Freeze-dryers design

Continuous freeze drying From the description of batch freeze drying, it can be seen that the utihty requirements vary considerably. During sublimation drying the requirements are 2 to 2.5 times the average requirement. To overcome this peak load and to meet the market request for high unit capacities, continuous freeze dryer designs have been developed. The special features are twofold ... 

Gieseler, H., Lee, G., 2008b. Effect of freeze-dryer design on drying rate of an amorphous protein-formulation determined with a vial-weighing technique. Pharm. Dev. Technol. 13 463 72. 

The freeze dryer is designed for steam sterilization of the chamber and condenser, as well as defrosting of the condenser with steam. The steam sterilization is carried out at an overpressure of 1 (provide value) bar. 

The flow volume and the pressure of the CIP system must be designed in accordance with the requirements of the freeze-dryer. The freeze-dryer must basically be capable of being cleaned with a CIP system. 

The functional relationship between product temperature, on the one hand, and shelf temperature and chamber pressure, on the other hand, is affected by many factors including the size and design of the lyophilizer, the characteristics of the product, and the time evolved since the start of primary drying. With a sucrose formulation in vials, we have observed a maximum primary drying product temperature rise of -i-5°C when the shelf temperature was varied from -15 to -i-30°C, whereas a pressure variation from 30 to 250 microbars generated an increase of around -i-2.5°C. With a lactose formulation in ampoules lyophilized in a larger freeze-dryer equipped with a plate-type condenser, the effect of pressure was found to be predominant -i-6.5°C for a pressure move from 50 to 300 microbars, versus -t-l°C for a shelf temperature move from 0° to 25°C. 

The circuit of refrigeration fluid is fitted with a secondary exchanger designed to pull down the temperature from 120°C to around 40°C after each sterilization cycle. This exchanger permits one to increase the disposability time of a freeze-dryer, which Serail puts in place on each sterilizable machine. 

The chamber pressure during the sublimation step (i.e. the primary drying process) has been found to be related to the product and shelf-surface temperatures [8] however, determining the shelf temperature required is more difficult as it depends on the nature of the heat transfer fluid used to control the shelf temperature and also on the particular design of the freeze-dryer. 

The sample container rests on a boundary layer at the top of the shelf surface. Such a layer is a region where the flow of heat transfer fluid is minimal or zero (i.e. the fluid is stationary). As a result, the sublimation step, which involves the transfer of heat from the fluid to the shelf surface, creates a temperature gradient across the boundary layer that depends on the thermal load exerted by the sublimation process and on the nature (viscosity, thermal conductivity and flow across the shelves) of the heat transfer fluid. The temperature gradient also depends on the number of shelves, their design and build, and on the pumping capacity of the circulation pump. These variables in turn depend on the size and particular manufacturer of the freeze-dryer, so the software used should include an input of data for the materials used, and for the dryer s design and build. 

Changes and advances in mechanical design of freeze-drying equipment and control systems have had a strong impact. Modem freeze-dryers are easier to use, require less operator intervention and are applicable to a wide variety of products. Current, automated freeze-dryers allow the initial steps of the protocol to be implemented, thereby providing the operator with more data of interest also, they are safer and easier to operate than previous models. 

A variety of small devices has been designed to meet specific functions not effectively served by commercially available freeze-dryers. Such devices were preceded by a number of customized dryers that were developed for various analytical purposes. Thus, Nakaguchi et al. [10] designed a new drying apparatus equipped with a device for trapping evaporated substances that was used to condition biological samples prior to determining trace elements. 

With the flow rate at 1 mbar of approximately 1 mV(s-m of tray area), the thermodynamic design of the vapor trap is the main issue for a well-designed freeze dryer. 

A suitably sized solution preparation system similar to that mentioned under the previous sections can be used to provide material for bulk freeze drying. (Since product solutions can be sterile-filtered directly into the final container, microbial and particulate exposure will be minimized.) The sterile solution is subdivided into trays and placed into a sterilized freeze dryer. Aseptic transfer of sterile product in trays to the freeze dryer must be validated. After tray drying, the sterile product is aseptically transferred through a mill into suitably designed sterile containers. The preparation of sterile bulk material is usually reserved for those cases where the product cannot be isolated by more common and relatively less expensive crystallization methods. Due to recent advances in this field, a freeze drying process should be considered as a viable option. ... 

It is important to report at this point that since a batch of pharmaceutical product in an industrial freeze dryer can easily be worth significant amounts of money, it is of paramount importance that the units of the plant and the control systems of the process should always operate under conditions at which there is insignificant loss in the quality of the product that is freeze-dried. For this purpose, the freeze dryer usually has one additional refrigeration or vacuum unit in a standby condition and furthermore the control instrumentation is designed in such a way that the control policies can be implemented either automatically by computer or by manual override. 

---