Lyophilization

Introduction
Lyophilization, also called freeze drying, is widely used in the biopharmaceutical industry as it in most cases increases the shelf life of the drug product (and gives a large reduction in weight).

General overview
The aqueous drug formulation is filled under sterile conditions into partially stoppered glass vials, which are placed on a cooled temperature controlled shelf within the freeze-dryer. The shelf temperature is reduced in a controlled rate to a defined temperature, the sample uniformly frozen under the process. After complete freezing, the pressure in the dryer is lowered to a defined pressure to initiate the primary drying. The shelf temperature is kept at a low constant temperature as the water vapour is removed from the frozen sample by sublimation. Thereafter, is the secondary drying is initiated by increasing the shelf temperature and reducing the chamber pressure further so that water absorbed to the semi-dried sample can be removed until the residual water content decreases to the desired level. The vials can in most cases be sealed, in situ, under a protective atmosphere if so required.

Freezing
The freezing rate is a very important factor during the freeze-drying development. Nucleation and formation of ice crystals occurs at a certain temperature throughout the solution. The solute composition and the freezing rate influence the freezing pattern and the morphology of the product. Fast freezing gives small ice crystals whilst slow freezing causes large ice crystals. Large ice crystals creates large pores during the primary drying and thus faster primary drying, but also smaller surface areas which may slow down the secondary drying. More importantly, the freezing rate can also cause freezing-induced protein denaturation and impact the storage stability of the final product. The final temperature is set to be below the lowest eutectic temperature (for crystalline material) or below the glass transition temperature of the freeze-concentrated phase (Tg’, for amorphous materials).

Primary Drying
The frozen water sublimes and the drying front gradually retracts the frozen core leaving a dry cake. The formed water vapour passes through the dried cake to the surface and then through the chamber to the condenser. Heat is transferred from the shelf and the chamber walls to the drying front mainly by conduction and radiation. A higher drying temperature results in a higher saturated vapour pressure and a shortened lyophilisation process. The upper primary drying temperature must however be below the system collapse temperature (Tc).

Secondary Drying
Secondary drying involves the removal of the water that does not separate out as ice during the freezing, and hence does not sublimate off. It is difficult to transfer energy into a porous matrix placed under vacuum, since it behaves like an almost perfect insulating material. Therefore, the secondary drying stage takes almost as long time as the primary drying stage although much less water is removed from the product during this stage.

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