PFI-TT: A High-Throughput Instrument for Measuring the Stability of Liquid Formulations of Therapeutic Proteins

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The broader impact/commercial potential of this Partnerships for Innovation-Technology Translation (PFI-TT) project is the development of an instrument that will reduce the time required to screen the stability of therapeutic proteins, which have revolutionized the ability to fight diseases like cancer, Alzheimer's disease, and arthritis. The stability of these protein-based drugs is a major concern for ensuring a 2-year shelf-life for liquid formulations under refrigerated temperatures. Currently, the industry assessment standard involves 1-month long stability tests under stressed storage conditions. Improving the efficiency and accuracy of alternative pre-formulation and formulation screening tools should reduce the time required for phase 1 of drug development and make it possible to explore more proteins and more solution conditions. It is expected that the incorporation of this technology into the formulation workflow should help increase the number of therapeutic proteins that can be brought to market and reduce the cost of the products being sold. The proposed project involves the construction of a device designed to measure the susceptibility of a therapeutic protein to phase separation. Like oil and water, concentrated therapeutic protein solutions can separate into two distinct phases below a phase separation temperature, where the solution becomes cloudy. The phase separation temperature and the kinetics of the phase separation provide valuable metrics for instability and can be monitored by simple light scattering measurements via dark-field microscopy. Herein, we outline the development of hardware and software for a temperature gradient microfluidics device that can induce phase separation and extract parameters describing the underlying protein-protein interactions of the phase transition. The goals of this project are to engineer an automated system for controlling the temperature gradient, optical instrumentation, and data analysis. Ultimately, these research and development efforts will provide a prototype version of the temperature gradient microfluidics technology that can be implemented for measuring the stability of a variety of therapeutic proteins. Such high-throughput measurements will enable the exploration of pH, salt, buffers, and protein chemistries that contribute to formulation instability.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.