Product Quality Research for Developing and Assessing Regulatory Submissions for Generic Cyclosporine Ophthalmic Emulsions

Abstract

Approval of the first generic 0.05% cyclosporine ophthalmic emulsion (COE) in the U.S. represents a milestone achievement of the science and research program in the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER). COE is a locally acting complex drug product indicated to increase tear production in patients whose production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. The path to approval required overcoming numerous scientific challenges to determining therapeutic equivalence to the reference listed drug. Researchers in CDER's Office of Pharmaceutical Quality and Office of Generic Drugs developed a quality by design approach to understand the effects of process and formulation variables on the product's critical quality attributes, including globule size distribution (GSD), turbidity, viscosity, zeta potential, surface tension, and osmolality. CDER researchers explored multiple techniques to perform physicochemical characterization and analyze the GSD including laser diffraction, nanoparticle tracking analysis, cryogenic transmission electron microscopy, dynamic light scattering, asymmetric field flow fractionation, and two-dimensional diffusion ordered spectroscopy nuclear magnetic resonance. Biphasic models to study drug transfer kinetics demonstrated that COEs with qualitative and quantitative sameness and comparable GSDs, analyzed using earth mover's distance, can be therapeutic equivalents. This body of research facilitated the review and approval of the first U.S. generic COE. In addition, the methods and fundamental understanding developed from this research may support the development and assessment of other complex generics. The approval of a generic COE should improve the availability of this complex drug product to U.S. patients.

Keywords: bioequivalence; complex formulation; critical quality attribute; cyclosporine ophthalmic emulsion; drug diffusion; generic drug product; globule size distribution; physicochemical characterization; polydisperse.