Basic process of biological freeze-drying

The technical procedures of drug freeze-drying consist of four processes: preparation and freezing, primary drying (sublimation drying), secondary drying (desorption drying) and package .The temperature, vacuum for each process have to be controlled precisely. The freeze-dried drugs are dry and porous solids. They can be stored in room temperature or in refrigerator for a long time. But a freeze-dryer is not a conventional balance; it does not perform in the same way with different products. There is no universal recipe for a successful freeze-drying operation and the repetitive claim that ''this material cannot be freeze-dried '' has no meaning until each successive step of the process has been duly challenged with the product in a systematic and professional way and not by the all-too-common ''trial-and-error' ' game.
1. Preparation and freezing of drugs
In order to form a stable porous structure after freeze drying, the concentration of drug solution must be a specific value. Excipients should be added into the low dose thermal sensitive drugs (hormone, enzyme, vaccine) to reinforce the structure of freeze-dried products. Lyoprotectant should be added into the biological protein-type drugs or slow-release drugs with bio-membrane to protect proteins from denaturation and the bio-membrane from damage. The type and concentration of lyoprotectants is drug dependent. Most of the lyoprotectants also play the role of excipient. The quality of the freeze dried biological drugs is affected by the types, concentration and pH values of the lyoprotectants and excipients. Freezing is a process to completely freeze or solidify the drug solution with controlled cooling rates. The ending temperature of pre-freezing must be lower than the glass transition temperature(Tg)or eutectic temperature (Te) of the drug solution.
2. Primary drying (sublimation drying)
Primary drying are performed at low temperature and in vacuum. The drying progresses gradually from the surface to the center of the products. The pores or channels formed by the sublimated ice become the ways for vapor to escape. The boundary between drying layer and frozen layer is known as the sublimation interface. In primary drying process, the temperature of frozen layer must be lower than Te or Tg. The temperature of dried layer must is lower than the collapse temperature (Tc). The temperature of the heater in the drying chamber should be controlled strictly.
3. Secondary drying (desorption drying)
The purpose of secondary drying is to remove a portion of the bound water. The moisture content of drugs is lower than 3% after secondary drying. Because of large absorption energy, the product temperature in secondary drying must be increased high enough to remove the bound water, and on the other hand, this temperature cannot induce denaturation of proteins and deterioration of biological drugs. The Tg of the products increases gradually with decrement of water in secondary process. So the drying temperature of the products can be increased gradually, but cannot be higher than Tg.
4. Encapsulation process
When the secondary drying process completes, plugging system in the chamber is adopted directly to plug the vials in order to prevent the freeze dried drugs from oxidation and water absorption. The encapsulation can also be accomplished after filling nitrogen gas into the chamber.