Equipment freeze dryer

A freeze-dryer must be purchased that either has a large built-in chamber, or to which a chamber can be attached. Some smaller ones are mainly for small-scale work when multiple samples are held in glass flasks or ampoules, which are attached to a manifold equipped with isolation valves. 

SOPs detailing step-by-step operational procedures for specific items of equipment (e.g. autoclaves, homogenizers, freeze-dryers, pH meters, product labelling machines, etc.) ... 

Five discrete cleaning validation protocols related to aseptic manufacturing equipments, solution preparation tanks, mobile tanks, filtration assemblies, freeze dryers, and vial filling machine parts are provided in Section Val. 2200. 

The package plant instrument specification details the instrumentation requirements and standards to be applied to any equipment packages. Typical equipment packages include Water for Injection (WEI) systems, chiller packages, gas scrubber packages, tablet presses, packaging machines, freeze dryers, autoclaves, and so on. Each specification should contain, or provide detailed reference to, the following information ... 

Manipulator. To test the residual moisture in a product in addition to the measurement of desorption rate, the freeze dryer could be equipped with a manipulator (Figure 31) and a vacuum lock, which permits one to take out the sample or to close marked vials with a stopper inside the chamber. 

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. 

With the equipment working as a continuous operation, production can be adjusted on demand and, at each time, only a minor proportion of the manufacturing load is inside the freeze-dryer, which drastically decreases the risks for product loss in case of an occasional breakdown of the machinery or failure of the electrical power. 

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. 

Freeze dryer with cooling system that allows plate temperatures of -55°C, e.g. Beta 2-16 (Martin Christ GmbH), equipped with cooling-trap and hybrid-pump (see Note 1). 

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

FIGURE 45.18 Continuous scraper-type freeze dryer (1) vacuum chamber (2) spray nozzles (3) scraper (4) radiators (5) cooling jacket (6) freezant (7) motor and (8) vacuum lock. (From Shumski, K.P., Vacuum Apparatus and Equipment in Chemical Industry, Mashinostroyenie, Moscow, Russia, 1974 (in Russian).)... 

Sealed (10 ml) reaction vessel Syringes (5 and 2 ml) and needles Gilson pipette (1000 ml) and tips Water bath and thermometer TLC equipment Rotary evaporator Freeze dryer... 

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... 

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