In order to effectively develop a lyophilization cycle, it is important to understand the glass transition temperature (through Differential Scanning Calorimetry “DSC”) and collapse temperature (through Freeze-Drying Microscopy “FDM”) of the formulation between the liquid, glassy, and frozen states. These values will help define the maximum product temperature that the product can achieve during primary drying in order to prevent collapse or melt back of the product due to incomplete sublimation of unbound moisture and/or solvent. This should happen prior to the ramp to secondary drying with final removal of the bound moisture and/or solvent.
Once the glass transition temperature and collapse temperatures are understood, a conservative lyophilization cycle can be run involving the various states of freezing, annealing (if necessary), freezing, primary drying, and finally secondary drying. Vacuum is applied during the beginning of primary drying through the end of secondary drying to aid in the sublimation process of moisture and/or solvent removal from the frozen state to gas state. The condenser temperature is held well below the chamber temperature to aid in transfer of the solvent to the condenser.
In order to evaluate the end of primary drying, the cycle can by monitored using the pirani gauge versus capacitance manometer gauge. In addition, a sample thief can be used to remove samples throughout primary and secondary drying to monitor the moisture or residual solvent levels to evaluate performance of the cycle. Ideally, the unbound moisture and/or solvent should be removed from the formulation prior to transitioning from primary to secondary drying. This will avoid collapse of the lyophilization cake and entrapment of moisture and/or solvent that will not be removed. In secondary drying, the bound moisture and/or solvent is removed at elevated temperatures.
Additionally, it is important to evaluate the robustness of the cycle as conditions are optimized. Robustness includes an evaluation of slight temperature and pressure changes, as well as impact on the performance of the product. Due to slight variability in shelf temperatures (front to back/side to side) and vacuum pressure fluctuations during scale-up, it is important to create a robust cycle that can be transferred effectively from lab-scale to production scale.
Understanding the limitations of the manufacturing freeze drier (minimum and maximum ramp rate, minimum and maximum shelf temperatures, condenser temperature, and vacuum) will provide the information required during laboratory lyophilization development to support the transfer to full-scale production lyophilization.