Understanding and optimization of the secondary drying step of a freeze-drying process: a case study

The objective of this study was to build an understanding and optimize the secondary drying step of a freeze-drying process using a drug formulation from Fresenius Kabi (FK1) as a case study. For this purpose, a design of experiments (DoE) was developed to study the influence of drying temperature, drying time, vial position, and chamber pressure on moisture content and glass transition temperature of FK1. The results obtained herein showed that the influence of drying temperature on moisture content and glass transition temperature was strong at short drying time, implying that increasing drying temperature could lead to a significant decrease in the required drying time to achieve a designed moisture content and glass transition temperature. Variation in chamber pressure from 0.05-0.40 mbar showed insignificant influence on moisture content and glass transition temperature. Small variations in moisture content and glass transition temperature with respect to vial position were also observed, where edge vials had higher moisture content and, consequently, lower glass transition temperature than center vials. Further, the results from the DoE were utilized to construct a process design space (PDS) for the secondary drying step of FK1. Experimental verification of the PDS demonstrated an excellent agreement between the PDS-defined and experimentally-determined moisture content and glass transition temperature values. Thus, the PDS facilitated process optimization of FK1 and could serve as an important tool during scale-up and transfer of the process.