Progress and challenges of biological reference standards for vaccine quality control and evaluation

INTRODUCTION: Advances in the development, manufacture, and testing of biological products, along with the application of the 'Replacement, reduction and refinement,' have driven a paradigm shift in the establishment and application of biological reference standards (BRS) for vaccine quality control and evaluation. Traditional WHO International Standard(s) (IS), historically used for potency harmonization, now face multiple challenges stemming from vaccine diversity, platform complexity, and other factors. AREAS COVERED: This review summarizes recent updates to WHO and other regulatory guidelines on BRS, analyzes 2019-2025 BRS practices of WHO and regional/national regulatory authorities, highlights the need to develop BRS to support the advancement of novel platforms/technologies, and emphasizes harmonized coordination among WHO, regional/national BRS, and manufacturers' in-house quality control working standards. EXPERT OPINION: To ensure that the establishment of BRS could keep pace with vaccine evolution, the following are required: (1) establish rapid-response mechanisms to address emerging pathogens; (2) retain traditional BRS for vaccine quality control and evaluation to maintain traceability of measurement values; (3) develop platform and quality-control BRS for novel technologies; and (4) support manufacturers in developing a product-specific working BRS using Quality by Design (QbD) principles - traceable to phase III protective efficacy.