Chapter 20: Freeze-Thaw Process Data Analysis and Mechanistic Modeling: Simplified Lumped Capacitance Analysis for Small Fill Volumes
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A mechanistic model of a freeze-thaw process for a small fill volume (10s of mL) of drug product in a primary package such as a glass cartridge with a stopper is developed based on the analytical solution of the lumped capacitance heat transfer equation. The model uses the heat transfer coefficient for a given package calibrated from data analysis of thermal history for the initial liquid cooling; it is applied to predict the freezing and thawing for different ambient temperatures and variability in the heat transfer coefficient. The predicted time to reach a specified temperature below the freezing point agrees with experimental measurements within 10–15%. The freeze-thaw temperature data for a 20 mL cartridge with 15 mL fill volume obtained using a temperature-controlled chamber at various ambient temperatures ranging from −23.5 C in the freezing stage to +4.7 C for the thawing stage and +60 C for the thermal aging stage have been used to estimate the heat transfer coefficient of the specific product formulation/package combination. The heat transfer coefficient is extracted from the initial liquid cooling during freeze operation and used to verify the modeling by comparison with the data for another heat transfer stage such as liquid heating during thaw. Additional formulation-specific parameters such as freezing point depression can be determined from analysis of the solidification stage data. The mechanistic modeling and data analysis provided a framework for Quality by Design of freeze-thaw of pharmaceutical drug-device products.
KeywordsFreeze-thaw Mechanistic modeling Quality by Design Drug-device combination
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