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feng1619

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[交流] USP中关于沉降菌检验频率

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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1楼2008-07-25 08:25:42
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huigenghao

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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.                               
                               
                               
1  Interaction Between Air Movements and the Dispersion of Contaminants: Clean Zones with Unidirectional Air Flow, Journal of Parenteral Science and Technology, 47(2), 1993.                               
2  NASA, 1967—Microbiology of Clean Rooms.                               
3  The Sixteenth Edition of Standard Methods for the Examination of Dairy Products (the American Health Association) provides a section on surface sampling.                               
4  A Parenteral Drug Association Survey (Technical Monograph 17) showed that out of 27 respondents, 50% were filling more than 3,000 units per run.                               
                               
Auxiliary Information— Staff Liaison : Radhakrishna S Tirumalai, Scientist       
Expert Committee : (MSA05) Microbiology and Sterility Assurance               
USP29–NF24 Page 2969                               
Pharmacopeial Forum : Volume No. 31(2) Page 524                       
Phone Number : 1-301-816-8339       

如果你有31版的话，就参考31版，不过这个没有什么改变的
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8楼2008-07-27 11:24:28
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feng1619

金虫 (小有名气)

小木虫管家
奇怪，怎么只有人看，没有人回答呢？
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2楼2008-07-25 15:24:28
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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！
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.”
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huigenghao

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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.
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4楼2008-07-27 11:18:30
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