Filling unit

Automatic White Phosphorus Filling Station. The filling station has eight complete filling units and consists of the following items ... 

During a more controlled study carried out within an environment artificially contaminated with high levels of individual nebulized spores of Bacillus subtilis [2], a level of contamination within the environment was achieved which led to the contamination of broth-filled units. The results were extrapolated to suggest a contamination rate of 1 unit in 4 X 10 with a smrounding environmental contamination of 1 cfu/ml... 

The internal surfaces of broth filled units should be fully wetted to ensure capture of any contaminants within the broth. This is commonly achieved by agitation or inversion of the imits before or during the incubation period. 

It is clearly impractical to produce a very high number of broth filled units on a routine basis, but if unpreserved products are manufactured, it is good practice to fill broth directly following product batches with no further machine flushing or sterilization. 

Incubator identification, and incubation time and temperature for the filled units... 

The containers are sealed and the medium-filled units are collected in sequentially numbered trays or boxes (notified to the filling time). It is preferable to use materials, components, and closures which have remained in the aseptic processing area for extended periods. 

It may be advisable to inspect containers midway through the incubation period. The filled units should be briefly inverted and swirled after filling to assure closure contact with the medium. Personnel who have had specific training in the visual inspection of media-filled units should perform these incubator checks. 

Control panel Feeding of empty bottles Detector for presence of bottles Detector for presence of liquid Terminal sterile filter unit Filling unit... 

The media fill units are then unloaded and crimped. 

Media fill units are treated in the same manner as product and require batch record documentation. All aseptically assembled products manufactured subsequent to a media fill failure are placed in quarantine until acceptable media fill results are obtained. 

Verification of media sterility In-process inspection Media fill unit inspection Management review... 

The containers are sealed and the medium-filled units are collected in sequentially numbered trays or boxes (notified to the filling time). 

Microorganisms present in contaminated units shall be identified to help determine the likely source of the contamination. Note Media-filled units should be chronologically identified within the batch to help identify the time at which a contaminated unit was filled. 

A minimum of 4800 units will be filled and incubated. For multiple shift fills, at least 3000 vials/ampoules are to be filled per shift. Table 3 shows the acceptance criteria for initial performance qualification of an aseptic processing line. Table 4 shows the acceptance criteria for requalification of an aseptic processing line. Table 5 shows alert and action levels when a 0.1% contamination rate is attained for large numbers of media-filled units, i.e., when one elects to media-fill more than 3000 units. 

Table 5 Alert and Action Levels for Large Numbers of Media-Filled Units...

Growth promotion of sterilized media during filling is most meaningful if performed concurrent with incubation of the media-fill units. Growth promotion at the end of incubation may not detect any interaction between contaminants and containers that may mask growth inhibition. 

Every week, all media-fill units shall be visually inspected by a trained microbiologist for the presence of microbial turbidity. 

All media-fill units showed no detected growth. 

In case of growth detection in any media fill unit (not just failure), at least the following points should be included ... 

The incubation temperature shall be the same as that used for the media-filled units. 

Following a periodic requalification media fill, production may resume while media fill units are incubating. No product can be released until media fill data are analyzed and acceptance criteria are met, however. 

Most of the contents are delivered in the proper dosage in a filled aerosol canister. It is important to recognize, however, that some nonsprayable formulation remains in each filled unit. Each filled canister will deliver at least the labeled number of doses, and the actual can contains an overage to ensure delivery of the labeled number of doses. As an example, Figure 2 shows the approximate doses found in a 20-g filled unit. 

Further improvement of this principle of factory-metered blistered unit doses was achieved when GlaxoSmithKline developed the Accuhaler device (also named Diskus in some countries (Fig. 8.7). This multiple-dose DPI device contains a blister strip of 60 unit doses that is transported to the next filled unit dose by pulling a small ergonomic lever prior to inhalation. The powder is presented for aerosolization by peeling back the foil from the blister, which is superior to simple piercing because it is not associated with variability in foil flap shape and device retention. The dose indicator on top of the device tells the patient how many doses are left and decreases each time the lever is pulled. This means that as with most other devices, operation of the dose indicator is associated with the loading operation and not with the inhalation maneuver. 

The MicroDose DPI (MicroDose Technologies, United States) is a breath-activated device that includes a piezoelectric vibrator that converts electrical energy from a battery to mechanical motion that is then transferred into the dry powder. The vibration energy deaggregates and aerosolizes the dose. By controlling the energy input, i.e., the amplitude and frequency of the vibration, the DPI is claimed to be usable for various compounds. As with the devices from Nektar and Dura, the MicroDose DPI uses accurately filled unit-dose blisters. 

Liquid-in-glass thermometers used mercury or alcohol as the liquid that expands as it gets warmer. Most countries mandate the removal of any mercury-filled devices due to its extreme toxicity, but alcohol and other fillings are still used. The expansion rate is linear with temperature and can be accurately calibrated. Bimetallic thermometers bond two dissimilar metals with different coefficients of expansion to produce the bimetallic element in thermometers, temperature switches, and thermostats. Filled System Thermometers can be filled with either liquid or vapor. Liquid-filled units are the most popular although they require compensation for the weight of the liquid head and for capillary length. Vapor-filled elements cannot be used if the operating temperature crosses the vapor/liquid point. 

Fig. 7.3. Representative picture of a 7.5 X 10 cm2 plate containing five individual nc-DSCs (active area 4 cm2). The coloration step is shown, flushing the dye solution after sealing through holes on a filling unit [7]...

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