Protein Adsorption of In-line Intravenous Infusion Filter and the Corresponding Mitigation Plans.

Abstract

Protein adsorption is one of the most frequently observed incompatibility issues during intravenous (IV) administration of therapeutic proteins, especially at low concentration, leading to a lower-than-expected drug recovery and potential insufficient therapeutic effect. With its porous structure and complex surface physicochemical property, the in-line filter is usually the main component where protein adsorption happens. Thus, comprehending the adsorption mechanism between proteins and filter membranes is essential for designing effective mitigation strategies. In this study, the adsorption behaviors for 4 proteins with different pI (isoelectric point) and hydrophobicity were evaluated after dilution to 5 μg/mL in 5% dextrose (D5W) and 0.9% sodium chloride (saline), respectively. The results showed that in-line filter is the main contributor to protein loss compared with IV bag and infusion line. The adsorption in D5W was dominated by electrostatic attraction between positively charged protein and negatively charged filter membrane. By adjusting the solution pH above the protein pI to have negatively charged protein or using positively charged filter membrane, the adsorption was effectively reduced by reducing the electrostatic attraction, while adding electrolyte solution could be similarly effective by shielding the surface charge to reduce the electrostatic attraction. In addition, adding surfactant could further reduce the adsorption induced by hydrophobic interaction between protein and contacting materials including IV bag, infusion line and in-line filter as well. When saline was used as a diluent, hydrophobic interaction between protein and filter membrane was the main cause for protein with high hydrophobicity. 0.005% (w/v) polysorbate 80 was demonstrated to be effective to elevate the dose recovery to about 100% for all the evaluated proteins. A decision tree was provided to guide the design of proper mitigation plans to reduce the protein adsorption during IV infusion based on the type of diluent, filter membrane and protein pI.