The freeze-drying process, also known as lyophilization, consists of three main stages, including freezing, primary drying, and secondary drying. The primary drying stage is usually the longest and most complex part of the process; therefore, automated methods for determining the end of primary drying can help optimize the process time. In some cases, operators may use multiple methods.

Fuzzy Water Phase Diagram

1. Product Temperature – End Point of Primary Drying

   During the sublimation, the frozen product has a lower temperature than the shelf. It can be assumed that when the product temperature reaches the shelf temperature or a temperature well above zero degrees Celsius, no ice remains in the product, indicating the end of the primary drying stage.

   A standard software program can use this method as follows: the user inputs the “end point of primary drying” product temperature. When the average product temperature reaches the set point in the primary drying procedure, the program automatically proceeds to the secondary drying stage according to the predefined procedure. This procedure ensures that all vials have completed the primary drying stages before moving to the secondary drying. If the end of the primary drying stage is not programmed, the procedure will automatically proceed to the secondary drying. This feature is particularly useful for processing large quantities of product.

2. Capacitance Manometer Compared to Pirani Vacuum Gauge (Both are necessary)

   The Pirani vacuum gauge is designed to change its gas composition pressure reading. In the presence of water vapor, Pirani vacuum gauges will have significant reading errors. This means that if a Pirani sensor is the only vacuum gauge present in the system, the pressure value may be incorrectly displayed, and transmitting this information to the freeze-dryer with a capacitance manometer is likely to be ineffective. The capacitance manometer is designed to display absolute vacuum and is not affected by water vapor in the system. If the freeze-dryer is equipped with both sensors on the freeze-dryer tray, the sensors can be used to signal the end of the primary drying stage. The first point of differentiation between Pirani and capacitance gauges in the freeze-dryer system is an empty and frozen system. The freeze-dryer device, according to the manufacturer’s factory guide, is on, and there is nothing on the shelf.

   The shelf temperature can be left at room temperature or set to a low temperature. The condenser is activated to be completely turned on, and the vacuum pump system is activated. Time is given to the freeze-dryer to stabilize under these conditions to read the pressure on the Pirani and capacitance manometers. The pressure readings of the freeze-dryer in them, whether empty, frozen, or empty, will be relatively negligible when the system is working correctly. These two gauges should not be calibrated against each other. Due to different designs, there may always be minor differences in their readings. The pressure difference between these two gauges when dry, empty, or frozen indicates that when water vapor in the gas mixture is very low or absent, they are very similar to each other.

   The goal of primary drying is to maximize the sublimation rate inside the product. Therefore, there is a significant amount of water vapor in the chamber during the primary drying stage. Subsequently, the Pirani sensor will display a higher number than the capacitance gauge. With the progression of the freeze-drying process and the conversion of ice to vapor through the sublimation process, the product becomes lyophilized from top to bottom. Eventually, Pirani and capacitance manometers reach the pressure difference defined in the dry, empty, or frozen system. Approaching this pressure difference indicates the end of the primary drying stage. In most freeze-dryers, this process is built into the software. The operator must determine the pressure difference for the two sensors, as mentioned earlier.

   In most freeze dryers, this process is embedded in the software. The operator must determine the pressure difference for the two sensors, as mentioned earlier. The user enters the pressure difference, which indicates the end of the first drying phase in the software program. During the first drying phase, when the pressure difference is applied, the software program reaches the end of the first stage and then proceeds to the secondary drying.

   The user enters the pressure difference, which indicates the end of the first drying phase in the software program. During the first drying phase, when the pressure difference is applied, the software program reaches the end of the first stage and then proceeds to the secondary drying.

3. 
   Dew Point Measurement via Humidity Sensor (Humidity sensor is required)

   A humidity sensor may be installed in the freeze dryer to measure the remaining humidity in the product. Humidity sensors measure the dew point (in degrees Celsius). Humidity sensors can detect the presence of liquids or ice in amounts less than 1%; therefore, a significant reduction in the dew point at the end of the primary drying stage indicates that the water in the freeze dryer chamber has been converted from solid ice to vapor. The user needs to determine an acceptable dew point for the system, indicating a dry product.

   A standard software program can utilize this method as follows: the user enters a dew point (in degrees Celsius), and when the product reaches this point, the program sequentially reaches the end and then enters the secondary drying stage. Humidity sensors measure the moisture level in the freeze dryer and can determine and display the end point of the primary drying cycle.

4. Barometric Pressure (Isolation Valve is required)

   The approach of increasing barometric pressure is better applied in a system that is dry, empty, and frozen. Similar to the approach used for the capacitance and Pirani gauges, the freeze dryer is operated, and the isolation valve is closed. An increase in pressure in the system is determined for a period (usually a few minutes). This pressure increase creates a basis for closing the isolation valve. During the process, when the freeze dryer chamber is separated from the condenser and vacuum pump (via the isolation valve), the sublimation of ice to vapor increases the system’s pressure. With ice in the pressure vessel, the rate of increase is faster than the dry, empty, and frozen system, indicating that the sublimation process is still ongoing. The acceptable pressure increase for determining the end of the primary drying stage is 6 milliTorr (mT) in 30 seconds with 3 or more readings within an hour.

   A standard software program can also use this method. The user enters an acceptable pressure increase and the number of times to repeat the test during the primary drying stage. When the preset pressure increase is reached rapidly, the program concludes, and then the secondary drying stage begins.

5. Tunable Diode Laser Absorption Spectroscopy (TDLAS)

   This technique, also known as TDLAS (Tunable Diode Laser Absorption Spectroscopy), is a specialized system typically connected to the freeze dryer port between the product chamber and the condenser. TDLAS controls the mass flow between these two areas with sensitivity to water vapor flow and can indicate the end time of the primary drying.

6. Random Heat Flux Monitor (AccuFlux)

   Measuring heat flow from inside the shelf in the product chamber provides information about the sublimation state. As sublimation continues, with vapor molecules disappearing, energy (heat) is lost. When sublimation is almost starting to decrease, simultaneously, thermal flow into the product decreases, and heat flow decreases.