Categories

WHO PQ covers medicines in the following therapeutic areas (as defined by WHO Invitations for EOI):

WHO periodically publishes Invitations for Expressions of Interest that specify which products are currently open for PQ applications. Manufacturers cannot apply for PQ of products outside the current invitations.

What WHO PQ Is Not

• WHO PQ is not a substitute for national regulatory approval. Manufacturers must still register products with the national regulatory authority (NRA) in each country where they intend to sell.
• WHO PQ does not guarantee procurement. It qualifies the product for consideration, but procurement decisions depend on price, supply capacity, and programmatic needs.
• WHO PQ does not itself authorize commercial sale in any country. National registration and local regulatory requirements still apply.

Eligibility Criteria

Product Eligibility

To be eligible for WHO PQ assessment, a product must:

1. Fall within an active EOI category: WHO must have an open invitation for the specific product type
2. Be a Finished Pharmaceutical Product (FPP): WHO PQ applies to finished dosage forms, not active pharmaceutical ingredients (APIs) alone
3. Be manufactured at a site with demonstrated GMP compliance: The manufacturing site must be GMP-compliant per WHO GMP standards
4. Meet the applicable WHO procedure requirements: Eligibility depends on the active EOI and the current WHO medicines prequalification procedure for the product type and assessment route.

Manufacturer/Applicant Eligibility

• The applicant must be the manufacturer of the finished product or the holder of the marketing authorization in the country of manufacture
• The applicant must be a legal entity with the ability to enter into supply agreements
• The applicant must demonstrate the capacity to produce the product at commercial scale and in quantities sufficient to supply international procurement programs

Assessment Pathways and Reliance

WHO's medicines prequalification materials describe more than one assessment route. In practice, applicants need to check the current WHO procedure, the active EOI, and any reliance-based or abridged options that WHO has opened for the relevant product category.

WHO has also introduced the broader WHO Listed Authority (WLA) concept in its regulatory framework. At the same time, some medicines prequalification materials and procurement policies still refer to Stringent Regulatory Authorities (SRAs). For line-by-line eligibility questions, the safest approach is to use the exact current WHO medicines procedure and the relevant EOI rather than rely on older shorthand.

The Expression of Interest (EOI) Process

Step 1: Identify the Applicable EOI

WHO publishes Invitations for Expressions of Interest on its website, specifying:

• The product(s) eligible for assessment
• The comparator product for bioequivalence studies
• The dossier format and content requirements
• The submission deadline (for some EOIs) or open-ended submissions

Manufacturers should monitor WHO's PQ website for new and updated invitations.

Step 2: Prepare and Submit the Product Dossier

The product dossier must be submitted in CTD (Common Technical Document) format. WHO does not currently require eCTD for most PQ submissions, though it accepts eCTD. Paper or electronic (PDF) CTD format is commonly used.

Required dossier content:

WHO-Specific Dossier Requirements

Beyond the standard CTD content, WHO PQ has specific requirements:

Quality Overall Summary (QOS)

WHO provides a specific QOS template that must be completed. This template is more prescriptive than the standard ICH QOS and includes specific fields and tables that WHO assessors expect. Using the WHO QOS template is mandatory.

Certificate of Pharmaceutical Product (CPP)

A CPP (also known as a WHO-type certificate) must be provided from the national regulatory authority of the country where the product is manufactured and/or approved. The CPP confirms that:

• The product is authorized for sale in the issuing country
• The manufacturing site has been inspected and found GMP-compliant
• The product meets the registered specifications

The CPP must follow the WHO format specified in the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce.

Finished Pharmaceutical Product (FPP) Questionnaire

The FPP questionnaire collects information about the product, manufacturing sites, and active pharmaceutical ingredient (API) sources. It is a structured form provided by WHO.

Site Master File (SMF)

Each manufacturing site involved in the production of the FPP must provide a Site Master File following the WHO/PIC/S format. The SMF provides an overview of the site, including:

• Quality management system description
• Personnel and organizational chart
• Premises and equipment
• Production operations
• Quality control
• Self-inspection program

Step 3: WHO Screening

WHO screens the dossier for completeness and administrative compliance. If the dossier is incomplete, WHO issues a query or returns the submission for correction.

Step 4: Dossier Assessment

WHO assessors (both in-house and external experts) review the dossier content:

• Quality assessment: Evaluation of drug substance and drug product CMC data, specifications, stability, and manufacturing process
• Bioequivalence/clinical assessment: Review of comparative bioavailability studies (for generics) or clinical data (for novel products)

WHO may issue questions and requests for additional information during assessment. Multiple rounds of questions are common.

Step 5: GMP Inspection

WHO conducts an on-site GMP inspection of all manufacturing sites involved in the production of the FPP. Inspections cover:

• Quality management system
• Personnel qualifications and training
• Premises and equipment
• Manufacturing operations
• Quality control laboratory
• Documentation and record-keeping
• Validation
• Complaints and recall procedures
• Self-inspection

WHO GMP inspections follow the WHO Technical Report Series (TRS) standards, particularly WHO TRS No. 986, Annex 2 (WHO Good Manufacturing Practices for Pharmaceutical Products). These standards are broadly aligned with PIC/S GMP but have some WHO-specific elements.

Inspection outcomes:

Step 6: Prequalification Decision

After satisfactory dossier assessment and GMP inspection, the WHO Prequalification Team issues a prequalification listing. The product is added to the WHO List of Prequalified Medicinal Products, which is publicly available on the WHO PQ website.

Timeline Expectations

WHO medicines prequalification timelines vary by product, dossier quality, the assessment route used, the need for inspections, and how quickly the applicant answers WHO questions. Because WHO uses different procedures and may update them, it is safer to treat timing as product-specific rather than rely on a single published median.

In practice, the calendar is often driven by:

• Whether the product is covered by an open EOI
• Whether WHO uses a full assessment, abridged assessment, or another reliance-based route
• The number and complexity of assessment questions
• Inspection readiness and CAPA closure, if WHO inspects the sites
• Applicant response speed

Bioequivalence Requirements for Generic Products

Most WHO PQ applications are for generic products, which require bioequivalence (BE) studies demonstrating equivalence to a WHO-specified comparator product.

Comparator Product Selection

WHO specifies the comparator product in the Invitation for EOI. This is typically:

• An innovator product identified by WHO in the relevant EOI or supporting guidance
• A WHO-prequalified product (in some cases)

The comparator must be sourced from an approved market. WHO provides specific guidance on acceptable comparator products in its publication "WHO Technical Report Series, No. 992, Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability."

Bioequivalence Study Standards

BE studies must comply with WHO guidelines on bioequivalence:

• Study design: Randomized, crossover (2-period, 2-treatment for most products)
• Subjects: Healthy volunteers (unless otherwise justified)
• Fasting and fed conditions: As specified by WHO for the product
• Bioanalytical method: Must be validated per WHO guidelines
• Acceptance criteria: 90% confidence interval for AUC and Cmax within 80.00-125.00%
• GCP compliance: Study must comply with ICH E6 (R2) Good Clinical Practice
• Study site: Must be a site with appropriate capabilities; WHO may inspect the BE study site

Biowaivers

WHO accepts Biopharmaceutics Classification System (BCS)-based biowaivers for certain products per WHO TRS guidelines. BCS Class I and, in some cases, Class III products may qualify for waiver of in vivo bioequivalence studies if the product meets specified dissolution criteria.

Collaborative Registration

What Is Collaborative Registration?

The WHO Collaborative Registration Procedure (CRP) allows national regulatory authorities (NRAs) in WHO member states to use WHO PQ assessment findings when registering a WHO-prequalified product in their country. This accelerates national registration by avoiding duplicative review.

How CRP works:

1. The manufacturer applies for national registration in a participating country
2. The NRA requests WHO PQ assessment reports for the product
3. WHO shares its assessment reports and inspection findings with the NRA
4. The NRA conducts its own review, relying on WHO's findings to reduce assessment workload
5. The NRA makes an independent registration decision

Benefits of CRP

Benefits of WHO Prequalification

Procurement Access

WHO PQ listing is widely used in procurement and quality-assurance frameworks for priority global health products. The exact acceptance rule depends on the product, purchaser, and program policy. Manufacturers should verify the current policy of each procurement channel rather than assume a single rule applies everywhere.

Reputational and Regulatory Benefits

• Quality signal: WHO PQ listing signals that the product meets international quality standards, which can support registration in other markets
• NRA confidence: National regulators in markets without full assessment capacity may prioritize or fast-track registration of WHO PQ products through CRP
• Competitive differentiation: In markets where multiple generic manufacturers compete, WHO PQ listing differentiates on quality

Maintenance Requirements

WHO PQ listing is not a one-time event. WHO's medicines post-prequalification procedures require ongoing management of changes and continued demonstration that the prequalified product remains acceptable.

Variation Procedures

Any change to a prequalified product must be notified to WHO PQ through a variation procedure. WHO classifies variations similarly to other regulatory frameworks:

Requalification and Ongoing Oversight

WHO's medicines post-prequalification procedures state that a prequalified FPP is requalified every five years from the date of prequalification, or earlier if WHO requests it. WHO also continues oversight through review of variations and other post-prequalification information.

Reasons for Delisting

Products may be removed from the WHO PQ list for:

• Failure to maintain GMP compliance
• Failure to address quality concerns identified during assessment or inspection
• Voluntary withdrawal by the manufacturer
• Withdrawal of the national marketing authorization

WHO PQ vs. National Registration

WHO PQ and national registration solve different problems:

Manufacturers usually need both a product strategy for WHO PQ where relevant and a country-by-country registration strategy.

References