On the role of excipients in biopharmaceuticals manufacture: Modelling-guided formulation identifies the protective effect of arginine hydrochloride excipient on spray-dried Olipudase alfa recombinant protein.

ABSTRACT

Biopharmaceuticals are labile biomolecules that must be safeguarded to ensure the safety, quality, and efficacy of the product. Batch freeze-drying is an established means of manufacturing solid biopharmaceuticals but alternative technologies such as spray-drying may be more suitable for continuous manufacturing of inhalable biopharmaceuticals. Here we assessed the feasibility of spray-drying Olipudase alfa, a novel parenteral therapeutic enzyme, by evaluating some of its critical quality attributes (CQAs) in a range of excipients, namely, trehalose, arginine (Arg), and arginine hydrochloride (Arg-HCl) in the sucrose/methionine base formulation. The Arg-HCl excipient produced the best gain in CQAs of spray-dried Olipudase with a 63% reduction in reconstitution time and 83% reduction in the optical density of the solution. Molecular dynamics simulations revealed the atomic-scale mechanism of the protein-excipient interactions, substantiating the experimental results. The Arg-HCl effect was explained by the calculated thermal stability and structural order of the protein wherein Arg-HCl acted as a crowding agent to suppress protein aggregation and promote stabilization of Olipudase post-spray-drying. Therefore, by rational selection of appropriate excipients, our experimental and modelling dataset confirms spray-drying is a promising technology for the manufacture of Olipudase and demonstrates the potential to accelerate development of continuous manufacturing of parenteral biopharmaceuticals.