Achieving Containment in High-Potency Manufacturing: A Case Study for Solid Dosage Manufacturing

PharmTech: A key challenge in high-potency manufacturing is to maintain the level of containment throughout the manufacturing process. Before examining how that is achieved operationally, what are the key considerations when designing a high-potency manufacturing facility and in equipment selection?

Cascone: The concept of risk management was a major element of the facility design discussion at Metrics. The team (consisting of director-level managers from pharmaceutical development, environmental, health and safety, quality assurance, and operations as well as personnel from external engineering firms) considered the risks associated with locating a high-potency solid-oral dosage form facility adjacent to one designed for compounds with occupational exposure limits greater than 10 μg/m³ time weighted average. These risks were placed into two major categories. The first were risks associated with protecting the employee. The second were risks associated with protecting the drug product(s).

Interior of the multiuse isolator with a high-shear granulator, conical mill, and roller compactor installed. (IMAGE IS COURTESY OF METRICS)

To manage the risks of operator exposure, the team adopted the following tenets:

• Operators will not work with an unclassified compound.

• Operators will not work with a compound that cannot be suitably contained.

• The containment capabilities of equipment will be tested and quantified.

• Secondary protection will be available in the event of a containment breach.

• Engineered solutions (i.e., hard-wall isolators) were preferred to work-practice solutions (i.e., laminar-flow enclosures).

• Operators will be monitored for adverse health effects.

To manage the risks of a cross-contamination event, the team established the following requirements:

• Potent compounds will be processed under hard-wall isolation.

• Potent compounds would be processed in rooms discrete from other GMP manufacturing areas.

• Operators will not transit one GMP area to access another GMP area in which potent compounds are processed. Multiple airlocks (i.e., gray areas) will separate rooms in which potent compounds are processed from surrounding areas.

• Air handling and utilities will be separate; room pressurization will be such that dust is contained.

• Equipment used in the manufacture of potent products will not be used outside the potent facility.

• Equipment will be chemically tested for cleanliness by high-performance liquid chromatography and total organic carbon analysis after each processing event.

• Disposable accoutrements will be used where feasible.

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.