OPTIMIZATION OF BIOEQUIVALENCE PROGRAMS AND PHARMACOECONOMIC DECISION-MAKING FOR GENERIC METFORMIN HYDROCHLORIDE IMMEDIATE-RELEASE TABLETS: A REGULATORY BIOPHARMACEUTICS FRAMEWORK

Abstract

Generic medicinal products are essential for improving access to long-term pharmacotherapy and reducing healthcare expenditure. However, generic substitution requires scientifically justified evidence that the test product is interchangeable with an appropriate reference medicinal product. Bioequivalence (BE) studies remain the principal regulatory instrument for demonstrating comparable systemic exposure between test and reference products, but conventional in vivo BE programs may be associated with substantial clinical, bioanalytical, organizational and economic burden. This article proposes a regulatory biopharmaceutics and pharmacoeconomic framework for optimizing BE programs for generic metformin hydrochloride immediate-release tablets. Metformin hydrochloride was selected as a model active substance because it is widely used in type 2 diabetes mellitus, has broad generic representation, and combines high aqueous solubility with absorption-limited pharmacokinetics. The framework integrates reference product selection, pharmaceutical equivalence confirmation, formulation and excipient risk screening, comparative in vitro dissolution testing, similarity factor evaluation, Biopharmaceutics Classification System (BCS)-based biowaiver considerations, in vivo study design, bioanalytical method validation, sample size justification and cost-impact analysis. The proposed strategy is not intended to reduce regulatory requirements. Instead, it aims to minimize avoidable clinical and economic burden by identifying formulation-related risks before human studies, supporting evidence-based biowaiver decisions when scientifically acceptable, and improving the quality of BE planning. For generic metformin products, particular attention should be paid to the relationship between dissolution behavior, excipient composition, absorption limitations, pharmacokinetic variability and regulatory expectations. Product-specific validation using comparative dissolution data, validated plasma metformin quantification, pharmacokinetic analysis and formal cost calculations is required before implementation.