Effects of Impurities from Sugar Excipient on Filtrate Flux during Ultrafiltration and Diafiltration Process

Abstract

Sugar excipients such as sucrose and maltose are widely used for biopharmaceutical formulation to improve protein stability and to ensure isotonicity for administration. However, according to recent literature, pharmaceutical-grade sucrose contained nanoparticulate impurities (NPIs) that result in protein aggregation and degradation. The objective of this study was to evaluate the filtrate flux behavior of sugar solution during ultrafiltration (UF) and diafiltration (DF). Filtrate flux data were obtained using either a tangential flow filtration (TFF) system for DF experiments or a normal flow filtration system for UF experiments. In diafiltration experiments, which were performed using 7 g/L of human immunoglobulin G in a 20 mM histidine buffer with the 100 mM sucrose or maltose, the filtrate flux with sucrose solution decreased significantly. In contrast, the one with maltose solution was in good correspondence with the calculated filtrate flux accounting for the effects of solution viscosity. This large decline in the flux was also observed during UF experiments, in which the presence of NPIs was identified by dynamic light scattering analysis and by capturing an SEM image of the membrane surface after filtration. In addition, highly purified sucrose resulted in a much lower flux decline in TFF in the absence of NPIs. These results provide important insights into the factors governing the optimization of the UF/DF process using appropriate excipients for biopharmaceutical formulation.