Active Freeze Drying for the Pharmaceutical Industry

With ‘Active Freeze Drying’, disadvantages of the conventional tray-type lyophilizer such as lump forming, relatively low heat transfer, labor intensive handling, risk of exposure to operators and contamination of the product can be avoided by freeze drying in a closed vessel. Active Freeze Drying technology can be regarded as an important step in the world of freeze drying and powder technology.

Discovered about one hundred years ago, freeze-drying (also called lyophilization) has gone through a tremendous development in the previous century. From a curious lab experiment it has evolved into a mature production technique for materials which are instable at room temperature when having their natural moisture content.

Freeze drying involves the freezing and sublimation of a solvent, in most cases water. The substrate is brought into trays in a chamber and after freezing the substrate, the solvent is sublimated from the solid state directly in the vapor phase by applying a deep vacuum. Typical vacuum levels are between 1 mbar and 0.01 mbar.

For example, when water is sublimated such deep vacuum levels ensure sublimation temperatures of -20ºC or lower during the drying process.

A major disadvantage of the conventional tray-type freeze dryer is the lump formation when the material is dried on a larger scale. Despite the optimal structure of the individual product particles, the layer on the plates will usually form one piece of hard baked material. Often the material has to be crushed, which can lead to damage of the product structure. Another disadvantage can be the relative low heat transfer rate, due to the quiescent state of the material.

The handling necessary for filling the trays with a thin layer of liquid and the scraping to collect the dried material in containers is very labor intensive. Dust formation is inevitable.

Exposure of the operator to the product and contamination of product, in particular when handling APIs (Active Pharmaceutical Ingredients), is not easy. Altogether this makes traditional lyophilization technology one of the most expensive unit operations in pharmaceutical industries.

The principle of Active Freeze Drying

Early experiments at Hosokawa Micron B.V. started about 10 years ago with a prototype dryer, operated at low temperatures and low pressures, showed that it was possible to operate a freeze dryer under active, stirred conditions. The result was a lump-free, free-flowing product.

Today the Active Freeze Dryer (AFD) consists of a dedicated designed drying chamber and collecting filter. In the chamber the material to be dried is frozen very fast with the aid of a freezing medium, vacuum or jacket cooling. This step results in a free flowing, granular, frozen substrate.

After freezing, the vacuum level is lowered to a pressure below the triple point of the liquid. After evacuation of the freezing agent the sublimation process will start.

During sublimation the heat is supplied through the jacket and efficiently distributed throughout the product by the stirring motion of the frozen substrate. The initially coarse granules will gradually reduce in size due to the sublimation of the connecting ice structure in between the frozen material.

The released dried particles will make up a loose powder moving to the filter. Towards the end of the drying process, when most of the frozen solvent is sublimated, the product temperature will start to rise.

Finally the product temperature will equalize the wall temperature, indicating that the drying process is finished.

By then all material is transformed into a fine and loose powder which does not need additional crushing or handling. After breaking the vacuum the powder can be discharged easily from the filter or dryer vessel.

Compared to traditional tray-type lyophilizers, Active Freeze Dryers exhibit a superior heat transfer rate due to the continuous mixing of the frozen granular product, which can shorten the drying process.

Overall, Active Freeze Drying considerably simplifies the lyophilization process because all steps are done in a single processing unit instead of handling trays filled with product between freezing units, drying chambers and crushers. This results in minimal risk for contamination.

Because all phases of the Active Freeze Drying process are executed in a fully contained and closed vessel, the process allows for aseptic and completely sterile operation. The unit allows CIP (Cleaning in Place) and SIP (Sterilization in Place) by pressurized steam or VHP (Vaporized Hydro Peroxide).


The main applications of Active Freeze Drying are found in the pharmaceutical industry, such as antibiotics, electrolytes and other API’s. Other products, typically produced by freeze drying include proteins, hormones, viruses, vaccines, bacteria, yeast, blood serum, liposomes and transplant materials like collagen sponge.

Another promising market is the Active freeze drying of nanomaterials. During the active freeze drying of nanomaterials, produced via wet processes keeps the suspended particles to remain separated during drying. In the high-end food industry successfully tested are nutra-ceuticals, vitamins, vegetables, herbs, milk derivatives, insects and flavors.


With the introduction of the Active Freeze Drying technology a new type of bulk freeze drying technology has become available. AFD batch volumes can range from a few liters for lab- and pilot-scale to bulk drying on an industrial scale. This new technology offers rapid drying, simple product handling, contained processing and a unique product quality.