(M1430-10-63) Assessing In Vitro Release Testing (IVRT) in Bioequivalence Studies for Complex Products - Considerations for Ophthalmic versus Topical Dermatological Dosage Forms

Purpose: In Vitro Release Testing (IVRT) is one of the major studies used by the generic drug industry to support demonstrations of bioequivalence (BE) for proposed complex generic products including ophthalmic dosage forms and topical dermatological products due to the complex route of delivery associated with these products and the potential complexity of certain formulations. IVRT serves as part of a collective weight of evidence in the in vitro characterization based approach that may be used to evaluate the performance of a proposed generic product (test) and the corresponding reference standard. The purpose of this analysis is to describe the scientific principles and considerations for evaluating IVRT studies and to compare the IVRT methods and validation used to support a demonstration of BE for ophthalmic and topical dermatological drug products.

Methods: FDA Guidance for Industry documents, product specific guidances and scientific publications on IVRT method development, validation and conduct of pivotal studies were reviewed. More than twenty-five case studies of Abbreviated New Drug Applications (ANDAs) submitted (2014 to 2022) for topical (15) and ophthalmic (10) products were assessed to understand the scope and type of IVRT method development, validation, and statistical analysis conducted for the pivotal IVRT study. The study also compares differences in the key attributes of IVRT method and validation recommendations for ophthalmic versus topical dermatological drug products. Furthermore, selected ANDA case studies were evaluated to understand the BE assessment observations /deficiencies for the IVRT studies submitted for the ophthalmic and topical dermatological drug products considering the route of administration and the physical forms of the products.

Results: The analysis showed that in most cases, observations/deficiencies in IVRT studies were comparable across the two dosage forms. The common deficiencies ranged from the choice/justification of the IVRT apparatus, discriminatory ability of the method, appropriate membrane selection, IVRT method validation and analytical method validation. A deficiency specific to certain ophthalmic product is missing data to support the IVRT method measurement of the release of active pharmaceutical ingredient (API) from the formulation rather than the transfer of formulation/oil droplets across membranes. In general, the analysis shows that the generic drug applications may lack proper understanding of factors controlling release rates for these different dosage forms, hence, pivotal IVRT studies are often conducted using insufficiently qualified apparatus and methods that are not validated to be accurate, sensitive, robust, discriminatory, and reproducible. Comparison of the key attributes of IVRT methods for complex ophthalmic versus topical dermatological drug products indicates there are differences in the number of batches used, sampling times, apparatus types, and method validation recommendations. Furthermore, statistical analysis of the comparable rate of release (slope of regression) for topical dermatological products using the Wilcoxon rank sum/Mann Whitney rank test based on the USP Chapter < 1724 > was in some cases utilized for the data analysis of ophthalmic products, which is not considered appropriate for this dosage form. The analysis from the case studies further provides insights that varied IVRT methods (for example, selection of apparatus and filter) are used for BE demonstration for ophthalmic products which are impacted by the different types of formulations (i.e., suspensions, emulsions, ointment/gels, and inserts), which is different from the topical dermatological drug products.

Conclusion: The IVRT draft general guidance for topical drug products (October 2022) has addressed how to properly conduct well-validated IVRT studies for topical dermatological products; however, observations /deficiencies described in the Results section are still observed in some ANDAs. This analysis should alleviate some of the challenges for the generic drug industry during ANDA submission as well as during FDA BE assessment for both topical dermatological products and ophthalmic drug products, especially in understanding the different expectations of the IVRT for these two different dosage forms. For example, statistical comparison of release rate for ophthalmic products is different from the analysis recommended for topical dermatological products. Additionally, the generic industry should consider the complexities of the different types of ophthalmic drug products (suspensions, emulsions, ointments/gels, and inserts) when developing and validating the IVRT study for generic product development.

Acknowledgements: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.