title: Computational fluid dynamics (CFD) insights into agitation stress methods in biopharmaceutical development.
abstract: Agitation of small amounts of liquid is performed routinely in biopharmaceutical process, formulation, and packaging development. Protein degradation commonly results from agitation, but the specific stress responsible or degradation mechanism is usually not well understood. Characterization of the agitation stress methods is critical to identifying protein degradation mechanisms or specific sensitivities. In this study, computational fluid dynamics (CFD) was used to model agitation of 1 mL of fluid by four types of common laboratory agitation instruments, including a rotator, orbital shaker, magnetic stirrer and vortex mixer. Fluid stresses in the bulk liquid and near interfaces were identified, quantified and compared. The vortex mixer provides the most intense stresses overall, while the stir bar system presented locally intense shear proximal to the hydrophobic stir bar surface. The rotator provides gentler fluid stresses, but the air-water interfacial area and surface stresses are relatively high given its low rotational frequency. The orbital shaker provides intermediate-level stresses but with the advantage of a large stable platform for consistent vial-to-vial homogeneity. Selection of experimental agitation methods with targeted types and intensities of stresses can facilitate better understanding of protein degradation mechanisms and predictability for "real world" applications.
authors.affiliation: Formulation Sciences, MedImmune LLC., One MedImmune Way, Gaithersburg, MD 20878, USA. Baig@medimmune.com
authors.forename: Ge
authors.initials: G
authors.lastname: Bai
authors.forename: Jared S
authors.initials: JS
authors.lastname: Bee
authors.forename: James G
authors.initials: JG
authors.lastname: Biddlecombe
authors.forename: Quanmin
authors.initials: Q
authors.lastname: Chen
authors.forename: W Thomas
authors.initials: WT
authors.lastname: Leach
mesh_terms: D001702:Biopharmaceutics / Q000295:instrumentation / Q000379:methods*; D003198:Computer Simulation; D004355:Drug Stability; D004867:Equipment Design; D057446:Hydrodynamics; D008956:Models, Chemical; D009038:Motion; D009716:Numerical Analysis, Computer-Assisted; D011312:Pressure; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry*; D015203:Reproducibility of Results; D013314:Stress, Mechanical; D013499:Surface Properties; D013997:Time Factors; D014783:Viscosity
chemical_list: D011506:Proteins