title: Sterile Filtration of Highly Concentrated Protein Formulations: Impact of Protein Concentration, Formulation Composition, and Filter Material.
abstract: Differences in filtration behavior of concentrated protein formulations were observed during aseptic drug product manufacturing of biologics dependent on formulation composition. The present study investigates filtration forces of monoclonal antibody formulations in a small-scale set-up using polyvinylidene difluoride (PVDF) or polyethersulfone (PES) filters. Different factors like formulation composition and protein concentration related to differences in viscosity, as well as different filtration rates were evaluated. The present study showed that filtration behavior was influenced by the presence or absence of a surfactant in the formulation, which defines the interaction between filter membrane and surface active formulation components. This can lead to a change in filter resistance (PES filter) independent on the buffer system used. Filtration behavior was additionally defined by rheological non-Newtonian flow behavior. The data showed that high shear rates resulting from small pore sizes and filtration pressure up to 1.0 bar led to shear-thinning behavior for highly concentrated protein formulations. Differences in non-Newtonian behavior were attributed to ionic strength related to differences in repulsive and attractive interactions. The present study showed that the interplay of formulation composition, filter material, and filtration rate can explain differences in filtration behavior/filtration flux observed for highly concentrated protein formulations thus guiding filter selection.
authors.affiliation: Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd., Basel, 4070, Switzerland.|Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, 4056, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Allmendinger
authors.affiliation: Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd., Basel, 4070, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Mueller
authors.affiliation: Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, 4056, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Huwyler
authors.affiliation: Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd., Basel, 4070, Switzerland.
authors.forename: Hanns-Christian
authors.initials: HC
authors.lastname: Mahler
authors.affiliation: Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd., Basel, 4070, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry; D005374:Filtration / Q000379:methods*; D008567:Membranes, Artificial; D011108:Polymers / Q000737:chemistry; D011145:Polyvinyls; D016062:Porosity; D011506:Proteins / Q000737:chemistry*; D012212:Rheology; D013242:Sterilization / Q000379:methods*; D013450:Sulfones / Q000737:chemistry; D014783:Viscosity; D005465:Fluorocarbon Polymers
chemical_list: D000911:Antibodies, Monoclonal; D001688:Biological Products; D005079:Excipients; D008567:Membranes, Artificial; D011108:Polymers; D011145:Polyvinyls; D011506:Proteins; D013450:Sulfones; C024865:polyvinylidene fluoride; D005465:Fluorocarbon Polymers; C022840:polyether sulfone
keywords: PES filter; PVDF filter; excipients; highly concentrated monoclonal antibody formulation; polysorbate; protein formulation; proteins; sterilizing-grade filter; surfactant; viscosity