2024-02-20-世界卫生组织-Report_of_a_WHO_workshop_on_implementation_of_the_WHO_manual_for_the_preparation_of_reference_materials_for_use_as_secondary_standards_in_antibody_testing_20页_433kb

WHO Workshop on Implementation of the Manual for Preparation of Reference Materials for Use as Secondary Standards in Antibody Testing

Report Summary

Event: Workshop held in Denpasar, Indonesia, 14-16 November 2023, bringing together national regulatory authorities, control laboratories, and industry representatives.

• Purpose: Implement guidance on establishing and calibrating secondary standards in antibody testing.
• Key Outcomes: Improved understanding of manual content (WHO TRS 1043, Annex 2), identified gaps for further guidance, enhanced networking among participants.

Background

WHO develops international standards (ISs), managed by the Expert Committee on Biological Standardization (ECBS), to ensure quality and consistent dosing of biological medicines. Secondary standards (WHO TRS 1043, Annex 2) address supply needs for limited quantities of ISs and are crucial for evaluating vaccines and diagnostic tests. The manual provides a standardized approach for developing, characterizing, and calibrating secondary standards for antibody detection. Prior workshops were requested to implement its recommendations.

Manual Overview

The manual (WHO TRS 1043, Annex 2) offers a 17-section framework on:

• Principles of secondary standard establishment (single homogeneous batch, defined unitage, suitability, stability, comparability).
• Detailed procedures for production, pooling, screening, filling, calibration, commutability assessment, stability, and uncertainty estimation (using log-transformed data, GCV, geometric mean).
• Calibration design: Multi-laboratory studies for national standards, single-laboratory for manufacturer-specific standards, requiring parallel line or dose-response analysis.

Key Recommendations & Practices Discussed

Establishment Process

• Source Material: Patient/plasma, vaccinees, normal blood; case-by-case selection due to variability.
• Calibration: Transfer unit from WHO IS using collaborative multi-laboratory studies or single-laboratory analysis; mathematical models (parallel lines, probit, sigmoid) recommended.
• Commutability: Essential for harmonization; requires representative patient samples covering concentration ranges.

Uncertainty of Measurement

• Calculation of uncertainty (combined standard uncertainty, expanded uncertainty) is critical.
• Representative precision studies were presented.

Case Studies Analysis

Case Study 1: RSV National Standard Calibration

• Outcomes: Identified candidate A with lower GCV as suitable; test samples showed good commutability relative to candidate A; high inter-lab variability noted for non-human samples.

Case Study 2: HPV-16 Secondary Standard Calibration

• Issues: Inadequate precision due to one dilution; correct calibration requires multiple dilutions and sufficient dilution points.

Case Study 3: In-house SARS-CoV-2 Standard Calibration

• Design: Correct choice of WHO IS (21/340 and 21/338 depending on assay); proper handling of invalid assays and outlier exclusion.

Case Study 4: Secondary Standard Re-testing due to Antigen Change

• Relevance: Validation required upon critical reagent change; confirms stability is necessary for ongoing use.

Conclusion & Future Directions

Networking and reliance between NRAs/NCLs, manufacturers, and laboratories are encouraged to improve efficiency and standardization globally, particularly facilitating mutual recognition agreements (MRA) to enhance accessibility to vaccines, especially in low- and medium-income countries (LMICs). WHO plans future workshops on harmonization and guidance on uncertainty reporting.