Characterization of protein rheology and delivery forces for combination products

Delivery Considerations of Highly Viscous Polymeric Fluids Mimicking Concentrated Biopharmaceuticals: Assessment of Injectability via Measurement of Total Work Done “WT”

“…These results clearly indicate that syringe volume or barrel size in addition to the rheology of the formulation has a disproportionate increase in total work done to extrude the syringe content. This observation is consistent with that of others who have shown existence of exponential relationship between viscosity increases of model antibody formulations as concentration of antibody increased (3,4).…”

“…Biologics having high molecular weights (i.e., insulin 5.8 kDa; Humira consisting of 1330 amino acids, and MW 148 kDa) and high concentrations per milliliter (mg/mL) and their means of delivery as opposed to small molecular weight drugs (i.e., epinephrine 183 Da) are associated with many challenges including their rheology. With advances in formulation design, the complexity of the formulations that are designed to enhance the solubility of insoluble drugs and provide greater stability for concentrated biologicals which tend to undergo aggregation, deamination, denaturation, hydrolysis, or oxidation has also changed dramatically (2)(3)(4). Multiple excipients, agents, and environmental factors have been investigated that can ensure both physical and chemical stability of biopharmaceuticals including the use of small sugars such as trehalose (5,6), dextran (7), surfactants like pluronic, polysorbate (8), and influence of pH, temperature, and ionic strength.…”

“…Typically, viscosities of liquids range from one to several thousand centipoise (cPs). For example, viscosity of water is 1-5 cP, blood is 10 cP, corn syrup 50-100 cP, maple syrup 150-200 cP, castor oil 250-500 cP, and many concentrated biologicals have viscosities of 10-200 cPs (4,(11)(12)(13).…”

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

“…However, such highly concentrated antibody solutions can demonstrate high viscosities in some cases, 10 which can lead to serious difficulties in their development as drug products suitable for subcutaneous administration 10 because high viscosity may increase the injection time and pain at the site of injection, adversely affecting patient compliance. 12,13 High viscosity of a concentrated antibody solution also poses difficulties during bioprocessing of the drug substance. During downstream ultrafiltration and diafiltration steps, high viscosity of the antibody solution may increase the back pressure of the pump and decrease the transmembrane flux, which may increase the processing time, destabilize the drug substance and increase manufacturing costs.…”

“…High viscosity of concentrated antibody formulations is the primary focus here, although we recognize that many other challenges associated with the development of high concentration antibody formulations, such as opalescence, solubility and aggregation, can also potentially delay the time to market. Additionally, this review focuses on Newtonian viscosity behavior of antibody solutions even though recent reports in literature have identified nonNewtonian behavior in certain antibody solutions 13,16,17 and the increase in viscosity due to accumulation of antibody molecules on the air/water interface. 18 …”