Application of thin gap rheometry for high shear rate viscosity measurement in monoclonal antibody formulations

Abstract

The key highlight of this work was to develop a thin gap methodology on a mechanical rheometer for characterizing high concentration monoclonal antibody formulations. This work was done from applied formulation perspective to provide guidance on an additional measurement protocol with the objective of further reducing sample volume requirement for biopharmaceutical formulation rheology measurements and provide viscosity data over a wide shear rate range. This is especially relevant for early stage discovery where there are sample volume limitations. This developed methodology in addition to an understanding of the diffusion interaction parameter was then in turn utilized to elucidate the effect of surfactants and excipients on the high shear rate viscosity of high concentration monoclonal antibodies. In this study, gap dependent changes in the fundamental rheological behavior were observed. At higher gaps, an initial shear thinning behavior was observed at lower shear rates and this trend was found to disappear at thin gaps. This shear thinning which is due to air water interface disappears as the gap size decreases. At high shear rates, there is a convergence of all the viscosity data for all the gaps. This also converges with the mVROC data. However, at smallest gaps studied (50 µm) shear thickening is observed at intermediate shear rates. This maybe attributable to the protein molecules undergoing flow induced aggregation due to increased confinement thereby causing shear thickening and an increase in viscosity. However, this trend eventually diminishes at higher shear rates which could be attributed to flow induced alignment of protein aggregates thereby causing a decrease in viscosity. Addition of either excipients (like Arginine- HCl, NaCl) or surfactants (like polysorbate80) seem to have a drastic impact on shear thickening caused potentially by flow induced aggregation. Addition of excipients also resulted in approximately 33–50% decrease in the viscosity of monoclonal antibody (mAb) solution and the diffusion interaction parameter kD was seen to be indicative of the high shear rate viscosity behavior of these formulations.