A product control framework for extracellular vesicle therapeutics: Quality attributes, stability, analytical...

Extracellular vesicle (EV) therapeutics are being developed as native or minimally modified products and as engineered delivery systems, yet their composition and activity depend strongly on source cells, manufacturing, formulation, and storage. This review examines how established pharmaceutical and regulatory principles can be applied to EV product development in the United States, the European Union, Japan, and the Republic of Korea. We organize candidate quality attributes into four domains: identity, purity, potency, and safety-related quality attributes and controls. Criticality should be established through product-specific risk assessment rather than a fixed assay panel. We propose a three-axis framework for describing stability evidence by biological source, product state and storage, and downstream process sequence, supplemented by key study descriptors. Analytical procedures are evaluated according to the quality decisions they support in characterization, process control, release, stability, and comparability. For products with a complex or partly defined mechanism of action, we propose that a functional procedure anchor the potency strategy. For nonclinical biodistribution, we propose a modular framework from which blood or biofluid kinetics, longitudinal imaging, quantitative tissue analysis, and cellular or spatial localization can be selected. Interpretation depends on defining the measured entity and establishing the stability of product-label association. Although legal classifications differ across jurisdictions, the underlying scientific questions are similar. Near-term regulatory convergence should focus on common technical product descriptions, transparent CQA decisions, measurement comparability, and consistent reporting of stability and biodistribution studies. These frameworks support product-specific development rather than universal specifications or fixed acceptance criteria.