Experimental Aspects of Measuring the Vial Heat Transfer Coefficient in Pharmaceutical Freeze-Drying

Abstract

One of the current methods for cycle optimization in primary drying to is develop a graphical design space based on quality by design (QbD). In order to construct the design space, the vial heat transfer coefficient (K_v) is needed. This paper investigated experimental factors that can affect the K_v result, examined the relationship between the batch average K_v and K_v values for individual vials, and recommended best practices for measuring K_v. Factors investigated included the technique for measuring ice temperature, shelf temperature, the use of a radiation shield on the door of the freeze-dry chamber, and shelf spacing. All experiments reported here used a chamber pressure of 100 mTorr. The most important factor was the technique for ice temperature measurement, where it is important to assure that any restrictions to vapor flow at the top of the vial are the same between monitored and non-monitored vials. Another factor that was found to play a role was the shelf temperature whereby the lower the shelf temperature, the larger the “edge effect,” and the larger the average K_v. Factors that were found to not have a significant effect were the use of a radiation shield inside the chamber door and the shelf spacing. Being aware of these factors and knowing best practices when determining the vial heat coefficient will lead to more accurate design spaces and better cycle optimization.