Designing biopharmaceutical facilities.
Production of pharmaceuticals is one of the most highly regulated industries in the world. Regulatory guidelines known as Good Manufacturing Practices (GMP) must be followed to ensure that safe, pure, and efficacious pharmaceuticals are produced. These guidelines cover every aspect of production--from facility design and equipment selection to day-to-day operations.
In the United States the Food and Drug Administration is empowered to regularly update the GMPs for manufacturing, processing, packaging, and storage of pharmaceuticals. Consequently, the GMPs change often and the latest ones are often referred to as current GMPs (or CGMP).
The CGMPs affect the design of equipment and facilities as well as basic operating procedures. They do not specify or approve a specific technology or practice for the manufacture of pharmaceuticals; rather, they are written to provide general guidance.
The major GMP concerns for a biopharmaceutical facility are generally the same as for any pharmaceutical plant. These include layout of the facility, equipment selection, utility support systems, and design for validation. Layout. The principal considerations here include attention to people and material flows within the facility, HVAC classification of work areas, equipment arrangements, and the fit and finish of the different work areas. Separate areas are needed for storage and work-up of the inoculum, media preparation, the bioreactors, and product recovery and purification. These are very important for the prevention of contamination of the process and product. The spatial arrangement of these areas is important to assure controlled access and flow of people through the facility. The design may require air lock access and change rooms for personnel working in certain critical areas of the plant.
Of particular importance to the layout is the flow of material through the facility. Ideally, the flow should be from "dirty" areas to progressively cleaner ones. Furthermore, the path of raw materials should not cross through areas where intermediate or finished product is handled or stored. Equipment Selection. The basic criteria for selection of equipment for pharmaceutical applications are that it be constructed of nonreactive, noncontaminating materials; easily and efficiently cleaned and sterilized; and safely accessible for performing preventive maintenance and speedy repairs.
In certain biopharmaceutical applications, equipment selection criteria may be even more critical from the standpoint of the biological process. Bioreactors and some downstream operations must operate under aseptic conditions to prevent contamination by ubiquitous micro-organisms. In mammalian cell culture, some cell lines are very sensitive to their physical and chemical environment. Particular attention to metallurgy, welding techniques, and the selection of suitable elastomeric components can be crucial to the manufacturing process. Utility Support Systems. Conventional bioprocesses in the pharmaceutical industry are based on microbial fermentation. These processes are run in large stirred tank reactors typically holding between 10,000 and 100,000 gallons. The medium is prepared using natural products such as soy flour, starch, molasses, lime, and tap water. The processes are highly aerobic and consequently generate high metabolic heat loads that must be removed. This type of production plant has very specific and substantial utility requirements. These include large air compressors for process and instrument air, massive cooling tower and chilled water systems, and large steam boilers. Finally, fermenters and some downstream processing areas typically have no HVAC requirements.
The recombinant bioprocesses, however, have different requirements. Typically, mammalian cells are used to produce very large protein molecules, which have high pharmacological activity. In some cases, the worldwide supply can be satisfied with 1 to 10 kilograms of product per year. These mammalian cells are usually commercially grown in bioreactors that range in size from 5 to 2500 gallons. These and other differences affect the size and type of utility systems required to support production.
Usually small air compressors are needed for instrument air and/or process air. In many cases process gases such as carbon dioxide, oxygen, and nitrogen are supplied with compressed gas cylinders. Cooling systems and steam demand for processing are much smaller. Conversely, the HVAC requirements for process areas are substantial.
A major support system needed in these new biopharmaceutical facilities is the water system for the bio-process areas. This can include systems to provide purified water, USP water, or water-for-injection (WFI) systems. Because these types of utilities are an integral part of the process, they must be validated. Validation. Within the pharmaceutical industry, a major CGMP is validation of the process, which aims to provide documented evidence that a process can consistently and reproducibly produce on-spec product within the facility and its equipment by following specific written operating procedures. All operations that affect the process and, ultimately, the product quality itself must be validated.
Fifteen to 20 years ago it was commonly believed that validation should start after the design and construction of a pharmaceutical facility. This was inefficient and expensive. In some cases, entire process systems had to be retrofitted or redesigned to meet validation criteria.
It is now recognized that validation must begin with the design of the facility. This has a direct bearing on the basics of facility design, including layout, equipment and material selection, equipment layout, and piping design.
Biosafety and Recombinant Organisms
Our ability to produce commercial quantities of large therapeutically active proteins through the insertion of foreign DNA into a suitable host has raised some uncertainties about the safety of these recombinant DNA cells. These biosafety concerns depend on the type of recombinant cell. For example, the EPA recognizes that mammalian cells cannot survive outside the very specific environmental conditions maintained within a bioreactor. However, the EPA has placed recombinant microorganisms in a special category subject to the provisions of the Toxic Substances Control Act. Manufacturers using these organisms must have controls designed into their facilities and operational procedures that prevent the escape of these organisms into the environment.
In fact, uncertainty about the potential risks of this technology have resulted in some factions within the technical and regulatory communities proposing increasingly stringent regulatory controls on liquid and solid wastes from these processes. According to the voluntary NIH Guidelines for Recombinant DNA Research, it is sufficient to kill the recombinant organisms in the waste streams prior to removal from the closed process system using validated procedures. Recently, however, it has been suggested that validated inactivation of all recombinant DNA be required.
There are three major requirements that form the basis for large-scale biosafety practice: closed systems must be used to handle live recombinant organisms, aerosols must be controlled, and the waste streams containing organisms must be controlled.
The requirement for use of closed systems is the cornerstone of large-scale biosafety. In addition to meeting basic GMP requirements, these systems must be specifically designed to minimize or prevent the escape of the organism. The guidelines specify that the organisms must be inactivated using a validated procedure prior to removing them from the closed system. In most cases, this requirement poses interesting design challenges because the product is usually cell-bound, thermolabile, and/or adulterated/inactivated by chemical sterilants. As a result many designs incorporate operations to separate the organism from the product. Once this is accomplished the organism can be inactivated in a separate kill system. In this case, the emptied closed system, which contains residues of live organism, must be designed to permit sterilization by a validated method before it can be opened for cleaning or maintenance.
Controlling aerosols in unit operations that may contain live organisms can present further design challenges. The major points for aerosol generation are the sampling points, sparging of the batch, and seals around rotating equipment. Closed sampling systems have been designed in various forms to solve the aerosol problem at sample points. These can vary in complexity based on the user's preference and the size of the process equipment. Sparging of the batch creates aerosols containing the organism in the head space and exhaust air of the bioreactor. In a mildly pressurized bioreactor, this can result in aerosols being generated into the work space at head penetrations with faulty design, machining, or gasketing. Control of aerosols around rotating shafts in bioreactors, pumps, and centrifuges is one area for further improvement. The guidelines specify the use of rotating seals to prevent leakage to the environment for minimal and moderate levels of containment. Typically, double mechanical seals with a hot condensate or live steam purge are used in these applications. The concept of intelligent seals may offer a solution to this problem, but further development and evaluation are required.
The final major biosafety requirement is to control waste streams containing live organisms. Two major categories of waste streams are involved: gases and liquid/solid wastes. Bioreactors usually are sparged with various gases to maintain optimal life-support conditions for the organism. The exhausted gases contain aerosolized microscopic organisms or cells. These gases can be either incinerated or sterile filtered. Currently, most facilities use sterile filtration of gases as the more cost-effective alternative. These systems usually include redundant filters to assure a high level of operational reliability.
Liquid and solid wastes from process streams are usually pumped to specially designed waste stream kill systems. There are several design alternatives. These systems can use either steam or chemicals to sterilize the wastes. Although both types of systems are used, steam sterilization is favored because it can be easily validated and monitored. The volume of daily waste will be a major factor in choosing between a batch- or continuous-operating system. These systems must be reliable and operated in a validated state at all times. To accomplish this, they are designed with elaborate interactive controls and alarm systems.
It is difficult to predict future developments in recombinant biosafety requirements. The biotechnology industry has been following the voluntary NIH guidelines for over a decade without a major incident. In fact, as the volume of data has grown, the guidelines have been relaxed to reflect this knowledge. However, U.S. biotechnology policy has shifted toward increasing regulatory involvement.
A statement of that policy was issued in the Federal Register in 1986. The two key elements of that policy included the use of existing laws for regulation of research and products and the formation of the Biotechnology Science Coordinating Committee (BSCC). The function of the BSCC is to coordinate and aid various government agencies with policies. The key regulatory agencies involved with the biopharmaceutical industry are the FDA, the EPA, and the Occupational Safety and Health Administration. The result of this policy statement has been to promote rigorous scientific reviews of biotechnology research proposals, products, and projects among the agencies. Currently, the regulatory agencies are reviewing and evaluating their policies and existing laws as they apply to the biotechnology industry. In following their charter to protect the general public's interest, we can expect a very conservative and strict approach to all areas of recombinant DNA biosafety issues for at least the next 10 years.
References Salant, R.F., "Intelligent Dynamic Seals and Their Application to Bioprocessing Technology," Proceedings of the Bioprocess Engineering Symposium at the 1988 ASME Winter Annual Meeting, pp. 29-35.
Casimir A. Perkowski Principal Biotechnologist United Engineers and Constructors, Inc. Philadelphia, Pa.
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|Author:||Perkowski, Casimir A.|
|Date:||Sep 1, 1989|
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