Automatic control of a freeze-drying process: Detection of the end point of primary drying

Abstract

In freeze-drying, the detection of the end of primary drying is a crucial aspect for both the process economics and product quality. Furthermore, the extreme process conditions (low temperature, high vacuum, and sterility) require monitoring devices with a high degree of assurance. In this paper, the most promising methodologies for the detection of the end point of primary drying were investigated and compared. These devices include thermocouples, comparative pressure measurement, condenser pressure, controlled leakage, vacuum shut-off valve, microbalance, mass spectrometers, moisture sensors, and pressure rise test. Furthermore, a multi-scale model of the process was used to describe the process dynamics during the last part of drying, showing that the time difference between the onset and offset points depends on the batch heterogeneity, as well as process conditions and batch size. Ultimately, an automatic stop criterion, named EPD, has been designed and experimentally tested in a wide range of process conditions, batch size, vial size, and drug products. In particular, the experimental validation involved some of the most used excipients as model products, i.e., mannitol, dextran, lactose, and sucrose. In all the runs, the EPD drying times reasonably agreed with the comparative pressure measurement, which was the most reliable way to detect the end of primary drying. Thus, EPD can effectively be used to optimize primary drying without risking the product collapse because of a premature increase in shelf temperature for secondary drying.