Drug Product Characterization of High Concentration Non-Aqueous Protein Powder Suspensions

Abstract

High concentration protein formulations for subcutaneous injection represent a substantial number of development projects in the pharmaceutical industry. Such concentrated aqueous protein solutions face some specific challenges such as increased viscosity and aggregation propensity. Protein powder suspensions in non-aqueous vehicles could be an alternative providing lower viscosity than the respective aqueous solution. The choice of potential suspension vehicles is limited as traditional non-aqueous liquids, such as oils, show an inherent high viscosity. We studied suspensions prepared by dispersing spray-dried protein powder in different vehicles including sesame oil and medium chain triglycerides, as well as fluorinated and semifluorinated alkanes. We found, that semifluorinated alkanes enable formulations with high concentrations up to 280 mg/ml monoclonal antibody with a low viscosity of less than 10 mPa·s and low injection forces. The glide force of suspensions containing 210 mg/ml protein was not affected by the particle size of the spray-dried powders with medians ranging from 1 to 14 µm. In contrast, suspensions prepared with cryo-milled powder showed markedly higher viscosities and were not injectable at the same concentration. Protein powder suspensions were syringeable using a 25G needle. Vial filling using a peristaltic pump was possible and lead to a uniform filling. Sedimentation of the suspension was slow and does not lead to challenges upon vial filling during manufacturing or transfer of the suspension into syringes. Thus, we could show that dispersions of spray-dried protein powders in non-aqueous vehicles, such as semifluorinated alkanes, are a promising alternative to aqueous protein solutions at high concentrations.