A comprehensive industrial perspective on microstructural characterization and relation to bioequivalence of topical dosage forms

The effectiveness of topical semi-solid formulations, such as ointments, creams, and gels, relies on their qualitative (Q1) and quantitative (Q2) composition, but most critically, on their internal microphysical and chemical structure (Q3). This review, from an industrial perspective, emphasises the crucial importance of evaluating Q3 in research, development, quality control, and regulatory approval processes. Assessing Q3 involves detailed characterization and comparison of key physicochemical and structural features, such as appearance, rheological properties (e.g., viscosity, yield stress), microstructure (using microscopy, particle size analysis), the drug’s physical state (crystal form and state), in vitro release testing (IVRT), water activity, pH, and drying rate. These parameters create the formulation’s “structural fingerprint, " bridging manufacturing, product quality, and clinical performance. By examining the scientific rationale, methodologies (including development and validation), and strategies underlying Q3 evaluation within bioequivalence frameworks, the review provides researchers, students, and industry professionals with a comprehensive understanding of these topics. It highlights that, according to the Quality by Design (QbD) approach, thorough knowledge and proper application of Q3 assessments are vital for ensuring consistent performance of locally acting semi-solid drugs, supporting rational generic development, and meeting stricter regulatory standards (e.g., FDA and EMA guidelines). As analytical techniques improve and QbD principles deepen, Q3 assessment will advance semi-solid formulation science from empirical methods to precision-based approaches. Ultimately, this progress will help develop high-quality, accessible medicines that are safe, effective, and cost-efficient for public health. In industrial practice, Q3 evaluation of semi-solid formulations has evolved from a scientific regulatory concept into a core tool that spans research and development, manufacturing, and quality control. By systematically integrating Q1, Q2, and Q3 consistency assessments, this strategy enables precise control of key process parameters during manufacturing, establishes a real-time quality control system based on process analytical technology, and significantly reduces product development and lifecycle management costs. Drawing on industrial applications elucidates the practical value of Q3 evaluation in enhancing process robustness, optimising quality release protocols, and supporting global regulatory submissions, thereby providing a practice-oriented reference for the efficient development and lean manufacturing of semi-solid formulations.