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Darby Kozak, Mohammad Absar, Peter Petrochenko, Xiaoming Xu, Jiwen Zheng, Yong Wu; Scientific Considerations for In Vitro Bioequivalence Studies of Generic Cyclosporine Ophthalmic Emulsions. Invest. Ophthalmol. Vis. Sci. 2017;58(8):493.
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© ARVO (1962-2015); The Authors (2016-present)
Currently, the FDA recommends two options to demonstrate bioequivalence (BE) for cyclosporine ophthalmic emulsion (COE): (1) a clinical endpoint study or (2) in vitro studies with comparative physicochemical characterization. As the in vitro option relies on demonstrating product sameness, the FDA requires generics approved by this option be formulated qualitatively and quantitatively similar to the reference product. A summary of scientific considerations when conducting studies to support the in vitro option was compiled and certain complex parameters such as particle size and viscosity were evaluated.
For development of the in vitro option, a systematic approach was adopted to identify the physicochemical parameters that are critical to the COE formulation properties as well as considerations of analytical and compartive methods. Particle size distribution (PSD) at different dilutions was measured using dynamic light scattering, laser diffraction and transmission electron microscopy (TEM). Both negative staining TEM and cryo-TEM – was used to measure globule size and morphology of the formulation. A full viscosity profile as a function of applied shear was measured using a cone-and-plate geometry.
In addition to product manufacturing conditions, analytical procedures can impact the measured physicochemical properties of COE. COE appears to have a polydisperse/multimodal PSD, which can range from a few nanometers up to a micron depending on the instrument and sample preparation. As such complementary analytical sizing methods are recommended as no one single method may be suitable to measure the entire size range. In addition, more complex histogram analysis, such as earth mover’s distance, is suggested for comparing PSD sameness. Finally, the COE formulation is non-Newtonian shear-thinning; therefore, viscosity profiles as a function of applied shear rate are recommended.
The BE guidance on COE provides further essential details on the in vitro study parameters and evaluation criteria. Due to the polydisperse nature of COE (ex. oil globules, micelles) and presence of a carbomer copolymer excipient, special considerations must be employed for particle size and viscosity measurements as well as in the method for comparative analysis to ensure generic and reference product sameness.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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