Automated Process Control of Pharmaceutical Lyophilization: PAT Enabled Freeze-Dryer

Develop and test a PAT enabled Freeze-Dryer, with automated process control based on critical product parameters.

Industry Need

Current pharmaceutical lyophilization methods have an extended process duration.

Approach

Develop a new process development and control software that accounts for intra- and inter-batch product drying heterogeneity.

Impacts

The PAT Enabled Freeze-Dryer will use real-time measurements to automatically control lyophilization processes based on key product parameters (KPPs), such as the critical product temperature and target product temperature during primary drying.

Value Statement/Outcomes

By implementing this project’s PAT‑Enabled Freeze‑Dryer with real‑time critical product temperature control and model‑based endpoint detection, an organization will reduce primary‑drying cycle time and the associated cost drivers for equipment‑occupancy and energy cost drivers by ~29%, enabling higher throughput, faster tech transfer, and uniform, collapse‑free product quality across all vial locations, without compromising product quality or regulatory compliance.

Outputs/Deliverables

The project team developed a Process Analytical Technology, PAT-Enabled Freeze-Dryer that automatically develops and controls pharmaceutical lyophilization, resulting in high product quality for all vials within the drying chamber

The project demonstrated the ability to use a 1oC safety margin between the product target temperature of the warmest vials and the product collapse temperature while maintaining all vial classes below the collapse temperature. Saved ~29% primary drying time compared to the use of a 3oC safety margin for a 5% sucrose formulation.

Demonstrated the automated, independent use of both Pirani gauge pressure measurements (as an indication of water vapor concentration) and Tunable Diode Laser Absorption Spectroscopy (TDLAS)- based water concentration measurements to determine the endpoint of primary drying.

Demonstrated the successful use of the automated process control algorithm to handle twodifferent process anomalies: 1) 10% overfilling of 10% of the center vials; 2) lack of process pressure control due to water contamination of the vacuum pump oil

The PAT-Enabled Freeze-Dryer utilizes a heat and mass transfer model of freeze-drying that accounts for both intra- and inter-batch drying heterogeneity.

The PAT-Enabled Freeze-Dryer does not use predetermined shelf temperature, chamber pressure and drying times (like baking a cake) but rather uses real-time PAT measurements / determinations of the critical product temperature to develop and control the lyophilization process.

Applied the PAT-Enabled Freeze-Dryer to lyophilize excipient formulations and industry drug substances (DS), demonstrating the ability of the process model to accurately predict product temperature for all vial locations (center, inner edge and outer edge).

Posters

Kessler, B., Gong, E., Hinds, M., Bogner, R. H., Yoon, S., Marx, R. J., Tchessalov, S., Zhao, J., Bhambhani, A., Stanbro, J., Yusoff, Z., & Whitehall, I., Automated Process Control of Pharmaceutical Lyophilization: PAT Enable Freeze-Dryer, NIIMBL National Meeting, Washington, DC, July 15, 2021.

Kessler, B., Gong, E., Yu, T., Yusoff, Z., Schomber, L., Bogner, R. H., Yoon, S., Morris, C., Marx, R. J., Magill, G., Stanbro, J., & Tchessalov, S., Automated Process Control of Pharmaceutical Lyophilization: PAT-Enabled Freeze-Dryer, NIIMBL National Meeting, Washington, DC, July 25, 2022.

Kessler, B., Presenter, PC3.1-114 Automated Process Control of Pharmaceutical Lyophilization: PAT Enabled Freeze Dryer, NIIMBL National Meeting, Washington, D.C., July 27, 2022.