Particle Engineering for High Concentration Protein Suspensions
Erica Schlesinger, Ph.D
VP of Technical Development
There is a growing interest across the industry in developing technologies for subcutaneous delivery of high dose protein therapeutics. High concentration protein solutions are limited in their application to this space by viscosity and stability; both phenomena are driven by protein-protein interactions in solution. Three primary approaches have emerged to overcome the technical challenges associated with high dose delivery: high volume delivery, viscosity reducing excipients, and high concentration suspensions. While high concentration suspensions represent the furthest departure from traditional parenteral formulations for therapeutic proteins, this approach has the potential to address both the syringability and stability challenges as well as to provide a broadly applicable technology platform.
Development of high concentration suspensions consists of two components, the solid-state formulation of the therapeutic and the vehicle, with a focus on achieving maximum syringable doses while maintaining protein stability. The protein must remain stable during the manufacturing process, in the solid state as an intermediate, and in suspension under appropriate storage conditions for autoinjectors (2-8 °C or ambient). Formulation and vehicle selection are largely driven by protein stability considerations, leaving particle form to be a key parameter in optimizing syringability. While there are a variety of proprietary technologies being developed to produce solid state protein for use in these systems, this talk focuses on the use of spray drying as a precedented and well-understood pharmaceutical unit operation to engineer particles for maximum performance in suspensions.
For a formulation to be considered syringable from a pre-filled syringe for use in an autoinjector, it must be dispensable with forces no more than 50 N and with no blockage. Particle properties such as size, polydispersity, morphology and density all impact the maximum concentration at which a suspension can be delivered using a given device and vehicle. In this talk, we show that high concentration suspensions comprised of spray-dried protein and a non-aqueous vehicle at greater than 20 wt% solids exhibit non-Newtonian behavior, and that the trends in syringe force as a function of solids loading are not significantly impacted by vehicle composition when normalized to syringe force of the vehicle alone. We additionally investigate how particle size and distribution, formulation, and morphology impact dispensing force – comparing empirical syringe force data to the fundamental equations governing suspension viscosity. We identify that density is the key particle and powder attribute impacting syringability and consider how formulation and powder properties tied to density can be tuned in spray dried products to maximize deliverable doses in non-aqueous suspensions.
Protein suspensions forsubcutaneous delivery of high dose protein therapeutics
Target product profile for highconcentration protein suspensions
Theoretical properties of particlesimpacting suspension viscosity
Properties of spray dried particlesimpacting syringe dispensing force