Contamination of Anti-Vegf Drugs for Intravitreal Injection

Abstract

All three tested agents are available in similar quality regarding particulate purity and silicone oil microdroplet count. Repackaging can have a major impact on the quality.

Observation of Silicone Oil Within the Vitreous and Sclera Following Intravitreal Administration of Biotherapeutics Using Insulin Syringes in Cynomolgus Monkeys

“…The IVT studies are routinely conducted in the cynomolgus monkey and accepted by regulatory agencies because the anatomy of the monkey eye is very similar to that of the human eye. The location of the silicone oil droplets at the dosing site and appearance as multifocal clear spheres or smaller fine white vitreous floaters is consistent with silicone droplets reported in the human clinical studies 4,5,7,13,14 indicating that this preclinical finding translates from cynomolgus monkeys to humans and that the monkey model can be used to further investigate this phenomenon. Investigation into previous preclinical studies revealed 2 studies conducted in dog and 1 in rabbit that did not support our hypothesis that this phenomenon would translate for all species.…”

“…These structures had thicker walls and, as in the 14-week study, appeared identical to those described as silicone oil droplets in humans dosed with a variety of biologics in a clinical setting. 4,5,7,13,14 The affected animals in the historical studies also exhibited no appreciable impact on vision associated with the floaters/spheres (although our abilities to detect such changes in animals is limited), and there was also no evidence that the material was associated with a greater inflammatory response or alteration in intraocular pressure.…”

“…Their location at the dosing site and appearance as multifocal clear spheres or smaller fine white vitreous floaters were consistent with silicone oil droplets reported in clinical settings in humans. 4,5,7,13,14 The spheres and floaters were not associated with an appreciable inflammatory response on ophthalmic examination, and their multifocal nature suggested that they represented emulsified silicone oil.…”

Release of silicone oil droplets from syringes

“…For instance, if the silicone oil lubrication were similar in two syringe types, fewer oil droplets would be expected in the syringe in the syringe with more dead space. Schargus et al [16]. conducted steady-state biophysical analyses that showed that original prefilled ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA) glass syringes, original vials with aflibercept, and repacked ready-to-use plastic syringes filled with bevacizumab (Avastin, Genentech, Inc.) from a compounding pharmacy are similar regarding particulate purity and silicone oil microdroplet counts.…”

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

“…Manufacturing processes (e.g., fermentation, purification, formulation, filling, shipment and storage) of biopharmaceuticals can also lead to aggregation, especially upstream prior to formulation [ 28 ]. Aggregation can occur due to shear and filling steps, multiple freeze–thaw cycles, compounding and mechanical shock [ 29 , 30 ]. Aggregation also presents significant challenges in manufacturing due to reduction in yields [ 31 ].…”