Drying equipment freeze dryers

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 outcome of this self-accelerating process was a strong increase in condenser temperature (up to - 0°C) and an elevation of product temperature by a few degrees (up to -30°C). However, the difference of temperature between the product and the condenser temperature was still sufficient to ensure a very rapid drying of the product, much faster than in freeze-dryers equipped with an effective coil condenser cooled at -80°C. The observation that the primary drying was... 

The flow chart of full-scale production is shown in Figure 6. CET slurry at a scale of about 100 L per batch containing 28 kg of CET is turned into a supersaturated solution by the above-mentioned equipment. The solution is filtered by ultrafiltration to remove endotoxins and sterilized by a membrane filter. Seed crystal is added in the sealed condition and then subdivided into vials. All of these procedures are carried out at around 5°C. The vials are frozen in the chamber of the freeze-dryer at 0°C and freeze-dried. Three batches are achieved per day. The mean times required are 25 min (at the longest) from the preparation of the supersaturated solution and 15 min (at the longest) from seeding to freezing, respectively. In our preliminary experiment adequate products were obtained even when the samples were left for 2 h before addition of seed crystal and for 2 h after seeding at standstill condition. No product defect occurred in the first batch of full-scale production. 

Most freeze-dried pharmaceuticals—and, of course, all injectable products—need to be sterile. Until now, the usual rule to achieve that goal has been to start with a sterile solution and, from there on, to carry out an entirely sterile process. Indeed, the time is over when the manufacturers could add a 1/10,000 merthiolate to get rid of an accidental contamination. Today all freeze-dryers have their cabinets opening within a sterile room while the machinery is sitting behind the wall in the engine room. Moreover, the drying chambers are all equipped with clean-in-place (CIP) systems and can be sterilized by pressure steam before each operation. Finally, those products that are prepared in vials are sealed directly within the chamber thanks to moving pressure plates that drive the stoppers tight into the neck of the vials. 

The freeze-dryer is equipped with a mechanical pumping system that removes noncondensable gases. With oil sealed mechanical pumps, one should be careful to operate the dryer so that no hydrocarbon vapours from the pump can backstream into the drying chamber. 

The dryer should possess temperature sensors to measure the shelf and product temperatures throughout the freeze-drying process. Most freeze-dryers can be equipped with a computer system to control the pressure in the chamber and the shelf temperature as a function of time. The product temperature allows one to confirm that the shelf temperature and chamber pressure are within their preset limits. 

Operating currently available freeze-dryer models is less labour-intensive also, modern equipment affords the implementation of some initial production stages. Once the few sample (melting point) and protocol data (final tray temperature) required is input by the operator following insertion of the product, the apparatus conducts an entire freeze-drying... 

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. 

Depending on the number of containers to be used at once, some freezer-dryers use a multiport turret (a manifold) or a tray module. The former is suitable for containers of varying shape or size that need not be processed simultaneously the latter is to be preferred when a large amount of product or number of containers is to be processed in a simultaneous manner. The tray module can be equipped with an electromechanical device to close the containers after the products are freeze-dried in order to avoid external contamination. One example of this type of freeze-dryer is the model from FTS Systems. 

For the first group the following types of dryers are generally used convective (tray, band, fluid bed, flash dryers, and their modifications) or contact (vacuum dryers such as double-cone dryer-blender, conical dryer with rotating helical mixer, paddle dryer). Pastelike materials are dried in tray dryers, band dryers equipped with extruding devices, and spin-flash dryers. Finally, thin pastes can be dried in spray dryers or on fluid beds or spouted beds of inert particles. Small amounts of solutions and suspensions are generally freeze-dried, especially if the product is thermolabile. 

Condenser All freeze dryers are equipped with condensers to remove water vapor from the gases coming out of the drying chamber. 

Finally, although the equipment should only provide a safe environment for the product and the necessary operating parameters for the lyophilization process, differences in freeze-drying equipment can affect the process. One should be aware of such differences, especially when transferring a process from one dryer to another. So in any discussion of the lyophilization process, the freeze-drying equipment should not be overlooked. 

The capability to freeze-dry up to 10 1 of containment level 3 materials using a freeze-dryer interfaced with a negatively pressured pharmaceutical-grade isolator containing vial filling/capping equipment. This should significantly increase the availability and ease of supply of these key reference materials which currently are available only as liquid preparations. 

The pressure rise analysis method (PRA method), recently proposed by Chouvenc et al. (2004a), derived from the MTM method originally developed by Milton et al. (1997) and next modified by Obert (2001), appears to be a very promising noninvasive control method. It is a rapid, simple to implement and averaging tool that requires a freeze-dryer equipped with an external condenser and a very fast closing separating valve. The values of the main freeze-drying parameters, such as the temperature of the sublimation front, T , the resistance to water vapor mass transfer of the dried layer, J p, and the overall heat transfer coefficient, could be... 

Besides the use of thermocouples and RTDs, various other techniques have been proposed to monitor freeze-drying in a vial. A quick mention can be made of the various analytical techniques, such as low-temperature X-ray powder diffractometry (Cavatur and Suryanarayanan, 1998), low-resolution pulse nuclear magnetic resonance (Monteiro Marques et al, 1991), FTIR spectroscopy (Remmele et al, 1997), and visual microscopic observation (Mackenzie, 1964), that have been used for in situ characterization of samples being lyophilized in special lyophilization equipment, connected to the analytical instrument. These techniques are very useful for process understanding and process design, but at the moment it seems very difficult to use them in a conventional freeze-dryer. 

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