Figure 3: Penetrator with cone attached to the base with small breakable bridges. Once these bridges are broken by the vertical
movement of the shelves, the cone slides inside the base. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
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After classical freeze-dryer loading and once the door is closed, the shelves move down, pushing on the penetrators located
above the closed stoppers. The penetrator is molded as one piece but has two subcomponents linked with six breakable bridges
(see Figure 3). The subcomponents are:
- A cylinder base that ensures the holding (by light snapfit) on the top ring and its adequate centering.
- A cone that can slide inside the base when the shelf is pushing. Three large side openings in the upper part of the cone enable
gas passage between the cone and shelf.
As the shelf moves down at constant speed, the six bridges are broken (taking about 25 to 30 N/vial), releasing the cone for
further pushing work on the stopper. At the end of the downward stroke of the shelves, the front tip of the cone pushes on
the stopper around the pierced spot, without penetrating the stopper. By radial elastomeric expansion, the cone reopens the
piercing trace and the lyophilization cycle can begin (see Figure 2, position 4). The opening cross-section of the stopper
is adequate to allow vapor exit (as tested in fast cycles and with sucrose 10%). The reopening of the piercing trace requires
about 45 N/vial, slightly below the classical stoppering pressure needed for glass vials (industrial freeze dryers are classically
calculated for a minimum of 10 tons/m2 of stoppering pressure). During the entire cycle, shelves are kept in that low position, keeping the stoppers open.
At the end of the cycle, as the temperature rises above 25 °C, the stopper fully recovers its elastomeric resilience. When
the shelves are lifted, the stopper takes its original shape, lifts the penetrator cone back on top of itself and self-reseals
(see Figure 2, position 5). This happens even during long lyophilization cycles (e.g., three days).
After exiting the freeze dryer's chamber under barrier conditions, the penetrators need to be removed. This step is easily
achieved because the penetrators are linked to the vial with three very light snapfits. A passage of the vial along a fixed
side-cam finger is sufficient to withdraw the penetrator (see Figure 2, position 6). At that time, the vial is ready for laser
and capping.
Laser resealing is performed using a 6 mm-diameter laser spot which ensures proper cover of the piercing area. Finally, capping
is completed as usual. These last three steps are performed under an ISO 5 (Class 100/Grade A) environment to avoid contamination
before laser-resealing. This environment also ensures asepsis of the stopper top surface as it remains protected against contamination
until use.
Packaging
It is recognized that water still present in washed, steam-sterilized stoppers after a lyophilization cycle can cause a 1%
elevation of moisture content during shelf-life in glass vials. However, with closed vials, this problem does not occur because
the stopper processing does use water.
Despite the fact that the plastics used in the Crystal vial (COC and TPE) have low water-vapor transmission rate (WVTR), they
do not warrant the high protection required for keeping freeze-dried cakes in a low-percentage humidity range during full
shelf-life (e.g., as recommended by World Health Organization). Therefore, additional barriers against moisture ingress should
be obtained and can be easily achieved with adequate secondary packaging (e.g., an aluminum pouch [pinhole-free Al thickness
of 20 µm, within a multilayer film] or a blister cavity with aluminum lidding and a low WVTR transparent thermoformable film
[polyvinylidene chloride multilayers have very low WVTR]).
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