主题：【资料】MICROBIOLOGICAL EVALUATION OF CLEAN ROOMS AND OTHER CONTROLLED ENVIRONMENTS

An Overview of the Emerging Technologies for Advanced Aseptic Processing
Because of the strong correlation between human involvement and intervention and the potential for product contamination in aseptic processing, production systems in which personnel are removed from critical zones have been designed and implemented. Methods developed to reduce the likelihood of contamination include equipment automation, barriers, and isolator systems. Facilities that employ these advanced aseptic processing strategies are already in operation. In facilities where personnel have been completely excluded from the critical zone, the necessity for room classification based on particulate and environmental microbiological monitoring requirements may be significantly reduced.
The following are definitions of some of the systems currently in place to reduce the contamination rate in aseptic processing:
Barriers— In the context of aseptic processing systems, a barrier is a device that restricts contact between operators and the aseptic field enclosed within the barrier. These systems are used in hospital pharmacies, laboratories, and animal care facilities, as well as in aseptic filling. Barriers may not be sterilized and do not always have transfer systems that allow passage of materials into or out of the system without exposure to the surrounding environment. Barriers range from plastic curtains around the critical production zones to rigid enclosures found on modern aseptic-filling equipment. Barriers may also incorporate such elements as glove ports, half-suits, and rapid-transfer ports.
Blow/Fill/Seal— This type of system combines the blow-molding of container with the filling of product and a sealing operation in one piece of equipment. From a microbiological point of view, the sequence of forming the container, filling with sterile product, and formation and application of the seal are achieved aseptically in an uninterrupted operation with minimal exposure to the environment. These systems have been in existence for about 30 years and have demonstrated the capability of achieving contamination rates below 0.1%. Contamination rates of 0.001% have been cited for blow/fill/seal systems when combined media-fill data are summarized and analyzed.
Isolator— This technology is used for a dual purpose. One is to protect the product from contamination from the environment, including personnel, during filling and closing, and the other is to protect personnel from deleterious or toxic products that are being manufactured.
Isolator technology is based on the principle of placing previously sterilized components (containers/products/closures) into a sterile environment. These components remain sterile during the whole processing operation, since no personnel or nonsterile components are brought into the isolator. The isolator barrier is an absolute barrier that does not allow for interchanges between the protected and unprotected environments. Isolators either may be physically sealed against the entry of external contamination or may be effectively sealed by the application of continuous overpressure. Manipulations of materials by personnel are done via use of gloves, half-suits, or full suits. All air entering the isolator passes through either an HEPA or UPLA filter, and exhaust air typically exits through an HEPA-grade filter. Peracetic acid and hydrogen peroxide vapor are commonly used for the surface sterilization of the isolator unit's internal environment. The sterilization of the interior of isolators and all contents are usually validated to a sterility assurance level of 10 6.
Equipment, components, and materials are introduced into the isolator through a number of different procedures: use of a double-door autoclave; continuous introduction of components via a conveyor belt passing through a sterilizing tunnel; use of a transfer container system through a docking system in the isolator enclosure. It is also necessary to monitor closely an isolator unit's integrity, calibration, and maintenance.
The requirements for controlled environments surrounding these newer technologies for aseptic processing depend on the type of technology used.
Blow/Fill/Seal equipment that restricts employee contact with the product may be placed in a controlled environment, especially if some form of employee intervention is possible during production.
Barrier systems will require some form of controlled environment. Because of the numerous barrier system types and applications, the requirements for the environment surrounding the barrier system will vary. The design and operating strategies for the environment around these systems will have to be developed by the manufacturers in a logical and rational fashion. Regardless of these strategies, the capability of the system to produce sterile products must be validated to operate in accordance with pre-established criteria.
In isolators, the air enters the isolator through integral filters of HEPA quality or better, and their interiors are sterilized typically to a sterility assurance level of 10 6; therefore, isolators contain sterile air, do not exchange air with the surrounding environment, and are free of human operators. However, it has been suggested that when the isolator is in a controlled environment, the potential for contaminated product is reduced in the event of a pinhole leak in the suit or glove.
The extent and scope of an environmental microbiological monitoring of these advanced systems for aseptic processing depends on the type of system used. Manufacturers should balance the frequency of environmental sampling systems that require human intervention with the benefit accrued by the results of that monitoring. Since barrier systems are designed to reduce human intervention to a minimum, remote sampling systems should be used in lieu of personnel intervention. In general, once the validation establishes the effectiveness of the barrier system, the frequency of sampling to monitor the microbiological status of the aseptic processing area could be reduced, as compared to the frequency of sampling of classical aseptic processing systems.
Isolator systems require relatively infrequent microbiological monitoring. Continuous total particulate monitoring can provide assurance that the air filtration system within the isolator is working properly. The methods for quantitative microbiological air sampling described in this chapter may not have sufficient sensitivity to test the environment inside an isolator. Experience with isolators indicates that under normal operations pinhole leaks or tears in gloves represent the major potential for microbiological contamination; therefore, frequent testing of the gloves for integrity and surface monitoring of the gloves is essential. Surface monitoring within the isolator may also be beneficial on an infrequent basis.

GLOSSARY
Airborne Particulate Count (also referred to as Total Particulate Count)—Particles detected are 0.5 µm and larger. When a number of particles is specified, it is the maximum allowable number of particles per cubic meter of air (or per cubic foot of air).
Airborne Viable Particulate Count (also referred to as Total Airborne Aerobic Microbial Count)—When a number of microorganisms is specified, it is the maximum number of colony-forming units (cfu) per cubic meter of air (or per cubic foot of air) that is associated with a Cleanliness Class of controlled environment based on the Airborne Particulate Count.
Aseptic Processing—A mode of processing pharmaceutical and medical products that involves the separate sterilization of the product and of the package (containers/closures or packaging material for medical devices) and the transfer of the product into the container and its closure under microbiologic critically controlled conditions.
Air Sampler—Devices or equipment used to sample a measured amount of air in a specified time to quantitate the particulate or microbiological status of air in the controlled environment.
Air Changes—The frequency per unit of time (minutes, hours, etc.) that the air within a controlled environment is replaced. The air can be recirculated partially or totally replaced.
Action Levels—Microbiological levels in the controlled environment, specified in the standard operating procedures, which when exceeded should trigger an investigation and a corrective action based on the investigation.
Alert Levels—Microbial levels, specified in the standard operating procedures, which when exceeded should result in an investigation to ensure that the process is still within control. Alert levels are specific for a given facility and are established on the basis of a baseline developed under an environmental monitoring program. These Alert levels can be modified depending on the trend analysis done in the monitoring program. Alert levels are always lower than Action levels.
Bioburden—Total number of microorganisms detected in or on an article.
Clean Room—A room in which the concentration of airborne particles is controlled to meet a specified airborne particulate Cleanliness Class. In addition, the concentration of microorganisms in the environment is monitored; each Cleanliness Class defined is also assigned a microbial level for air, surface, and personnel gear.
Clean Zone—A defined space in which the concentration of airborne particles and microorganisms are controlled to meet specific Cleanliness Class levels.
Controlled Environment—Any area in an aseptic process system for which airborne particulate and microorganism levels are controlled to specific levels, appropriate to the activities conducted within that environment.
Commissioning of a Controlled Environment—Certification by engineering and quality control that the environment has been built according to the specifications of the desired cleanliness class and that, under conditions likely to be encountered under normal operating conditions (or worst-case conditions), it is capable of delivering an aseptic process. Commissioning includes media-fill runs and results of the environmental monitoring program.
Corrective Action—Actions to be performed that are in standard operating procedures and that are triggered when certain conditions are exceeded.
Environmental Isolates—Microorganisms that have been isolated from the environmental monitoring program.
Environmental Monitoring Program—Documented program, implemented through standard operating procedures, that describes in detail the procedures and methods used for monitoring particulates as well as microorganisms in controlled environments (air, surface, personnel gear). The program includes sampling sites, frequency of sampling, and investigative and corrective actions that should be followed if Alert or Action levels are exceeded. The methodology used for trend analysis is also described.
Equipment Layout—Graphical representation of an aseptic processing system that denotes the relationship between and among equipment and personnel. This layout is used in the Risk Assessment Analysis to determine sampling site and frequency of sampling based on potential for microbiological contamination of the product/container/closure system. Changes must be assessed by responsible managers, since unauthorized changes in the layout for equipment or personnel stations could result in increase in the potential for contamination of the product/container/closure system.
Federal Standard 209E—“Airborne Particulate Cleanliness Classes in Clean Rooms and Clean Zones” is a standard approved by the Commissioner, Federal Supply Services, General Service Administration, for the use of “All Federal Agencies.” The Standard establishes classes of air cleanliness based on specified concentration of airborne particulates. These classes of air cleanliness have been developed, in general, for the electronic industry “super-clean” controlled environments. In the pharmaceutical industry, the Federal Standard 209E is used to specify the construction of controlled environment. Class 100, Class 10,000, and Class 100,000 are generally represented in an aseptic processing system. If the classification system is applied on the basis of particles equal to or greater than 0.5 µm, these classes are now represented in the SI system by Class M3.5, M5.5, and M6.5, respectively.
Filter Integrity—Testing that ensures that a filter functional performance is satisfactory [e.g., dioctyl phthalate (DOP) and bubble point test].
Material Flow—The flow of material and personnel entering controlled environments should follow a specified and documented pathway that has been chosen to reduce or minimize the potential for microbial contamination of the product/closure/container systems. Deviation from the prescribed flow could result in increase in potential for microbial contamination. Material/personnel flow can be changed, but the consequences of the changes from a microbiological point of view should be assessed by responsible managers and must be authorized and documented.

Media Growth Promotion—Procedure that references Growth Promotion under Sterility Tests  71  to demonstrate that media used in the microbiological environmental monitoring program, or in media-fill runs, are capable of supporting growth of indicator microorganisms and of environmental isolates from samples obtained through the monitoring program or their corresponding ATCC strains.
Media Fill—Microbiological simulation of an aseptic process by the use of growth media processed in a manner similar to the processing of the product and with the same container/closure system being used.
Out-of-Specification Event—Temporary or continuous event when one or more of the requirements included in standard operating procedures for controlled environments are not fulfilled.
Product Contact Areas—Areas and surfaces in a controlled environment that are in direct contact with either products, containers, or closures and the microbiological status of which can result in potential microbial contamination of the product/container/closure system. Once identified, these areas should be tested more frequently than non-product-contact areas or surfaces.
Risk Assessment Analysis—Analysis of the identification of contamination potentials in controlled environments that establish priorities in terms of severity and frequency and that will develop methods and procedures that will eliminate, reduce, minimize, or mitigate their potential for microbial contamination of the product/container/closure system.
Sampling Plan—A documented plan that describes the procedures and methods for sampling a controlled environment; identifies the sampling sites, the sampling frequency, and number of samples; and describes the method of analysis and how to interpret the results.
Sampling Sites—Documented geographical location, within a controlled environment, where sampling for microbiological evaluation is taken. In general, sampling sites are selected because of their potential for product/container/closure contacts.
Standard Operating Procedures—Written procedures describing operations, testing, sampling, interpretation of results, and corrective actions that relate to the operations that are taking place in a controlled environment and auxiliary environments. Deviations from standard operating procedures should be noted and approved by responsible managers.
Sterile Field—In aseptic processing or in other controlled environments, it is the space at the level of or above open product containers, closures, or product itself, where the potential for microbial contamination is highest.
Sterility—Within the strictest definition of sterility, an article is deemed sterile when there is complete absence of viable microorganisms. Absolute sterility cannot be practically demonstrated without testing every article in a batch. Sterility is defined in probabilistic terms, where the likelihood of a contaminated article is acceptably remote.
Swabs—Devices provided that are used to sample irregular as well as regular surfaces for determination of microbial status. The swab, generally composed of a stick with an absorbent extremity, is moistened before sampling and used to sample a specified unit area of a surface. The swab is then rinsed in sterile saline or other suitable menstruum and the contents plated on nutrient agar plates to obtain an estimate of the viable microbial load on that surface.
Trend Analysis—Data from a routine microbial environmental monitoring program that can be related to time, shift, facility, etc. This information is periodically evaluated to establish the status or pattern of that program to ascertain whether it is under adequate control. A trend analysis is used to facilitate decision-making for requalification of a controlled environment or for maintenance and sanitization schedules.

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