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USP中关于沉降菌检验频率
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| 各位专家，我国GMP规定沉降菌与浮游菌只检一样即可，请问USP是如何规定的，浮游菌在各种环境级别的检测频率是多少？100000级的标准是多少？ |
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huigenghao
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Critical issues in performing media fills are the number of fills to qualify an aseptic process, the number of units filled per media fill, the interpretation of results, and implementation of corrective actions. Historically, three media-fill runs during initial qualification or start-up of a facility are conducted to demonstrate consistency of the aseptic processing line. The minimum number of units to demonstrate a contamination rate of not more than 0.1%, which is the criterion for acceptance of a successful media-fill run, is at least 3,000. It should be emphasized that many firms in the United States and other countries are filling more than 3,000 units in a single media-fill run.4 Pilot plant facilities used for preparing small clinical lots may use smaller media fills. A number of international documents (i.e., ISO and EU-GMP) have also cited an expectation of zero positives out of 3,000 media filled units at the 95% confidence level. However, it is recognized that repeated media runs are required in order to confirm the statistical validity of the observed contamination rate for the process. PDA Technical Monograph Number 17,4 “A Survey of Current Sterile Manufacturing Practices,” indicated that many manufacturers believe that their aseptic processes are capable of contamination rates below 0.1%. Since the most critical source of contamination in the clean room is the personnel, visual documentation that can be helpful in correlating production activities to contamination events during media fills is encouraged. The widespread use of isolator systems for sterility testing has demonstrated that elimination of personnel does reduce contamination in aseptic handling. 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 106. 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 106; 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. |
7楼2008-07-27 11:23:30
2楼2008-07-25 15:24:28
huigenghao
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feng1619(金币+10,VIP+0):非常感谢你的热心和你提供的资料！
feng1619(金币+10,VIP+0):非常感谢你的热心和你提供的资料！
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再usp 116节有明确的说明，下面是29版的内容，请你参考 U.S. PHARMACOPEIA USP29 1116 MICROBIOLOGICAL EVALUATION OF CLEAN ROOMS AND OTHER CONTROLLED ENVIRONMENTS The purpose of this informational chapter is to review the various issues that relate to aseptic processing of bulk drug substances, dosage forms, and in certain cases, medical devices; and to the establishment, maintenance, and control of the microbiological quality of controlled environments. This chapter includes discussions on (1) the classification of a clean room based on particulate count limits; (2) microbiological evaluation programs for controlled environments; (3) training of personnel; (4) critical factors in design and implementation of a microbiological evaluation program; (5) development of a sampling plan; (6) establishment of microbiological Alert and Action levels; (7) methodologies and instrumentation used for microbiological sampling; (8) media and diluents used; (9) identification of microbial isolates; (10) operational evaluation via media fills; and (11) a glossary of terms. Excluded from this chapter is a discussion of controlled environments for use by licensed pharmacies in the preparation of sterile products for home use, which is covered under Pharmaceutical Compounding—Sterile Preparations 797. There are alternative methods to assess and control the microbiological status of controlled environments for aseptic processing. Numerical values included in this chapter are not intended to represent absolute values or specifications, but are informational. Given the variety of microbiological sampling equipment and methods, one cannot reasonably suggest that the attainment of these values guarantees the needed level of microbial control or that excursions beyond values in this chapter indicate a loss of control. The improper application of microbiological sampling and analysis may cause significant variability and the potential for inadvertent contamination. Sampling media and devices, and methods indicated in this chapter, are not specifications but only informational. A large proportion of sterile products are manufactured by aseptic processing. Because aseptic processing relies on the exclusion of microorganisms from the process stream and the prevention of microorganisms from entering open containers during filling, product bioburden as well as microbial bioburden of the manufacturing environment are important factors relating to the level of sterility assurance of these products. Establishment of Clean Room Classifications The design and construction of clean rooms and controlled environments are covered in Federal Standard 209E. This standard of air cleanliness is defined by the absolute concentration of airborne particles. Methods used for the assignment of air classification of controlled environments and for monitoring of airborne particulates are included. This federal document only applies to airborne particulates within a controlled environment and is not intended to characterize the viable or nonviable nature of the particles. The application of Federal Standard 209E to clean rooms and other controlled environments in the pharmaceutical industry has been used by manufacturers of clean rooms to provide a specification for building, commissioning, and maintaining these facilities. However, data available in the pharmaceutical industry provide no scientific agreement on a relationship between the number of nonviable particulates and the concentration of viable microorganisms. The criticality of the number of nonviable particulates in the electronic industry makes the application of Federal Standard 209E a necessity, while the pharmaceutical industry has a greater concern for viable particulates (i.e., microorganisms) rather than total particulates as specified in Federal Standard 209E. A definite concern for counts of total particulates in injectable products exists in the pharmaceutical industry (see Particulate Matter in Injections 788). The rationale that the fewer particulates present in a clean room, the less likely it is that airborne microorganisms will be present is accepted and can provide pharmaceutical manufacturers and builders of clean rooms and other controlled environments with engineering standards in establishing a properly functioning facility. Federal Standard 209E, as applied in the pharmaceutical industry is based on limits of all particles with sizes equal to or larger than 0.5 µm. Table 1 describes Airborne Particulate Cleanliness Classes in Federal Standard 209E as adapted to the pharmaceutical industry. The pharmaceutical industry deals with Class M3.5 and above. Class M1 and M3 relate to the electronic industry and are shown in Table 1 for comparison purposes. It is generally accepted that if fewer particulates are present in an operational clean room or other controlled environment, the microbial count under operational conditions will be less, provided that there are no changes in airflow, temperature, and humidity. Clean rooms are maintained under a state of operational control on the basis of dynamic (operational) data. Table 1. Airborne Particulate Cleanliness Classes* Class Name Particles equal to and larger than 0.5 µm SI U.S. (m3) (ft3) Customary M1 — 10 0.283 M1.5 1 35.3 1 M2 — 100 2.8 M2.5 10 353 10 M3 — 1,000 28.3 M3.5 100 3,530 100 M4 — 10,000 283 M4.5 1,000 35,300 1,000 M5 — 100,000 2,830 M5.5 10,000 353,000 10,000 M6 1,000,000 28,300 M6.5 100,000 3,530,000 100,000 M7 — 10,000,000 283,000 * Adapted from U.S. Federal Standard 209E, September 11, 1992—“Airborne Particulate Cleanliness Classes in Clean Rooms and Clean Zones.” |
3楼2008-07-27 11:17:51
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Importance of a Microbiological Evaluation Program for Controlled Environments Monitoring of total particulate count in controlled environments, even with the use of electronic instrumentation on a continuous basis, does not provide information on the microbiological content of the environment. The basic limitation of particulate counters is that they measure particles of 0.5 µm or larger. While airborne microorganisms are not free-floating or single cells, they frequently associate with particles of 10 to 20 µm. Particulate counts as well as microbial counts within controlled environments vary with the sampling location and the activities being conducted during sampling. Monitoring the environment for nonviable particulates and microorganisms is an important control function because they both are important in achieving product compendial requirements for Particulate Matter and Sterility under Injections 1. Microbial monitoring programs for controlled environments should assess the effectiveness of cleaning and sanitization practices by and of personnel that could have an impact on the bioburden of the controlled environment. Microbial monitoring, regardless of how sophisticated the system may be, will not and need not identify and quantitate all microbial contaminants present in these controlled environments. However, routine microbial monitoring should provide sufficient information to ascertain that the controlled environment is operating within an adequate state of control. Environmental microbial monitoring and analysis of data by qualified personnel will permit the status of control to be maintained in clean rooms and other controlled environments. The environment should be sampled during normal operations to allow for the collection of meaningful data. Microbial sampling should occur when materials are in the area, processing activities are ongoing, and a full complement of operating personnel is on site. Microbial monitoring of clean rooms and some other controlled environments, when appropriate, should include quantitation of the microbial content of room air, compressor air that enters the critical area, surfaces, equipment, sanitization containers, floors, walls, and personnel garments (e.g., gowns and gloves). The objective of the microbial monitoring program is to obtain representative estimates of bioburden of the environment. When data are compiled and analyzed, any trends should be evaluated by trained personnel. While it is important to review environmental results on the basis of recommended and specified frequency, it is also critical to review results over extended periods to determine whether trends are present. Trends can be visualized through the construction of statistical control charts that include alert and action levels. The microbial control of controlled environments can be assessed, in part, on the basis of these trend data. Periodic reports or summaries should be issued to alert the responsible manager. When the specified microbial level of a controlled environment is exceeded, a documentation review and investigation should occur. There may be differences in the details of the investigation, depending on the type and processing of the product manufactured in the room. Investigation should include a review of area maintenance documentation; sanitization documentation; the inherent physical or operational parameters, such as changes in environmental temperature and relative humidity; and the training status of personnel involved. Following the investigation, actions taken may include reinforcement of training of personnel to emphasize the microbial control of the environment; additional sampling at increased frequency; additional sanitization; additional product testing; identification of the microbial contaminant and its possible source; and an evaluation of the need to reassess the current standard operating procedures and to revalidate them, if necessary. Based on the review of the investigation and testing results, the significance of the microbial level being exceeded and the acceptability of the operations or products processed under that condition may be ascertained. Any investigation and the rationale for the course of action should be documented and included as part of the overall quality management system. A controlled environment such as a clean zone or clean room is defined by certification according to a relevant clean room operational standard. Parameters that are evaluated include filter integrity, air velocity, air patterns, air changes, and pressure differentials. These parameters can affect the microbiological bioburden of the clean room operation. The design, construction, and operation of clean rooms varies greatly, making it difficult to generalize requirements for these parameters. An example of a method for conducting a particulate challenge test to the system by increasing the ambient particle concentration in the vicinity of critical work areas and equipment has been developed by Ljungquist and Reinmuller.1 First, smoke generation allows the air movements to be visualized throughout a clean room or a controlled environment. The presence of vortices or turbulent zones can be visualized, and the airflow pattern may be fine-tuned to eliminate or minimize undesirable effects. Then, particulate matter is generated close to the critical zone and sterile field. This evaluation is done under simulated production conditions, but with equipment and personnel in place. Proper testing and optimization of the physical characteristics of the clean room or controlled environment is essential prior to completion of the validation of the microbiological monitoring program. Assurance that the controlled environment is operating adequately and according to its engineering specifications will give a higher assurance that the bioburden of the environment will be appropriate for aseptic processing. These tests should be repeated during routine certification of the clean room or controlled environment and whenever changes made to the operation, such as personnel flow, processing, operation, material flow, air-handling systems, or equipment layout, are determined to be significant. Training of Personnel Aseptically processed products require manufacturers to pay close attention to detail and to maintain rigorous discipline and strict supervision of personnel in order to maintain the level of environmental quality appropriate for the sterility assurance of the final product. Training of all personnel working in controlled environments is critical. This training is equally important for personnel responsible for the microbial monitoring program, where contamination of the clean working area could inadvertently occur during microbial sampling. In highly automated operations, the monitoring personnel may be the employees who have the most direct contact with the critical zones within the processing area. Monitoring of personnel should be conducted before or after working in the processing area. Microbiological sampling has the potential to contribute to microbial contamination due to inappropriate sampling techniques. A formal personnel training program is required to minimize this risk. This formal training should be documented for all personnel entering controlled environments. Management of the facility must assure that all personnel involved in operations in clean rooms and controlled environments are well versed in relevant microbiological principles. The training should include instruction on the basic principles of aseptic processing and the relationship of manufacturing and handling procedures to potential sources of product contamination. This training should include instruction on the basic principles of microbiology, microbial physiology, disinfection and sanitation, media selection and preparation, taxonomy, and sterilization as required by the nature of personnel involvement in aseptic processing. Personnel involved in microbial identification will require specialized training on required laboratory methods. Additional training on the management of the environmental data collected must be provided to personnel. Knowledge and understanding of applicable standard operating procedures is critical, especially those standard operating procedures relating to corrective measures that are taken when environmental conditions so dictate. Understanding of regulatory compliance policies and each individual's responsibilities with respect to good manufacturing practices (GMPs) should be an integral part of the training program as well as training in conducting investigations and in analyzing data. The major source of microbial contamination of controlled environments is the personnel. Contamination can occur from the spreading of microorganisms by individuals, particularly those with active infections. Only healthy individuals should be permitted access to controlled environments. |
4楼2008-07-27 11:18:30