title: High concentration biotherapeutic formulation and ultrafiltration: Part 1 pressure limits.
abstract: High therapeutic dosage requirements and the desire for ease of administration drive the trend to subcutaneous administration using delivery systems such as subcutaneous pumps and prefilled syringes. Because of dosage volume limits, prefilled syringe administration requires higher concentration liquid formulations, limited to about 30 cP or roughly 100-300 g L-1for mAb's. Ultrafiltration (UF) processes are routinely used to formulate biological therapeutics. This article considers pressure constraints on the UF process that may limit its ability to achieve high final product concentrations. A system hardware analysis shows that the ultrafiltration cassette pressure drop is the major factor limiting UF systems. Additional system design recommendations are also provided. The design and performance of a new cassette with a lower feed channel flow resistance is described along with 3D modeling of feed channel pressure drop. The implications of variations in cassette flow channel resistance for scaling up and setting specifications are considered. A recommendation for a maximum pressure specification is provided. A review of viscosity data and theory shows that molecular engineering, temperature, and the use of viscosity modifying excipients including pH adjustment can be used to achieve higher concentrations. The combined use of a low pressure drop cassette with excipients further increased final concentrations by 35%. Guidance is provided on system operation to control hydraulics during final concentration. These recommendations should allow one to design and operate systems to routinely achieve the 30 cP target final viscosity capable of delivery using a pre-filled syringe. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:113-124, 2017.
authors.affiliation: Biomanufacturing Sciences Network, EMD Millipore Corporation, 900 Middlesex Turnpike, Billerica, MA, 01821.
authors.forename: Herb
authors.initials: H
authors.lastname: Lutz
authors.affiliation: Biomanufacturing Sciences Network, EMD Millipore Corporation, 900 Middlesex Turnpike, Billerica, MA, 01821.
authors.forename: Joshua
authors.initials: J
authors.lastname: Arias
authors.affiliation: Bioprocess R&D, EMD Millipore Corporation, Bedford, MA, 01730.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
mesh_terms: D001288:Attention; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004339:Drug Compounding; D054796:Drug Dosage Calculations; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D011312:Pressure; D013696:Temperature; D014462:Ultrafiltration; D014783:Viscosity
chemical_list: D004364:Pharmaceutical Preparations
keywords: concentration; high concentration protein formulation; tangential flow filtration; ultrafiltration