The Impact of Formulation Composition and Process Settings of Traditional Batch Versus Continuous Freeze-Drying On Protein Aggregation

Abstract

The long-term stability of therapeutic protein products can be extended by freeze-drying. However, the freeze-drying process itself has several harmful stresses. A rationalized formulation design can significantly mitigate protein damage caused by freezing, dehydration and interfacial stresses of lyophilization and reconstitution. Recently, a continuous spin-freeze-drying concept was proposed as a more economical, controllable, flexible and qualitative alternative to batch freeze-drying. The purpose of this work is to compare spin-freeze-drying to traditional batch freeze-drying with regard to protein physical stability. The impacts of spinning, freezing and drying were investigated for both processing methods. Herewith, the interaction between these process phases and two common rational formulation strategies, (i.e. adding a disaccharide and a surfactant) was examined. Protein aggregates formed due to the process phase stresses were characterized with particle counting techniques and size exclusion chromatography. It was found that spin-freeze-drying exhibited essentially identical stresses causing comparable aggregation in all the process phases as compared to batch freeze-drying. Moreover, there were also analogous impacts of the formulation excipients. These observations led to the conclusion that similar freeze-drying formulation excipients and strategies tested for decades in batch freeze-drying of proteins can be utilized for spin-freeze-drying; in order to maintain protein stability during processing.