title: Rheological characterization and injection forces of concentrated protein formulations: an alternative predictive model for non-Newtonian solutions.
abstract: Development of injection devices for subcutaneous drug administration requires a detailed understanding of user capability and forces occurring during the drug administration process. Injection forces of concentrated protein therapeutics are influenced by syringe properties (e.g., needle diameter) and injection speed, and are driven by solution properties such as rheology. In the present study, it is demonstrated that concentrated protein therapeutics may show significantly reduced injection forces because of shear-thinning (non-Newtonian) behavior. A mathematical model was thus established to predict/correlate injection forces of Newtonian and non-Newtonian solutions with viscosity data from plate/cone rheometry. The model was verified experimentally by glide-force measurements of reference and surrogate solutions. Application of the suggested model was demonstrated for injection force measurements of concentrated protein solutions to determine viscosity data at high shear rates (3 × 10(4)-1.6 × 10(5)s(-1)). By combining these data with viscosity data obtained by different viscosity methods (plate/cone and capillary rheometry), a viscosity-shear rate profile of the protein solution between 10(2) and 1.6 × 10(5)s(-1) was obtained, which was mathematically described by the Carreau model. Characterization of rheological properties allows to accurately predict injection forces for different syringe-needle combinations as well as injection rates, thus supporting the development of injection devices for combination products.
authors.affiliation: Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd, Basel, Switzerland; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, 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, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, 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, Switzerland.
authors.forename: Hanns-Christian
authors.initials: HC
authors.lastname: Mahler
authors.affiliation: Device Development, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Edward
authors.initials: E
authors.lastname: Schwarb
authors.affiliation: Late Stage Pharmaceutical Development, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Isidro E
authors.initials: IE
authors.lastname: Zarraga
authors.affiliation: Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: robert.mueller.rm1@roche.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Mueller
mesh_terms: D000906:Antibodies / Q000008:administration & dosage* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems / Q000295:instrumentation; D004867:Equipment Design; D005079:Excipients / Q000737:chemistry; D007279:Injections, Subcutaneous; D008956:Models, Chemical; D009339:Needles; D012212:Rheology; D033081:Shear Strength; D013314:Stress, Mechanical; D013594:Syringes; D013678:Technology, Pharmaceutical / Q000379:methods*; D014783:Viscosity
chemical_list: D000906:Antibodies; D005079:Excipients
keywords: High protein concentration; Injection device; Injection forces; Monoclonal antibody formulation; Non-Newtonian; Rheology; Shear-thinning behavior; Subcutaneous drug administration; Viscosity