Stoppering steam-sterilized

Stoppers steam sterilization temperature =. minutes and pulse drying... 

Fig. 1. 100. Water content of 100 mg lactose at +25 °C as function of time. The vials have been closed with 13-mm stoppers of different pretreatment. Pretreatments SV1 steam-Sterilized U, untreated SV8, steam-sterilized followed by vacuum-drying of minimum 8 h. The lines are calculated by a model system (Fig. 4 from [1.87]).

Earle et al. [1.89] showed, that the RM in the product Pedvax HIB TM did not change during storage at 2-8 °C for 24 months if the stoppers were steam-sterilized, vacuum dried for 6 h and finally dried at +143 °C for 4 h. If the vials were closed with stoppers which had not been dried, the RM increased in 12 months to approx. 5.3 %. Danielson [1.90] warned against toxic components which could diffuse or migrate from the stopper to the product. A protective coating does not avoid the extraction of these substances, but Teflon coating is better than none. 

The rules of steam sterilization are well described [2.15], including some guide-lines for the validation of the sterilization process. The special problems with the steam sterilization of closing systems for vial stoppers has been discussed above. Similar problems... 

Lyophilizer media fills will consist of a simulation of all filling and handling procedures that would be required when processing a lyophilized product, such as steam sterilization of lyophilizer 12 hours (minimum) before loading the first tray of media, introduction of the vials into the lyophilizer, holding vacuum for a minimum of 24 hours, and subsequent releasing of vacuum and activation of the stoppering mechanism. 

If the stopper is as small as technically possible and its material optimized, the water content of the stopper depends on its prehistory Steam-sterilized stoppers take up water (e.g. 1.1% of their weight), which can only be removedby 8 h of vacuum drying... 

The water absorption and desorption by the stoppers, used to close the vials after drying, depends on the various materials from which they are made [11]. It is possible to reduce the water absorption by changing the materials for the stopper, but a certain amount will always be absorbed, especially after steam sterilization, e.g., 1% of weight. Processes to reduce the water content before using the stoppers are mentioned in Section IV.D. 

For pushing the stoppers into the closed position in the vials, the shelves are pressed together by a plate. For this operation 1 kg per stopper can be expected. If there are more than 1000 vials per shelf substantial forces have to be applied. This can be done by motor-driven spindles or steel ropes or by a piston rod, as shown in Figure 26. The piston rod system can be steam-sterilized and excludes abrasion. The part of the piston rod that is moved into the chamber during compression is sterilized in a separate chamber. The only disadvantage is the additional space required below or above the drying chamber for the length of the rod. 

The most common method of sterilization for stoppers is steam sterilization. To prevent a product from regaining moisture during storage, stoppers must be dried after steam sterilization those that absorb relatively high amounts of water may need to be dried more thoroughly than those that absorb less. How to assess and control moisture in stoppers is discussed at length in Section III.C, below. 

Application of heat, vacuum, or a combination of both can accomplish removal of occluded moisture from stoppers. Vacuum drying is a simple procedure, i.e., merely the drying of stoppers in the autoclave following steam sterilization. Alternately, sterilized stoppers could be transferred to a dry-heat oven and dried at an appropriate temperature. 

Fig. 11 Kinetics of water transfer from stoppers to 25 mg freeze dried lactose. The stoppers were 13 mm finish West 1816 gray butyl stoppers that were steam sterilized and vacuum dried for 1 hour. Circles = 40° C triangles = 25° C squares = 5°C. (From Ref. l)...

Leak test Steam sterilization Pre-stoppering Stoppering... 

Stopper and caps Sterilization through steam sterilizer... 

Fig. 2.43. Schema of a steam-sterilizable closing mechanism for vials. The pressure plate (1), by which the stoppers are pushed into the vials is sterilized jointly with the chamber. The shaft (2) to which the pressure plate is connected, moves into the chamber during stoppering. It is not sterilized with the chamber. Therefore the shaft is sterilized in a separate chamber (3). This chamber can also be connected to the vacuum pumping system (4) as to the steam supply (5). Water condensing during the sterilization can be drained by (6). A special seal (7) can (by (8)) also be connected to steam or vacuum, and be sterilized (schematic drawing from information by AMSCO Finn-Aqua, D-50354 Hiirth).

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 ... 

The increase of RM in the product to equilibrium depends on [23] the mass and the water content of the stopper, the mass and the water content of the product and the absorption characteristic of the dried product. The water content of the stopper depends on its treatment. Stoppers sterilized by steam can contain more than 1% (wt/wt) water. After 8 h of vacuum drying or 8 h of air drying at 110°C [24], the water content can be reduced to 0.1%. The time to reach equilibrium between the water in the stopper and in the product depends on the storage temperature, e.g., for a product 50% of equilibrium is reached at 40°C in 4 days, at 5°C it takes 10 months. 

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. 

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