Brief Article pubs.acs.org/molecularpharmaceutics
Comment on “Quality by Design Approach for Understanding the Critical Quality Attributes of Cyclosporine Ophthalmic Emulsion” Anuradha Gore,*,† Mayssa Attar,‡ Chetan Pujara,† and Sesha Neervannan† †
Pharmaceutical Development and ‡Pharmacokinetics and Drug Disposition, Allergan Inc, 2525 Dupont Drive, Irvine, California 92612, United States
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The authors’ conclusion that, if the five characteristics of droplet size, zeta potential, viscosity, turbidity, and osmolality are controlled for emulsions with similar ingredients, bioequivalence may be assumed is thus unsupported by any clinical evidence. 2. In addition, the authors offer no clinical data or other evidence to support a position that the five characteristics listed are the only product attributes that must be controlled for a clinically substitutable product. Allergan’s proprietary data point to a need for more stringent control requirements involving additional product attributes. Indeed, the authors’ position that in vitro assessments of the five characteristics they identified are sufficient to establish bioequivalence is undercut by FDA’s Draft Guidance on Cyclosporine (June 19, 2013). The Draft Guidance itself is inadequate,2 but even that document sets forth six characteristics for in vitro assessment in evaluating bioequivalence of cyclosporine ophthalmic emulsions, two of which (pH and surface tension) are not even included among the five attributes that the authors deem significant. 3. The drug release methodology used is not appropriate for measuring cyclosporine A release from the emulsion dosage form. Currently, no in vitro release test exists for the approved drug product RESTASIS, and no public method has been validated for a topical ophthalmic emulsion. FDA has acknowledged the difficulties of developing suitable drug release tests for ophthalmic products in various workshops on in vitro/dissolution testing of novel/special dosage forms.3 Allergan has publicly discussed2 some of the challenges in developing a biorelevant in vitro release method that can accurately measure drug release and absorption from a complex emulsion in the dynamic ocular environment. The drug release/diffusion method discussed in the current publication faces these continuing limitations, including the following. a. The 3 h time point used for drug release is not relevant for ophthalmic formulations: Due to the short duration/residence time available for drug release (
