Containment
Figure 4: A closed-vial filling system surrounding a robotic filling line.
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The closed vial acts as a mini-isolator because exposed surfaces are limited to the stopper top surface and the needle. In
contrast, in a traditional glass vial, the inside of the vial, the inside surface of the rubber stopper, and the needle are
exposed until the vial is stoppered. The closed vial filling system (CVFS) offers a new barrier or containment concept, in
which only closed containers are handled (6, 7). The CVFS is suitable for installation in an ISO8 cleanroom, as illustrated
in Figure 4, in which a robotic filling line is surrounded by a CVFS.
The advantage of the CVFS over the traditional isolator is its simplicity, in that it can be sanitized with classical sporicidal
agents and does not require vapor hydrogen peroxide sanitization. The CVFS uses unidirectional, HEPA-filtered laminar airflow
that exits through the bottom of the system, which helps maintain laminar flow and prevent turbulence. Isolators are still
mandatory when the safety of the operator must be ensured (i.e., with highly potent drugs such as cytotoxics). Such isolators
must be installed in an ISO9 cleanroom.
The advantage of the CVFS versus the Restricted Access Barrier System (RABS) is that in the CVFS, operator access is only
possible via gloves, and the barrier environment is never compromised by door opening. Material entry is limited to secured
processes such as rapid transfer ports, airlocks, and e-beam irradiation units. With these limitations, an ISO8 clean room
environment for the surroundings is sufficient to ensure the ISO5 quality inside the barrier.
Lyophilization with closed-vial technology
Figure 5: In a lyophilization chamber, shelves push on the penetrator plate to reopen the piercing trace and allow sublimated
water to evacuate.
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Closed-vial technology has also been developed for lyophilized products (8). Lyophilization is performed through the piercing
trace, which is reopened inside the lyophilization chamber. After vial filling, a penetrator plate with multiple funnel shapes
that fit on top of each vial is placed on a set of prearranged, bee-nest vials. As shown in figure 5, the vial/penetrator
plate assembly is placed inside the lyophilization chambers and the shelves are moved down, thus pushing down the penetrator
plate and reopening the piercing traces. The lyophilization cycle is launched while keeping the piercing trace open to allow
evacuation of the sublimated water. At the end of the cycle, the shelves lift up and the natural elasticity of the stopper
causes it to regain its initial shape and push the penetrator plate up. After exiting the lyophilization chamber, the vials
are laser resealed and capped.
The lyophilization cycle with closed vials is very similar to that of glass vials, except that the primary drying phase is
longer. Tests show that closed-vial technology produces an improved cake surface, suggesting that the lyophilization process
is more homogeneous. In the closed vial system, vials are more stable than in glass vial systems. The bee-nest assembly increases
vial stability and the absence of contact between the shelves and the stoppers prevents stopper sticking. These factors reduce
the risk of a vial falling down and knocking other vials on the shelf over.
Validation
Changes to the container design and process that occur when using closed-vial technology must be validated. To ensure that
the technology is suitable for product approval, a series of tests that meet the required standards from Pharmacopeia and
International Conference Harmonization (ICH) guidelines should be performed on the container materials, the properties and
characteristics of the container closure, the processing technology, and the performance of media fill.
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