Mechanistic and predictive formulation development for viscosity mitigation of high-concentration biotherapeutics.

Proteins are an important class of therapeutics for combatting a wide variety of diseases. The increasing demand for convenient, patient-centric treatment options has propelled the development of subcutaneously delivered protein therapies and increased the interest in novel formulations and delivery methods. However, subcutaneous delivery of protein therapeutics remains a challenge due to the high protein concentrations ( >100 mg/mL) required to circumvent lower bioavailability and the smaller injection volumes required to enable the use of mature and cost-effective devices, such as standard prefilled syringes and autoinjectors. At high concentrations, protein solutions exhibit elevated viscosity, which poses injectability and manufacturing challenges. Here, we review the state of the art in experimental and computationally predictive formulation development approaches for viscosity mitigation of high-concentration protein solution therapeutics, and we suggest new directions for expanding the utility of these approaches beyond traditional monoclonal antibodies. Innovative approaches should leverage and combine advances in both experimental and computational methods, including machine learning and artificial intelligence, to rapidly identify formulation compositions for viscosity reduction, and subsequently facilitate the development of patient-centric biotherapeutics.