Freeze stoppering process

An important step in the freeze drying process with vials is the stoppering or closing of the vials either at the end pressure of SD, or at a chosen partial pressure of a specific gas. This avoids handling of open vials, which can lead to contamination and adsorption of water vapor from the atmosphere. 

This device makes it possible to sterilize the piston rod independently of the sterilization of the freeze-drying plant. The part of the piston rod that enters the chamber during the stoppering process is placed in a sterilization container, the so-called dome. This dome is equipped with a steam inlet line, condensate drain, temperature measuring point, pressure transmitter, etc. Sterilization takes place automatically in one of two possible cycles ... 

Sterilization alone and independent from the freeze-drying plant. This is usually done after loading has been completed. This makes sure that the piston rod is sterile for the next stoppering process. 

Media-hlled vials (soybean casein digest broth or fluid thioglycollate medium) are hlled on the hlling line, transported to the freeze drier, loaded into the chamber, subjected to a simulated lyophilization process, stoppered, sealed, and incubated for 14 days at 25°C. The minimum number of vials to be used is 5000. 

The heat transfer system provides cooling required for freezing the product and the subsequent heat needed to establish rate of sublimation. Temperature control is required over the entire process, from the time the product is loaded onto the lyophilizer shelves until it is removed after stoppering. Therefore, cooling and... 

A subtle aspect of stability analysis of freeze-dried products in vials with rubber stoppers is the tendency for water vapor to be transferred from the stopper to the solid during storage. Representative data for residual moisture as a function of time at different temperatures are shown in Figure 11. As expected, the residual moisture level increases more rapidly at higher temperature, but the plateau level is independent of temperature as equilibrium is established between the freeze-dried solid and the stopper. The extent to which this is observed depends on several factors. First, the nature of the rubber stopper formulation affects the diffusivity of water in the rubber. Second, the processing of the stopper can affect the level of residual moisture present. It is not uncommon for extended drying of the stopper to be necessary to minimize residual moisture. Finally, the mass of the freeze-dried solid determines the extent to which the percent residual moisture is affected by water vapor transfer from the stopper, where large cakes may be relatively unaffected by the small amount of water vapor that is... 

If the product is not freeze dried, the primary closure or stopper is applied shortly after completion of the filling process to better assure the sterility of the contents. When the product is to be lyophilized, the stopper may be partially inserted after filling and be fully seated after completion of the lyophilization cycle. Alternatively, the container could be left open and a stopper applied after completion of the drying. 

Lyophilization (or freeze-drying) is a process utilized to convert a water-soluble material filled into a container to a solid state by removal of the liquid while frozen. The process requires the use of deep vacuums and careful control of temperatures. By conducting the process under reduced pressure, the water in the container converts from ice directly to vapor as heat is applied and is removed from the container by the vacuum. The dissolved solids in the formulation cannot undergo this phase change and remain in the container. At the completion of the cycle, the container will be returned to near atmospheric pressure stoppers are applied or fully seated and crimped as described above. Lyophilization is particularly common with biological materials whose stability in aqueous solution may be relatively poor. The time period in solution and the temperature of the solution are kept at a specified low temperature to prevent product degradation [35],... 

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. 

Certain process steps may be easier to model than others and duplicating the freeze dry/dry heat step at small scale is very difficult. The conclusions drawn from virus clearance studies are reliable only when the appropriateness of the small-scale models can be demonstrated. During the freeze dry/dry heat step of Koate -DVI, virus reduction was dependent on moisture levels so even the formulation of stoppers, which could impact the absorption of water during autoclaving and its release to freeze dried material, must be considered and tested. 

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