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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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隔离器技术基于在无菌环境中预先放置已灭菌组件（容器/产品/闭包）原则。这些组件在整个操作过程中保持无菌状态，是因为没有任何人员或是非灭菌组件被带进隔离器。隔离器屏蔽是一个完全的屏蔽，它不允许保护环境与非保护环境中物质的互换。隔离器或者是物理水平的封闭外界环境污染的进入，或者可能是通过应用连续的超压起到有效的封闭作用。人员对原料的处理是通过手套、半身或全身工作服进行的。所有进入隔离器的空气都要通过HEPA或 UPLA过滤器，典型的废气通过HEPA-级滤器排出。过氧乙酸和过氧化氢蒸汽通常用于隔离器单位内部环境表面的灭菌。隔离器本身内部以及所有其内容物的无菌水平通常可以保证到达106。
设备、组件以及原料通过许多不同操作步骤被引入隔离器：运用双通道高压灭菌器；通过无菌通道用输送带连续引入组件；传送容器系统通过对接系统在隔离器外壳中的运用。对隔离器组件的完整性、校准以及保养的紧密监测也是必需的。
控制环境中围绕这些针对无菌操作的较新技术所需条件，应当依应用技术的类型而定。
限制了工作人员与产品的接触的Blow/Fill/Seal设备可能会放置在控制环境中，尤其是生产过程中工作人员可能以某种形式介入的区域。
阻挡层系统可能会对控制环境有些形式上的需要。由于阻挡层系统类型和用途的多样性，这就造成了阻挡层系统所需周围环境的多样性。因此制造商不得不将围绕这些系统的环境的设计和工作策略进行发展，以使其成为合理的有利的模式。如果不管这些策略，那么系统制造无菌产品的能力必须被验证有效，且与此前建立的标准相一致。
对于隔离器，空气通过整个HEPA级或更高质量的过滤器进入其中，且其内部经过典型的灭菌处理，其无菌程度保证在106水平。这样，隔离器就包含有无菌的空气，不与周围环境进行空气交换，且是隔离于操作人员的。有建议表明，当一个控制环境中存在隔离器时，手套和制服上的小孔渗漏事件对产品造成污染的潜在性是减少了。
这些先进系统对无菌操作的环境微生物监测的程度和广度，依赖于其应用的系统类型。制造商应当用通过监测结果而获得的利益来平衡需要人员介入的环境取样系统的频率。由于阻挡层系统的设计是为了把人员的介入减到最小，那么就应当用远距离取样系统来替代人员的介入。总的来说，一旦确立了阻挡层系统的有效性，用以监测无菌操作区域微生物状况的取样频率与传统的无菌操作系统的取样频率相比较，应当被减少。
隔离器系统的微生物监测频率相对较少。连续的总粒子监测就能够为隔离器内的空气过滤系统处于正常工作状态提供可靠保证。本章所述对微生物质量进行控制的方法，对于隔离器内部的环境测试来说，其敏感度可能不足。对隔离器的经验提示，在正常操作的情况下，手套上的漏洞或小孔是微生物污染潜在性的主要代表；因此，经常性的检测手套的完整性以及对其进行表面的监测是必需的。隔离器内的表面监测对于珍贵的主药也是有益的。

词汇表
空气播散颗粒计数（Airborne Particulate Count）(也指总颗粒计数)—检测0.5 µm 以及更大的微粒。当详细说明许多颗粒的时候，其指的是每立方米空气（或每立方英尺空气）中最大允许颗粒数 。
空气播散活性颗粒计数（Airborne Viable Particulate Count）(也指总的空气散播需氧微生物计数)—当详细说明许多微生物的时候，其指的是每立方米空气（或每立方英尺空气）中菌落形成单位(cfu)最大数值，此值与基于空气散播颗粒计数的控制环境的洁净级相关。
无菌操作（Aseptic Processing）—一种加工处理药学和医学产品的模式，包括产品的单独灭菌、产品包装（容器/闭包或医疗器械的包装）、产品装入容器的传递以及其闭包，均在微生物临界控制条件下进行。
空气取样器（Air Sampler）—用来采集在特定时间的测量空气样品，从而测量控制环境中空气颗粒或微生物情况的设备或装置。
换气（Air Changes）—控制环境中的空气每单位时间（分、小时等）被更换的频率。空气可以局部循环或整体更换。
行动标准（Action Levels）—控制环境中的微生物学标准，特指在标准操作过程，当超过此标准时，应当启动调查并基于此调查进行改善。
警告标准（Alert Levels）—微生物的水平，特指在标准操作过程，当超过此标准时，应当调查以确定进程是否仍然处于控制范围内。警告标准对于给定的设备是特定的，且是以环境的检测程序下制定的基线为根据建立的。这些警告标准可依赖检测程序中的趋势分析而修改。警告标准总是低于行动标准。
生物负担（Bioburden）—在项目中检测到的微生物总数量。以某条款为指导进行检测。
洁净室（Clean Room）—一房间，其空气播散颗粒浓度被控制达到特定的空气播散颗粒洁净级别。并且环境中的微生物浓度是被监测的，定义每一洁净级别也分配于空气、表面和全体传动装置的微生物水平。
洁净区（Clean Zone）—定义一个空间，控制其中的空气散播颗粒浓度和微生物浓度，使其能达到特定洁净级别。
控制环境（Controlled Environment）—一个无菌处理系统中的任何区域，其空气散播颗粒和微生物被控制在特定水平，以在此环境进行适当的操作。
控制环境试车（Commissioning of a Controlled Environment）—通过工程和质量控制证明，环境是依照期望洁净级别的规范建立的，且在正常操作条件（或最坏情况条件）中可能遇到的情况下，其有能力进行无菌处理。试车包括培养基填充运转和环境监测程序结果。
改善行动（Corrective Action）—在标准化操作规程中需执行的行动，当某一条件超标时即启动。
环境隔离群（Environmental Isolates）—从环境监测程序隔离出的微生物。
环境检测程序（Environmental Monitoring Program）—文件性程序，通过标准化操作规成实现，其详细描述了在控制环境中（空气、表面和全体传动装置）用于监测颗粒和微生物的程序和方法。此程序包括取样点、取样频率以及如果超过警告或活动标准后应采取的跟随调查和改善行动。同时也描述了用于趋势分析的方法学。
设备布局（Equipment Layout）—无菌处理系统的图解表示法，用来表示设备和人员之间的关系。此布局被用于危险率估计，并根据产品/容器/闭包系统微生物污染的潜在性，确定取样点和取样频率。改变必须经由责任管理人员的评估，因为未经认可的改变设备或人员的布局可能导致产品/容器/闭包系统污染潜在性的增加。
联邦标准209E（Federal Standard 209E）—“洁净室和洁净区内空气播散颗粒洁净级别”，是被the Commissioner, Federal Supply Services, General Service Administration核准的用于“所有联邦机构”的一项标准。此标准依据特定空气播散颗粒浓度，建立了空气洁净级别。这些空气洁净级别通常被发展为电子行业 “超净” 控制环境。在制药行业中，联邦标准209E 被用于特指控制环境的建造。无菌处理系统通常呈现为100级、10,000级和100,000级。如果此分级系统应用于颗粒等于或大于0.5 µm的基础上，那么这些级别就分别以M3.5、M5.5和M6.5，呈现为SI 系统。
过滤完整性（Filter Integrity）—确定过滤功能型操作是令人满意的 [如：邻苯二甲酸二辛酯(DOP)和始沸点测试] 测试。
原料流动（Material Flow）—原料和人员进入控制环境的流动应该遵循特定的和文件性的途径，其途径的选择是用以减少或最小化产品/闭包/容器系统微生物污染潜在性。偏离规定流程可能会导致微生物污染的潜在性增加。原料/人员流动可以改变，但是其改变的结果从微生物学角度看应该由责任的管理人员评估，且必须经认可和证明。
培养基生长促进（Media Growth Promotion）—此操作参考无菌检查（Sterility Tests）á71ñ指导下的生长促进 来证明用在微生物学环境监测程序中或培养基填充运行中的培养基，能够维持指示微生物以及通过监测程序获得样品的环境隔离群或他们相应的ATCC菌株的生长。
培养基填充（Media Fill）—无菌处理的微生物学模拟，通过以加工产品相似的方法并用相同的容器/闭包系统，处理生长培养基来实现。
不合规格事件（Out-of-Specification Event）—当包括在标准操作规程内的对于控制环境的一或多个需求未能实现时发生的暂时或连续性事件。
产品接触区（Product Contact Areas）—控制环境中的和产品、容器或闭包有直接联系的区域以及表面，并且其微生物学状况能够影响产品/容器/闭包系统微生物污染的潜在性。一旦标定，这些区域应当进行比非产品接触区以及表面频率更高的检测。
危险率估计分析（Risk Assessment Analysis）—控制环境中用于鉴别污染潜在性的分析，以建立严重性和频率的优先级别，从而来制定方法和规程以去除、减少、最小化或者缓和产品/容器/闭包系统微生物污染的潜在性。
取样策略（Sampling Plan）—一个文件性策略，描述控制环境中取样的操作和方法；标定取样点、取样频率以及取样数量；且对分析方法和结果解释均有描述。
取样点（Sampling Sites）—在控制环境中进行微生物评估的取样操作的地理位置。通常取样点的选择是根据其与产品/容器/闭包联系的潜在性来确定的。
标准化操作规程（Standard Operating Procedures）—书面规程，描述在控制环境和辅助环境中发生的与操作相关的操作、测试、取样、结果解释以及改善行动等内容。偏离标准化操作规程应受到注意并通过责任管理人员核准。
无菌区域（Sterile Field）—在无菌操作中或其它控制环境中，指的是在开放产品包装、闭包或产品本身同一水平或其上方，其微生物污染潜在性最高的区域。
无菌（Sterility）—在无菌的最严格定义中，当一个物品完全没有活性微生物的存在时，被认为是无菌的。在没有对一批中每一物品进行测试的情况下，不能证明其实际是绝对的无菌。 无菌被定义为概率性术语，指可能性的污染物品处于可接受的远距离。
水刷（Swabs）—用于进行常规和非常规表面取样以确定微生物状况的设备。水刷，通常由一个手柄和一个吸收远端组成，在取样前湿润，用于表面单位面积的取样。然后用无菌盐水或其它合适溶剂冲洗水刷，内含物被置于营养琼脂平板上培养，以获得附着于表面的活性微生物评估。
趋势分析（Trend Analysis）—从常规微生物环境监测程序得出的能够与时间、变化、设备等相关的数据。此信息为周期性的评估，以建立该程序的状态或模式来明确其是否处于适当的控制之下。趋势分析用于推进控制环境的资格再评估的决策制定或用于维护以及清洁卫生处理计划的决策制定。
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11楼2008-07-27 12:01:13
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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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3楼2008-07-27 11:17:51
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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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