Applications of the Tunable Diode Laser Absorption Spectroscopy: In-Process Estimation of Primary Drying Heterogeneity and Product Temperature During Lyophilization.

The aim of this research was to evaluate the impact of variability in ice sublimation rate (dm/dt) measurement and vial heat transfer coefficient (K) on product temperature prediction during the primary drying phase of lyophilization. The mathematical model used for primary drying uses dm/dt and K as inputs to predict product temperature. A second-generation tunable diode laser absorption spectroscopy (TDLAS)-based sensor was used to measure dm/dt. In addition, a new approach to calculate drying heterogeneity in a batch during primary drying is described. The TDLAS dm/dt measurements were found to be within 5%-10% of gravimetric measurement for laboratory- and pilot-scale lyophilizers. Intersupplier variability in K was high for the same "type" of vials, which can lead to erroneous product temperature prediction if "one value" of vial heat transfer coefficient is used for "all vial types" from different suppliers. Studies conducted in both a laboratory- and a pilot-scale lyophilizer showed TDLAS product temperature to be within ±1°C of average thermocouple temperature during primary drying. Using TDLAS data and calculations to estimate drying heterogeneity (number of vials undergoing primary drying), good agreement was obtained between theoretical and experimental results, demonstrating usefulness of the new approach.