Yingtai: Vacuum Freeze Drying - Pressure Rise As The Endpoint of Freeze Drying

Yingtai: Vacuum Freeze Drying - Pressure Rise as the Endpoint of Freeze Drying

In the past, many commercial freeze dryers still retained temperature probes, and in pilot to validation or even production stages, the product temperature was often used to determine the freeze-drying endpoint. Additionally, older freeze dryers relied heavily on manual operation, often resulting in vague descriptions of freeze-drying parameters such as "continue drying for X hours after the disappearance of the visual water line, then raise the temperature to X°C" or "continue drying for X hours when the product temperature approaches the shelf temperature," which continued to be used even in the era of automated freeze dryers. A more advanced way of describing the freeze-drying process was often to specify a confirmed time duration, such as increasing the temperature to X°C for X hours/minutes, then increasing to X°C for X hours/minutes, and so on, until the final stage where the drying program was stopped after the last period. In reality, temperature probes, which are intended to clean corners, are not suitable for use in commercial freeze dryers.

In the latest European GMP Annex 1, which focuses on "contamination control strategies," there is a strong emphasis on the hardware requirements for equipment and facilities. This is the first time that European GMP has highlighted this issue. Even though a freeze dryer might be equipped with wired thermocouples, it is not possible to insert them into the bottles due to fully isolated production equipment and facilities. Therefore, it is necessary to rethink how to use thermocouples effectively.

Even today, some organizations continue to use this approach, for example, laboratory freeze dryers that set gradient temperature increases and observe the visual water line changes. The duration of each temperature gradient is determined based on how close the product temperature gets to the shelf temperature. On fully-loaded commercial freeze dryers, however, it is impossible to replicate the freeze-drying parameters of a laboratory-scale dryer. Each temperature gradient lasts longer, the product moisture content is higher, and after extensive testing and optimization, commercial-scale freeze dryers can finally be used for full-scale production. However, the performance of the freeze dryer is still a significant factor affecting the freeze-drying curve. If the performance of the freeze dryer is subpar, the batch-to-batch variation in product quality may be significant. Furthermore, if the drying process is not completed within the specified time, should the drying time be extended? And if we set the time as a range, for example, X-X hours/minutes, how should we determine the exact time for execution? The problem with this approach is primarily the uncontrollability of product moisture content. As discussed earlier, water content affects the glass transition temperature (Tg) of the system. Products with higher moisture content have a lower Tg, leading to increased molecular mobility. For products with a lower Tg, larger batch-to-batch moisture variations can result in significant differences in chemical degradation levels. For protein products, excessively low moisture can cause protein denaturation, losing biological activity, while too much moisture accelerates chemical degradation. Significant batch-to-batch differences in moisture content could indicate substantial differences in chemical stability between batches. As for extending the freeze-drying time, how can we define the process as controllable, or how can we ensure that the process consistently produces products with the same quality? Even when using a time range, we cannot guarantee that the product moisture will meet the required limits by the end of the longest set time, and the process remains uncontrollable.

The purpose of using the freeze-drying duration as the endpoint indicator is to control moisture content. The simplest method is to use the product moisture content as the endpoint indicator for freeze-drying. Under constant temperature conditions, systems with different moisture contents release different amounts of water vapor when exposed to the same low-pressure environment, causing different pressure rises in the closed space. This pressure increase can be used to gauge the moisture content of the product at any given time. This is the most commonly used method, where the pressure rise test serves as the endpoint for freeze-drying. The pressure rise test is moisture-driven (i.e., it focuses on the final result) and only monitors the process at the later stages of freeze-drying. By setting up multiple pressure rise tests during the drying process, even if the freeze dryer experiences a drop in ice capture rate (e.g., due to thicker ice formation in the condenser after several consecutive batches), the drying time can be automatically extended to ensure that the product moisture meets the preset requirements.