Isolation Technology: An Integrated Approach to Containment
Designing a solid dosage facility for a low level of airborne, highly pharmacologically active material requires unusual, specialized approaches.
By Walter Feier,PE and Gregg Herreman
In today`s pharmaceutical industry, and for the foreseeable future, the compounds currently in use and under development are more potent and expensive than ever before. These highly pharmacologically active compounds require new, more sophisticated manufacturing techniques to replace operating methods and equipment that are largely unacceptable for contained production of highly potent materials.
“Contained production” is the use of specialized equipment and techniques to provide personnel and environmental protection in all phases of a manufacturing process, from raw material to finished product. “Isolation technology” is the specialty focusing on the planning and design of contained production facilities.
Isolation technology is one of the most significant movements in the pharmaceutical industry in the past 15 years. The pharmaceutical manufacturing plant of the future will integrate many innovations in equipment that have been developed in response to industry`s call for better containment and more consistent end products. These new equipment items will be balanced with proven equipment to provide personnel and environmental protection.
Optimum use of containment in all areas of processing pays dividends. These dividends are in the form of improved productivity, better quality, and better housekeeping, which lead to improved employee moral. Integrating containment principles with the proper equipment to feed a tablet press or encapsulator will provide increased productivity, consistency, better product quality and decreased handling problems.
There are two ways of operating a manufacturing plant: as a dedicated product production facility, or as a multipurpose facility. Both need state-of-the-art equipment that mirrors the ever-increasing commitment to consistency and containment in manufacturing.
Some of the factors influencing the degree and sophistication of the containment aspects incorporated into the design of a pharmaceutical manufacturing facility are:
Production personnel must not be exposed to highly pharmacologically active compounds.
Highly pharmacologically active or toxic compounds cannot be released into an already sensitive environment.
These compounds have to be manufactured in a manner consistent with cGMP requirements.
Because the active ingredients of these compounds are extremely expensive–often $20,000/kg or more–losses of material through cross-contamination, spillage, etc., must be minimized.
Pharmaceutical companies have become a prime target for lawsuits and must limit their potential liabilities. Adoption of proper containment procedures is an important step towards reducing litigation.
Properly contained manufacturing meets all the requirements of product and operator protection, environmental isolation, increased yields and lower potential liability.
Approach to containment
The task of designing a solid dosage facility, one which provides for an extremely low level of airborne, highly pharmacologically active material, requires unusual, specialized approaches. An effective containment design is a single, integrated system comprised of interfacing modules tailored for each processing step. Included in the system are processing and handling, HVAC and clean-in-place (CIP) equipment, barriers and any architectural nuances required to meet containment parameters. (See Figure 1.)
A design exposure level of less than 0.1 microgram/cubic meter is extremely low and cannot be achieved using conventional processing and handling techniques. The usual mixers/granulators and tray or fluid bed dryers are not designed for the levels of containment required for potent drug compounds. All modes of operation, including setup, normal production, maintenance and upset/emergency conditions should be covered in the design approach.
Architectural considerations
Architecturally, a facility designed for containment would embody all the architectural nuances for cGMP and FDA compliance. Because it is important that transfer of materials be minimized and carried out in a closed environment, and that CIP systems be incorporated as part of the design, the ideal contained facility should be of multilevel design. (See Figure 2.)
Gravity transfer of materials provides for closed transfer from one piece of processing equipment to another, or into intermediate bulk containers, for blending and/or transfer of materials between processing areas. (See Figure 3.) This eliminates the need for secondary equipment such as pneumatic transfer devices. The more equipment a process uses, the more chance for leakage and cross-contamination, and the greater the difficulty in cleaning between batches.
Multilevel design allows for sequential cleaning of equipment. The final rinse solution from one piece of equipment can be used for the initial rinse for the next, without the use of pumping equipment.
Containment system considerations
The normal approach in a conventional facility is to use local dust pick-ups, HEPA filtration and laminar flow rooms or hoods to reduce the amount of airborne material. Since this equipment cannot achieve the control levels required for the new potent compounds, personnel must wear full suits with breathing air lines or air packs. This is not an acceptable method of full-time protection, because the suits are cumbersome and have to be cleaned within the area to minimize cross-contamination.
Integrated equipment for containment design can be separated into four categories: primary, secondary, tertiary and integral.
1. Primary containment involves processing equipment that has been designed with containment in mind. The equipment itself, together with any separation devices for charging and discharging, the exhaust air and filters, and the internal parts of the equipment (such as seals and gasketing) must be integrated to form the containment system.
Selection of equipment is based on such factors as:
ease of cleaning or deactivation of material on equipment surfaces;
ease of servicing and adjusting of equipment without breaching areas which contact potent materials during operation;
separation between mechanical areas and areas exposed to potent materials.
2. Secondary containment requires the use of barriers and other devices to contain material if a leak occurs. It also includes an intermediate device to facilitate connections between processing components during transfers if the equipment itself cannot provide reliable containment. Spills occur most frequently during the transfer of materials. Proper “make-break” connections used to join pieces of equipment will ensure containment during material transfers.
3. Tertiary containment relates to HVAC equipment and system design. Ducts, filters and other components will need cleaning. They should be designed with “bag-in, bag-out” filters, as well as built-in CIP systems, to prevent maintenance personnel from being exposed to potent materials.
Additional dust pick-ups should be provided in key locations. If primary or secondary containment is breached, pressurization between pieces of equipment and the surrounding environment will provide an additional level of containment and safety.
4. An automated CIP system is an integral part of the containment system. Proper cleaning will eliminate exposure to personnel and cross-contamination of materials during changeovers and maintenance.
Equipment considerations
From the time potent raw materials are received until they are processed and finally packaged for shipment, they present a potential hazard to personnel exposed to them.
Receiving. Containment design starts in the receiving area, where incoming material containers must be opened for sampling prior to transport for dispensing and processing.
Depending upon the level of containment desired and the containment philosophy adopted, workers can wear protective clothing to prevent exposure, work in downflow work enclosures (laminar flow booths), or use high-containment workstations (gloveboxes). For containment levels of less then 100 µgram/m3, a high-containment workstation would be required.
Dispensing. After sampling, material will generally be transported to a storage location or directly to a dispensing area, where it will be weighed and then transferred into a container for transport throughout the processing cycle. Both the weighing and transfer of material have to be performed under contained conditions. For high-containment levels, a high-containment workstation should be used.
The principle of selecting multipurpose equipment should be applied to the transport container. If possible, the same container should be used for transport, blending, storage, and charging and discharging of materials from one piece of equipment to another. To accomplish this, the container`s charging and discharging ports should be capable of interfacing with other pieces of processing equipment, either directly or a through a docking station in a contained manner. If the container is dropped, it should be designed so that its contents will not be released into the surrounding environment.
Processing. After dispensing, material is transported to the processing area. Selection of equipment is extremely critical, especially in the granulation/drying area of the process. Here, the emphasis should again be on selecting equipment to perform multiple tasks and minimize material transfers. Ideally, to provide maximum protection to personnel, automated equipment should be selected, reducing operator exposure to potent materials.
Dryers. The fluid bed dryer, though efficient, productive and versatile, will need to be modified to meet the desired characteristics of a containment dryer. The normal dryer contains dust collectors or bag filters which control the propagation of fine particles, but are difficult to clean-in-place by personnel wearing protective clothing. Dryers are now designed with filters made of sintered metal or wire mesh, which are more easily cleaned.
Because the dryer exhausts large quantities of air or other gases that may be laden with fine particles not removed by the internal filters, further HEPA filtration may be necessary to bring exhaust air to design parameters.
A better dryer, from a containment aspect, would be a high sheer microwave granulator dryer. It does not require internal filtration or heated air or other gases to dry. Discharge is through a dry vacuum pump and HEPA filtration.
Clean-in-place
Multipurpose equipment, in addition to reducing the number of material transfers, must also be designed to be cleaned “in place” or “out of place” in special cleaning enclosures. The characteristics of the materials to be processed will dictate whether the CIP system should be either aqueous or solvent-based for handling flammable liquids.
Handling of the CIP waste stream and its subsequent decontamination and/or disposal is critical, particularly if materials cannot be chemically deactivated. The only recourse may be external incineration, which would require a design that would minimize the amount of clean-in-place liquid.
Piping system. The piping systems for both process and CIP need to be designed and fabricated with the same diligence as the equipment. To achieve containment, flanges or sanitary connections should be minimized. An all-welded system is preferable; however, compliance with cGMPs necessitates that some breakpoints be incorporated into the design.
Granulation/Drying. From the granulation/drying process, material is moved into a transfer container and then blended with excipients and/or lubricants prior to compression and encapsulation. If material is blended in the transport container, the only containment issue is the charging of the material, excipients or lubricants into the container.
Compression and encapsulation. After blending, material is transferred to compression or encapsulation equipment either by using a contained docking station or through a glovebox. Encapsulated material is generally considered safe and can be handled like any drug compound. On the other hand, tablets are friable, requiring special handling to prevent the release of dust into the environment until they can be coated and packaged.
HVAC considerations
The HVAC system provides clean, classified HEPA-filtered air and helps to maintain specified control levels. Pressurization between processing areas and adjacent areas will create air flow from areas of high pressurization to areas of low pressurization. Cross-contamination of products and exposure to personnel can be eliminated by directing any airborne particulate escaping from a contained process into an innocuous area. For example, if the internal pressure of a fluid bed dryer were held negative to the pressure in the room, and the room was in turn held negative to the corridor outside the room, a potential leak could not escape into the surrounding room, and airborne particulate could not escape into the adjacent corridor. Every space, including storage rooms, must be pressurized either positively or negatively.
Controlling pressure is equally important. Simply balancing the facility when it is constructed for a certain pressurization will not stand the test of time. Balancing dampers vibrate and move, filters get dirty and restrict airflow, doors open and close, and process equipment can have a radical effect on pressurization.
Outlook for the future
The pharmaceutical industry must provide a workplace that is safe for employees, ergonomically sound, and friendly to the environment. At the same time, for each new drug developed, regulatory agencies are requiring the industry to increase levels of containment, triggering an escalation in production costs. As a result, pharmaceutical companies and equipment manufacturers are under increasing pressure to develop new equipment and techniques to meet stringent requirements for higher containment while limiting drug price increases.
Alliances have been formed between pharmaceutical equipment manufacturers and manufacturers of gloveboxes and other isolation technology equipment for the purpose of redesigning and adapting existing equipment to containment requirements. At the same time, these alliances are designing and developing new equipment for filling, dispensing, milling, compacting, and other functions.n
Walter Feier is manager of technology-automation at Fluor Daniel, Inc. (Marlton, NJ). He has over 30 years` experience in industrial engineering, industrial automation, and systems integration in the pharmaceutical, nuclear and electronics industries.
Gregg Herreman is manager of technology-solid dosage forms at Fluor Daniel, Inc. (Marlton, NJ). He has over 27 years of pharmaceutical and biotechnology experience, with emphasis on granulation, tableting encapsulation, packaging equipment selection, installation, setup and operation. He is experienced in formulation, process development and process startup, as well as GMP compliance audit and training.
 |
Figure 1. A clean-in-place system is included in the overall solid dosage facility design. It is one part of an effective containment system.
 |
Figure 2. Shown is the facility material flow which should be a multilevel design.
 |
Figure 3. Contained granulation manufacturing includes a fluid bed dryer, a rotary valve, a dry mill, view and glove ports, and a chute.