It is well-known that recombinant HSA (rHSA) has the ability to stabilize proteins in in solution  preventing protein adsorption, protein aggregation and protein oxidation. At low protein drug concentrations (< 1mg/mL) the mechanism of action is relatively well understood and the beneficial effect is expected to act through coating of hydrophobic and hydrophilic surfaces on the primary packaging material thereby preventing depletion and surface induced aggregation of the protein drug. In contrast to this, the mechanism of action is more speculative for formulations with higher drug concentrations (> 10 mg/mL or >100+ mg/mL). Our current working hypothesis suggests that hydrophobic patches on rHSA interact with hydrophobic patches on the drugs thereby shielding surface areas on the drugs that would otherwise be prone to drive self-association. However, recent studies using small angle X-ray scattering spectroscopy (SAXS), dynamic light scattering (DLS), chromatography (AF4) and rheology to study the molecular interactions between rHSA and Bevacizumab do not confirm this model. A revised mechanism will be discussed.

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