PFI-RP: Sensors, Computational Modeling, and Bioanalytical Technologies for Closed-Loop Lyophilization

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The broader impact/commercial potential of this PFI project is in providing real-time sensor technologies, computational modeling and bioanalytical tools for accelerated manufacturing of lyophilized pharmaceuticals that will enable more cost-efficient manufacturing of life-saving medicines. Over 40% of the biopharmaceuticals approved by FDA since 2008 are marketed in lyophilized dosage forms, and many pharmaceutical products could not be commercially viable without lyophilization. However, lyophilization is among the most expensive and time-consuming unit operations in pharmaceutical manufacturing, with batch-mode operation, open-loop processing, and lack of real-time product quality monitoring. A typical production lyophilization cycle usually takes from a few days to two weeks with typical operating costs of over $50,000 per day. As much as 30% of this time is wasted because of overly conservative cycles due to lack of in-process product monitoring and closed-loop control. This project will translate to manufacturing readiness several technologies that are currently in development and will accelerate the transition to automated lyophilization and enable "self-driving" lyophilizers. The proposed project addresses three interconnected technical challenges by co-development of: (i) Noninvasive product temperature monitoring using wireless probes that are compatible with aseptic processing requirements; (ii) Accelerated biomolecule stability analytics by solid-state hydrogen-deuterium exchange mass spectrometry; and (iii) Real-time lyophilization rate measurement and closed-loop process control based on distributed wireless probes and computational modeling of the heat and mass transfer in the product, container and the lyophilizer equipment. The project activities are expected to advance knowledge in several fields, namely a) fluid/thermal transport in low-pressure conditions; b) flexible hybrid electronics for RF systems in extreme environments; c) biomolecule degradation mechanisms and analytical methods. The technologies will be implemented in a lyophilizer at Purdue's lyophilization technology demonstration facility and tested under realistic manufacturing constraints in collaboration with industry partners. The research and technology development activities will be complemented by dissemination of results to the lyophilization user community. Educational modules related to technologies developed in this program will be included in training courses organized by LyoHUB, an industry-university consortium based at Purdue University. Additionally, by cooperating with Purdue Foundry, the team will educate students in commercialization for engineering and pharmaceutical technology inventions.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.