High-potency solid dosage manufacturing at work
PharmTech:
Can you outline the process of manufacturing the high-potency solid dosage form and explain how the level of containment
is maintained during the various unit operations?
Cascone:
When the team first considered the company's high-potency suite, it clearly defined what it wanted to achieve before anything
was built or ordered. To maintain a given level of containment, the team had to make specific choices about which unit operations
would be offered and at what scale. In an ideal world, it would be advantageous to provide any unit operation at any scale,
but this desire had to be weighed against what was operationally and economically feasible. Once certain essential unit operations
were identified, such as blending, milling, granulation, and compression, processing equipment was purchased and isolated.
Placing the processing surfaces of equipment into a common isolated environment while separating the mechanical and electrical
areas of the machinery was deemed to be the most efficient and user friendly design.
Because of the small physical footprint of the renovation, a 1:1 ratio of equipment-to-isolators was not practical. Therefore,
a series of multi-use, hard-wall isolators were conceptualized. A variety of smaller-scale pieces of processing equipment
was purchased and further engineered to interface with these isolators. During the integration process, the product-contact
surfaces of the equipment were separated from the drives and controls by installing each through a separate stainless-steel
plate. The periphery of each steel plate was made identical, but each penetration is unique and based on the results of an
ergonomic modeling exercise. This exercise placed areas that needed to be accessed during operation within easy reaching distance
through glove ports. When the processing equipment is installed, the plate that it penetrates serves as the rear wall of the
isolator and the means by which the equipment is suspended for use. Any piece of processing equipment may be installed in
any of three locations in any of three separate isolators within the facility. This way, a given equipment train can be built
quickly and efficiently under total containment. The larger of the two processing rooms can accommodate up to eight unit operations,
and the smaller processing room can accommodate up to five. This arrangement provides maximum flexibility to meet any clients'
specific requirement.
Equipment needed for a given experiment, batch, or campaign is moved from the equipment storage room and docked to a bay on
a multi-use isolator. Equipment is docked into the isolators in the order of the required process train. Once equipment is
installed in the multi-use isolators, other pieces of isolated equipment, such as a contained tablet press or fluid bed processor,
can be located in the processing room.
Processing commences under total containment. If an interisolator transfer is required, the batch can be introduced into
the isolator using the beta-canister of the rapid-transfer port (DPTE, Getinge LaCalhene) technology. Once a dosage form is
produced and free of surface dust, the product is exported. Exportation of the product is achieved by placing the bulk product
in a primary container, (usually a high-density polyethylene bag. A continuous liner system (DoverPac, ILC Dover) is affixed
to the alpha flange of the rapid-transfer port. The bag containing the bulk product is pushed through the alpha/beta door
into the continuous liner. Once the section of liner is clear of the isolator and the product is contained with it, the liner
is crimped and removed. This process may be repeated for multiple portions of the batch; it may also be used to export waste,
supplies, or tools.
After product and waste is exported, the interior of the isolator is vacuumed by attaching a specially designed variable speed
high-efficiency particulate air vacuum that penetrates the rear of the isolator through a sanitary fitting. Each isolator
is equipped with a misting wand installed on the interior. Water is connected, and dusty surfaces are wetted to reduce any
airborne exposures upon disassembly. After the equipment is misted and before it is dry, the operators don powered air-purifying
respirators, the isolator is opened and disassembly begins. Processing equipment, such as the conical mill or roller compactor,
is transported to an adjacent washroom and cleaned. Once cleaned, it is immediately swabbed for residual API and detergent.
The equipment is returned to storage only after an acceptable cleaning-verification result is achieved.
These flows of equipment, personnel, and materials greatly mitigate opportunities for exposures and cross-contamination. The
result is an elegant, full-featured, development and clinical-supplies manufacturing facility that is state of the art.
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