We have extensively reviewed the critical role of sugars as effective stabilizers protecting protein against stress during the freeze-drying process and storage. However, they cannot overcome all liabilities inducing protein instability, such as interfacial stress. As discussed in Section 4.5, the protein adsorption at the ice-water interface formed during the freezing step can disrupt such interactions between protein and water, which can subsequently induce interfacial stressed-related protein aggregation. The primary goal of the formulation design is to achieve sufficient hydrogen bonding between protein and water during the freezing step to preserve the natural structure of proteins prior to the drying process which sugar can subsequently replace the water to interact with protein to retain protein stability in the dried state. To overcome such interfacial stress and ensure the adequate interaction between water and protein, blending of surfactants such as polysorbates 80 and 20 in the formulation is a common strategy if biologic drug is sensitive to interfacial interactions.