« LYOPHILIZATION Edge Vial Eff ect [27]
Any vial that is not surrounded by six other vials is defi ned as an edge vial. During primary drying, edge vials receive additional heat transfer via radiation from the walls and door of the freeze-dryer, which are at a higher temperature than the shelf. This temperature diff erential results in higher product temperature and shorter primary drying time for edge vials compared to the rest of the batch (i.e., the center vials). During primary drying, it is critical to ensure that the product temperature remains below the maximum allowable limit not only for center vials but also for edge vials to maintain product quality across the batch. Also, the edge vial eff ect is more dominant in a lab-scale dryer due to the plexiglass door and surfaces with high emissivity. In a production- scale dryer, the door and surfaces are highly polished stainless steel with relatively low emissivity. These diff erences in dryer design need to be considered when scaling up the freeze-drying process to ensure that the product thermal profi le is not altered for both edge and center vials.
Determining the End Point of Primary Drying [28]
Insuffi cient primary drying time results in product collapse or melt back due to premature progression into secondary drying, whereas a prolonged primary drying time results in an unnecessarily long cycle time. Several techniques are now available to mark the end of primary drying; unfortunately, few can be easily applied to a production- scale dryer. The Pirani gauge is an inexpensive and reliable technique to determine the end of primary drying both on a laboratory and production scale dryer. During primary drying, the Pirani gauge reads approximately 60% higher than the capacitance manometer (CM) because the thermal conductivity of water vapor is approximately 1.6 times that of nitrogen. The Pirani pressure drops sharply toward the end of primary drying as the gas composition changes from mostly water vapor to mostly nitrogen [29]. A representative profi le of the Pirani pressure during primary drying is shown in Figure 2.
Eff ect of Load [30]
As the load on the shelf increases, product temperature decreases and drying time increases. As shown in Figure 3, the primary drying time in diff erent freeze-dryers increases as the load increases. Dryer-X and Dryer-Y (lab-scale dryers) are similar in design and geometry and, therefore, the increase in primary drying time with batch size is similar. However, in Dryer-Z, which is a pilot-scale dryer, the same fraction of batch size takes longer to dry. Thus, understanding the eff ect of batch size on process performance and product quality is critical for defi ning the primary drying time.
Equipment Characterization
Dryer capabilities and capacity during tech transfer and process scale- up are just as important as formulation and process characterization. The ice sublimation test is routinely performed to identify the limitations and capabilities of the freeze-dryer [31]. Figure 4 shows that the minimum achievable chamber pressure increases as the sublimation rate increases. Further, the trend of increasing chamber
Figure 3. Eff ect of Load on Primary Drying Time Figure 2. Typical Pirani Pressure Profi le During Primary Drying
pressure with sublimation rate is dependent on dryer design and geometry. For example, Dryer-X and Dryer-Y, lab-scale dryers, show a similar trend, while Dryer-Z, a pilot-scale dryer, diff ers signifi cantly.
The limit (either due to choked fl ow or condenser overload) described by Figure 4 enables defi ning the Operational Space for a given dryer when designing and developing the freeze-drying process. Also, characterizing the ability of the freeze-dryer to control and maintain the shelf temperature (through shelf temperature mapping) and chamber pressure is critical for defi ning the practical range for process robustness. This systematic approach enables defi ning the Design Space and Control Space along with the Set Point for the primary drying step of the freeze-drying process as shown in Figure 5 [32]. Operating within the design space ensures that all product quality attributes will be met. The control space is based on the limitation and capabilities of the freeze-dryer to control chamber pressure and shelf temperature. The set point is selected within the control space such that the sublimation rate is fastest (i.e., shortest drying time), but with
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