In terms of application, products dried in freeze-dryers can be broadly categorized into vials and bulk. In terms of capacity, the devices are classified into laboratory, research, and industrial categories.

The capacity of a pharmaceutical freeze-dryer is determined based on the shelf area. For example, in each square meter of shelf space, 4000 vials (2R or 4R) can be accommodated. Shelf dimensions depend on the design, and the number of shelf layers is determined based on the device’s capacity and shelf dimensions. It’s important to note that the capacity of a pharmaceutical freeze-dryer is based on the useful area of sublimation (shelf) and not the number of shelf layers. For instance, a freeze-dryer with 5 square meters of useful shelf area may have 5 or 7 shelf layers, but the capacity remains the same in both cases.

The condenser vapor capacity should be proportional to the shelf area. On average, 15 kilograms of ice absorption capacity per square meter of shelf area is considered for the condenser. However, the condenser capacity may need revision depending on the type of product to be dried in the freeze-dryer.

For products dried in vials through injectable freeze-drying, the vial door has two steps. When the vial is placed inside the freeze-dryer, the rubber door is inserted into the vial’s glass up to the first step (essentially “Half Stoppering”), allowing vapor to escape through a groove next to this rubber door. At the end of the process, when the product is completely dry, the upper shelf moves down with a hydraulic jack, creating pressure on these rubber doors. The door is then fully pressed into the vial glass up to the second step, achieving a complete stoppering. This process, performed through a hydraulic system comprising a jack and a hydraulic unit with pressure control, is referred to as stoppering.

CIP stands for “Clean In Place”, referring to the cleaning operation of the device tank after completing the process and removing the product, preparing the device for the next loading. CIP is usually performed using Pure Water (PW) or Water for Injection (WFI), depending on the sanitary protocols and GMP requirements of the pharmaceutical.

   SIP stands for “Sterile In Place”. It involves the sterilization operation of the device tank with superheated steam. In this process, the device tank is exposed to Pure Steam at a temperature of 121°C to 134°C for the required duration (this time is determined based on the tank volume and according to specific tests).

A freeze-dryer should have the necessary capability to perform each freezing cycle according to the user’s desired rate. The freezing rate for pharmaceutical products typically ranges between 0.5 to 1.5 degrees Celsius per minute. The adjustability of the freezing rate is a standard feature in a freeze-dryer. It’s essential to note that a slower freezing rate leads to larger ice crystal formation, resulting in a shorter drying process but lower final quality. Conversely, a faster freezing rate leads to smaller ice crystals, a longer drying process, and higher final quality. However, the suitable freezing rate depends on the biological properties of the product, and excessively rapid freezing can cause issues such as vial breakage.

The maximum temperature a product can experience during a freeze-drying process depends on its biological properties. Typically, for vaccines, this temperature is up to positive 30 degrees Celsius. For probiotics, it varies between positive 25 and positive 35 degrees. For enzymes, the maximum temperature is up to 25 degrees. In any case, a standard freeze-dryer should have the capability to heat the shelves up to a positive 70 degrees Celsius.

The internal surface roughness of the main tank and shelves in an injectable freeze-dryer is crucial for preventing contamination buildup and facilitating easy cleaning during CIP. Typically, the surface roughness of an injectable freeze-dryer should be less than 0.4 micrometers, achieved through mechanical polishing and electropolishing.

The shelves of a freeze-dryer should be less than 1 millimeter per meter, metaphorically speaking. This level of flatness is crucial to ensure that the product is in complete contact with the shelf surface, preventing any disruption in conductive heat transfer during the freezing phase. In the stoppering phase, the lack of flatness in the shelves can lead to uneven distribution of pressure on the rubber doors of the vials.

The vacuum leakage rate refers to the increase in vacuum pressure over a specific period, measured statically when the main chamber is usually at 0.1 mbar pressure, and the connection between the vacuum pumps and the main chamber is completely cut off. In this state, the increase in chamber pressure is measured over a time period of 10 to 30 minutes, and then this pressure increase value is multiplied by the net volume of the chamber per second. This value should be less than 0.02 mbar.L/sec.11. What should be the appropriate temperature uniformity on the shelves of a freeze-dryer?

To ensure that the product is completely dried across the entire shelf area and that there is no difference in product quality at different points on the shelf, the surfaces of the shelves, as well as the shelves on different levels, should have the required temperature uniformity. Temperature differences at 5 points on a single shelf (4 corners and center) are measured, and the temperature difference at each of these points should not exceed positive or negative one degree Celsius compared to the average of the 5 points.

The vapor condenser is exclusively to protect vacuum pumps from water vapor intrusion. If the vapor condenser is functioning correctly, no water vapor should enter the vacuum pumps. The temperature difference between the shelves and the vapor condenser should always be greater than 15 degrees Celsius. The coil surfaces of the vapor condenser should have good temperature uniformity, and the piping position of the vacuum pumps should be arranged in a way that prevents direct entry of vapor. The vapor condenser capacity should also be proportionate to the maximum load of products inside the device and should consider sufficient safety factors.