Potency assignment of biotherapeutic reference standards

The role of biotherapeutic proteins in the prevention and treatment of diseases such as cancers, infectious diseases, and autoimmune disorders continues to grow. The biological activity or “potency” of a biotherapeutic reflects its mechanism of action and thus its efficacy. The potency of these complex biomolecules cannot be quantitatively correlated to chemical and physical properties and thus must be determined by comparison to a reference standard, typically using a cell-based bioassay. This lack of an absolute method for determining potency, along with test method variability and potential for bias make assignment and monitoring of reference standard potency a major challenge during pharmaceutical development and manufacturing. The reference standard links the potency of dosages administered to the patient with those of original clinical studies. Therefore, the assignment of potency to biotherapeutic reference standards is vital for assuring the quality of medicines for patients. In this work, we propose a comprehensive roadmap for assigning potency to reference standards that is compliant with the two-tier system of standards as recommended in regulatory guidance. The roadmap includes statistical approaches for study design and acceptance criteria that are risk-based and phase-appropriate. It also provides mitigation approaches for potential assay bias.