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 for 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.

Investigating the combination of single‐pass tangential flow filtration and anion exchange chromatography for intensified mAb polishing

“…For some mAb molecules, high viscosity (>10 cP) can create processing issues when operating at concentrations greater than 70–120 g/L . However, mAb A showed no significant viscosity increase with concentration; at approximately 100 g/L mAb A, the viscosity was 3.3 cP.…”

Model-Based Design and Process Optimization of Continuous Single Pass Tangential Flow Filtration Focusing on Continuous Bioprocessing

“…This leads to a significant pressure drop, which may exceed the pressure limit of the ultrafiltration systems and results in a higher operation cost expenditure (OPEX). By adjustment of the pH value or by adding excipients, the fluid properties are modifiable [13,14], but a risk for precipitation remains [15]. Another way to handle these highly concentrated solutions is by altering the geometries of the membrane channels.…”

Structure, heterogeneity and developability assessment of therapeutic antibodies

“…High concentration drug products administrated via subcutaneous (SC) injection require a formulation with manageable viscosity, making it another critical factor for evaluation at an early stage to ease developability concerns. 235 High viscosity can pose challenges to the final UF/DF step 28,236,237 and fill/ finish operation. 238,239 Viscous drug product can lead to difficulties in delivery causing low patient compliance.…”