High concentration formulation developability approaches and considerations

Abstract

The growing need for biologics to be administered subcutaneously and ocularly, coupled with certain indications requiring high doses, has resulted in an increase in drug substance (DS) and drug product (DP) protein concentrations. With this increase, more emphasis must be placed on identifying critical physico-chemical liabilities during drug development, including protein aggregation, precipitation, opalescence, particle formation, and high viscosity. Depending on the molecule, liabilities, and administration route, different formulation strategies can be used to overcome these challenges. However, due to the high material requirements, identifying optimal conditions can be slow, costly, and often prevent therapeutics from moving rapidly into the clinic/market. In order to accelerate and derisk development, new experimental and in-silico methods have emerged that can predict high concentration liabilities. Here, we review the challenges in developing high concentration formulations, the advances that have been made in establishing low mass and high-throughput predictive analytics, and advances in in-silico tools and algorithms aimed at identifying risks and understanding high concentration protein behavior.

Correlating Surface Activity with Interface-Induced Aggregation in a High-Concentration mAb Solution

“…As industrial trends shift toward the use of high-concentration (>150 mg/mL) protein drugs to simplify drug administration and increase patient compliance, understanding interface-induced protein aggregation vs. aggregation in bulk solution will become even more critical. 15 This is because high-concentration formulations exhibit physicochemical properties that differ from dilute solutions, such as higher bulk viscosities and possible liquid−liquid phase separation. Also, the effects of intermolecular interactions in concentrated protein solutions are much more pronounced, which can exacerbate aggregation.…”

“…It has been shown that the adsorption of protein molecules to interfaces can also lead to partial protein unfolding and interface-induced protein particle formation. ,− However, the mechanisms and variables involved in interface-induced protein aggregation are far less understood. As industrial trends shift toward the use of high-concentration (>150 mg/mL) protein drugs to simplify drug administration and increase patient compliance, understanding interface-induced protein aggregation vs. aggregation in bulk solution will become even more critical . This is because high-concentration formulations exhibit physicochemical properties that differ from dilute solutions, such as higher bulk viscosities and possible liquid–liquid phase separation.…”

“…This is because high-concentration formulations exhibit physicochemical properties that differ from dilute solutions, such as higher bulk viscosities and possible liquid–liquid phase separation. Also, the effects of intermolecular interactions in concentrated protein solutions are much more pronounced, which can exacerbate aggregation. − Current research efforts on protein instability and protein particle formation in high-concentration mAb solutions include experimental and molecular dynamics techniques that aid in understanding viscosity behavior, protein–protein interactions, clustering, and aggregation, but these studies focus on bulk properties and bulk-mediated protein instability. ,− While it has been shown that interface-induced protein aggregation is weakly dependent on bulk protein concentration for low to moderate-concentration solutions (<100 mg/mL), there is a lack of studies dedicated to investigating the impact of high-concentration mAb solutions on interface-induced destabilization. , …”

Quantifying Protein Shape to Elucidate Its Influence on Solution Viscosity in High-Concentration Electrolyte Solutions

“…Our early research, along with that of peers, consistently reveals that while the addition of certain amino acids or inorganic salts can effectively lower the monoclonal antibody (mAb) solution’s viscosity, the extent of viscosity reduction varies. ,,, Some mAbs experience a substantial decrease in viscosity, whereas for others, the reduction in solution viscosity is not as pronounced. Currently, reduction of protein viscosity mainly relies on formulation optimization in a trial-and-error style . The intrinsic relationship between the protein structure and solution viscosity remains unknown.…”

“…Currently, reduction of protein viscosity mainly relies on formulation optimization in a trial-and-error style. 13 The intrinsic relationship between the protein structure and solution viscosity remains unknown. A deeper understanding of how protein characteristics, such as shape, surface charge distribution, molecular flexibility, etc., influence viscosity would inform the rational design of next-generation, high-concentration protein therapeutics.…”