Mechanistic Study of Drying Phenomena of Highly Concentrated Protein Therapeutics-Drying Kinetics and Protein Aggregation

Abstract

The fill-finish process of highly concentrated protein formulations poses several technical challenges and, in particular, the filling process is critical to ensure filling accuracy. As highly concentrated formulations comprise a significant nonvolatile fraction, drying of drug product at the filling nozzle may occur during line interruptions. In many cases, this is a result of dripping at the filling nozzle and is dependent on environmental factors. The dried product may be picked up by the units after filling interruption and, although in small quantities, the effect of drying on the quality of the drug product is currently unclear. We investigated the drying phenomenon of a highly concentrated monoclonal antibody formulation (120 mg/mL) and studied the drying kinetics and associated aggregation propensity. In this regard, we established a robust method simulating the drying process dependent on environmental conditions such as relative humidity and air flow. We revealed that the drying kinetics were characterized by an initial fast evaporation phase, which was shorter for lower relative humidity and air flow, followed by a plateau phase. Protein aggregation particularly increased during the plateau phase and was positively correlated with relative humidity. Drying kinetics and aggregate formation were modeled using Hill's equation. We highlight that drying phenomena are relevant for small-volume drug products (magnitude of 100-200 µL), in particular for dosing accuracy, but less critical for larger fill volumes in the milliliter range. Especially for the latter, they might be negligible if the dried product can fully dissolve in the first units after filling interruption and in case of consistent drug product quality because of adequate formulation choice. Ultimately, we summarize technical options to avoid drying phenomena of highly concentrated protein formulations and emphasize the importance of adequate pump parameter setting.

Keywords: aseptic filling; drying events; fill-finish; highly concentrated protein formulation; monoclonal antibody; nozzle clogging.