title: Quality by design approach for understanding the critical quality attributes of cyclosporine ophthalmic emulsion.
abstract: Restasis is an ophthalmic cyclosporine emulsion used for the treatment of dry eye syndrome. There are no generic products for this product, probably because of the limitations on establishing in vivo bioequivalence methods and lack of alternative in vitro bioequivalence testing methods. The present investigation was carried out to understand and identify the appropriate in vitro methods that can discriminate the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion formulations having the same qualitative (Q1) and quantitative (Q2) composition as that of Restasis. Quality by design (QbD) approach was used to understand the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion. The formulation variables chosen were mixing order method, phase volume ratio, and pH adjustment method, while the process variables were temperature of primary and raw emulsion formation, microfluidizer pressure, and number of pressure cycles. The responses selected were particle size, turbidity, zeta potential, viscosity, osmolality, surface tension, contact angle, pH, and drug diffusion. The selected independent variables showed statistically significant (p < 0.05) effect on droplet size, zeta potential, viscosity, turbidity, and osmolality. However, the surface tension, contact angle, pH, and drug diffusion were not significantly affected by independent variables. In summary, in vitro methods can detect formulation and manufacturing changes and would thus be important for quality control or sameness of cyclosporine ophthalmic products.
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring, Maryland 20993, United States.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.forename: Usha
authors.initials: U
authors.lastname: Katragadda
authors.forename: Yellela S R
authors.initials: YS
authors.lastname: Krishnaiah
authors.forename: Lawrence
authors.initials: L
authors.lastname: Yu
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000737:chemistry*; D016503:Drug Delivery Systems; D004355:Drug Stability; D004655:Emulsions; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry*; D009883:Ophthalmic Solutions / Q000737:chemistry*; D010316:Particle Size; D011786:Quality Control; D013678:Technology, Pharmaceutical / Q000592:standards*; D013810:Therapeutic Equivalency
chemical_list: D004655:Emulsions; D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D016572:Cyclosporine
keywords: critical quality attributes droplet size; cyclosporine; diffusion; microemulsion; ophthalmic; quality by design; viscosity; zeta potential