Freeze drying stoppering

Lyophilised ATP standards are commercially available. However, part of the freeze-dried material is often lost with the freeze-drying stopper. We have overcome this by providing ready-made, stabilized liquid ATP standards (Fig. 1). 

Vials are stoppered under vacuum or dry nitrogen to preserve the internal environment and then capped. For ampoules, flame-sealing will cause failures due to the increase in internal pressure caused by the heat from the flame. For this reason, during processing, the ampoules are fitted with a capillary labyrinth [12] and a freeze-drying stopper. The capillary labyrinth reduces the rate of uptake of air and water as the ampoules... 

After dispensing, ampoules are individually fitted with the capillary labyrinth and freeze-drying stopper (vials are fitted with freeze-drying stoppers only) and packed into aluminum tins. They are then stored at the same temperature as required by the bulk product until the entire batch has been filled. 

In freeze-drying, a solution is filled into vials, a special slotted stopper is partially inserted into the neck of the vial (Fig. 3), and trays of filled vials are transferred to the freeze-dryer. The solution is frozen by circulation of a fluid, such as silicone oil, at a temperature in the range of — 35 to about — 45°C through internal channels in the shelf assembly. When the product has solidified sufficiently, the pressure in the freeze-dry chamber is reduced to a pressure less that the vapor pressure of ice at the temperature of the product, and heat is applied to the... 

Fig. 2.2. Automatic filling of a product to be freeze dried in vials, which are cooled by LN2. In the installation the following steps are carried out with a speed of up to 9000 vials per hour Precooling of the vials down to -180 °C, filling of the vials, shock freezing of the product, placing the stoppers on the vials (photograph Groninger Co. GmbH, D-7180 Crailsheim).

Fig. 2.10. Freeze drying plant of the type in Fig. 2.9 (a). 1600 cm2 temperature-controlled shelf area stoppering device for vials on four shelves, valve between chamber and condenser, for BTM and DR-measure-ments, freezing is possible between the condenser coils or in the shelves if they are cooled and heated by brine from a thermostat, Tco down to -55 °C (LYOVAC GT 2, AMSCO Finn-Aqua, D-50354 Hurth). 

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. 

During secondary drying, a small RM should be reached, since Tg of the dry product increases with decreasing water content. Tg- of amorphous, freeze dried sucrose increases from 16 °C with 8.5 % RM to 63 °C or 64 °C between 1.0 and 0.7 % RM. It should be taken into account, that RM cannot be taken only at the end of drying, but a possible increase during storage by water desorbed from the stopper has to be considered (see Section 1.3.2 and Pikal et al. [3.7]). 

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. 

Operationally, freeze drying of a final dosage form usually consists of filling glass vials with an aqueous solution of the solutes to be freeze dried, partially inserting a special slotted rubber stopper which allows water vapor to flow through slots in the stopper when in the partially inserted position, and transferring the vials to the shelves of the freeze dryer. Temperature... 

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... 

Figure 11 Changes in residual moisture during storage of freeze-dried solids due to water vapor transfer from the stopper at different storage temperatures 5°C (diamonds), 25°C (squares), and 40°C (triangles).

Fig. 2.11. Freeze-drying plant of the type in Figure 2.9 (b). 4000 cm2 shelf area, Tsh from -50 to +70 °C, stoppering device for vials, Tco down to -65 °C (Lyoflex 04 , BOC Edwards BV, NL-5107 NE Dongen, The Netherlands).

With a stoppering device vials are closed during SD at certain intervals and analyzed for RM after the end of freeze-drying. 

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],... 

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