Abstract
This work presents the design and evaluation of a fully wireless, multi-point temperature sensor system as a Process Analytical Technology (PAT) for lyophilization. Each sensor contains seven sensing elements which measure the product temperature at various positions of the contents of a glass vial. The sensor performance was studied by freeze drying experiments with sensor placement in both center and edge of full shelf of 6R glass vials with 4 ml fill volume. Product temperature profile and primary drying time measured at the bottom center position in the glass vial by the wireless sensor as well as the primary drying time are in close comparison with the thermocouple data. The drying times during primary drying were determined at the top, higher middle, lower middle and bottom positions which are 3.26 mm apart vertically in the vial by the wireless sensor based on the temperature profile measured at different positions. For a center vial, the drying time from the start of primary drying to each layer was measured at 3.9, 9.3, 14.2, and 21 h respectively, allowing to track the sublimation interface during primary drying phase. In addition, sublimation rate at each layer was calculated based on the drying time and theoretical weight loss of ice in the product. The sublimation rate at the beginning of the primary drying was similar to the sublimation rate by gravimetric method. Furthermore, the vial heat transfer coefficient (Kv) was also calculated based on the sublimation rate. Thus, allowing the use of the multi-point wireless sensor to rapidly monitor the sublimation rate and Kv for every batch as continuous process verification. Similar tests were also conducted with 3% w/v mannitol solutions and the results were consistent demonstrating potential for real-time monitoring, process verification and cycle optimization for pharmaceutical lyophilization.
Highlights
Lyophilization, or freeze-drying, is a commonly used and well-established process to preserve the original structure of a heat sensitive biological and/or pharmaceutical product (e.g., Anti-body, peptides, vaccines, etc.) during drying and, during long-term storage
The sensing probe and printed circuit boards (PCBs) with microcontroller was connected by a board-toboard connector and the Radio frequency (RF) energy harvester was connected via a ribbon cable
Five out of seven temperature profiles measured by wireless multi-point sensor are color coded from red to blue lines shown in Figure 5 representing sensing elements from top to bottom
Summary
Lyophilization, or freeze-drying, is a commonly used and well-established process to preserve the original structure of a heat sensitive biological and/or pharmaceutical product (e.g., Anti-body, peptides, vaccines, etc.) during drying and, during long-term storage (extending the shelf life of pharmaceutical formulations). Freeze-drying involves ice removal from a frozen product at Monitoring Pharmaceutical Lyophilization low pressure through a sublimation process. It was reported by the Food and Drug Administration (FDA) that about 50% of over 300 FDA and EMA approved biopharmaceutical products are freeze-dried (Corver et al, 2017). Variations across freeze dryers as well as the spatial distribution of vials inside a given freeze dryer often result in substantial differences in the vials heat transfer coefficients and temperature profiles While such differences may be tolerable in laboratory-scale experiments, they can cause considerable complications in production-level machines. In 2008, an innovative wireless sensor was reported (Schneid and Gieseler, 2008) which has great potential PAT tool in a large scale freeze dryer
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