Process control of heat and mass transfer in freeze-drying

Date of Completion

January 2010


Chemistry, Pharmaceutical|Engineering, Chemical|Health Sciences, Pharmacy




The overall objective of this research is to better understand the heat and mass transfer in freeze drying process and use this understanding to develop better guidelines for rational design, development and scale-up of freeze drying process. The main objective of a rational design of the freeze drying process is to obtain a stable and elegant product with minimal intra- and inter-batch variability. In addition, the designed freeze drying process should be robust and easily scaleable and transferable from one lyophilizer to another. During process development, there exist a number of manufacturing challenges such as differences in loading room environment, equipment design and capacity, load/batch size, container closure system, which needs to be taken into consideration during lyophilization cycle development and scale-up. ^ Variations in degree of supercooling between laboratory and production scale freeze-dryer results in differences in product temperature and drying time. To achieve homogeneous drying rate, the ice nucleation temperature for product vials within the same batch was controlled by using the reduced pressure ice fog technique. ^ Since primary drying is the longest step, optimization of this step is the focus in industry. Several analytical techniques (comparative pressure measurement (Pirani vs. Capacitance Manometer), dewpoint monitor, Tunable Diode Laser Absoprtion Spectroscopy (TDLAS), Lyotrack (Gas Plasma Spectroscopy), condenser pressure, pressure rise test, and product thermocouple were compared to determine the end point of primary drying. Besides being inexpensive, the midpoint of drop in the Pirani pressure is a good indicator of the end point of primary drying. ^ Further, gas flow dynamics in the duct connecting the chamber and the condenser imposes an upper limit to the maximum sublimation rate that a given lyophilizer can handle. At a fixed chamber pressure sublimation rate increases as the condenser pressure decreases. However, sublimation rate increases only until the gas flow velocity reaches Mach I limit (at which gas velocity equals speed of sound) at the duct exit. Further increase in sublimation rate results in loss of chamber pressure control (i.e., choked flow). From the sublimation test, choked flow was observed experimentally for the pressure range studied (60-200 mTorr) at different shelf temperature set point. Also, the Fluent simulation results predicted that the gas flow velocity reaches the speed of sound (i.e., Mach I limit) at the duct exit under the experimental conditions studied resulting in loss in chamber pressure control. ^ Key process parameters such as product temperature and drying time were significantly effected under different load conditions on a laboratory, pilot as well as a clinical scale freeze-dryer. Under partial load conditions, radiation effects dominate as the fraction of edge vials, which experience higher heat transfer via radiation, increases as the load on the shelf decreases. For an optimized process, even at 50% of full load condition, cycle adjustments are required to achieve same product temperature profile as at 100% of full load. ^ The container-closure system is another important variable during freeze-drying. There are freezing as well as drying difference between traditional containers (i.e., glass tubing vials) and glass syringes. An aluminum block holder system improved the heat and mass transfer compared to a plexiglass holder for freeze-drying in syringes. ^ The steady state theory of heat and mass transfer in freeze-drying was used to interpret the experimental data from various process development and scale up experiments and to make adjustments in cycles in different dryers to obtain equivalent product thermal histories. Further, general guidelines were developed to help in rational design, development and scale-up of the freeze-drying process. ^