Monoclonal Antibodies (mAbs) have widespread clinical use as prophylactics for various infectious diseases, and also as therapeutics for a number of clinical indications. The shear viscosity of mAb formulations is not only a key constituent engineering input for delivery device design, but is also a sensitive indicator of protein aggregation at molecular and larger lengthscales, e.g. reversible self-association, and sub-visible particle formation. For these reasons high-throughput measurement and prediction/ranking of formulation shear viscosity is an important activity during both early and late stage formulation development. Recent approaches that have been proposed postulate that the diffusion interaction parameter, kD, measured in dilute solutions is an accurate predictor of high concentration formulation viscosity. Indeed, some datasets published thus far seem to provide some evidence supporting this empirical hypothesis, underlying which is the implicit assumption that hydrodynamic interactions in concentrated solutions are negligible and that the only contribution to shear viscosity arises from protein-protein interactions (PPI). A critical examination of this hypothesis using data generated in-house as well as recent literature data leads to the conclusion that kD is a poor predictor of concentrated formulation viscosity. A theoretical explanation for this result is proposed, invoking the work of Harding & Johnson, who derived 2MB22 = kD + kS + ν, where M, B22, ν and kS denote the molar mass, osmotic second virial coefficient, partial specific volume and Gralen parameter, respectively. For Brownian diffusion of hard spheres, an admittedly crude approximation for proteins, Felderhof calculated kS in terms of virial, Oseen, short-range hydrodynamic and force dipole terms. The Oseen interaction parameter kO, which has hydrodynamic and electrical double layer contributions, and virial term provide a larger contribution to kD than the other terms. Felderhof’s theory makes it possible to understand why assumption of PPI (virial terms) as being the sole contributor to shear viscosity, while ignoring hydrodynamics, provides poor predictions of formulation viscosity.

Is the dilute solution diffusion interaction parameter a robust predictor of concentrated monoclonal antibody formulation shear viscosity?

253rd National Meeting (2017)

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