Annex 2(QC) 世界卫生组织药品微生物实验室管理规范

© World Health Organization 世界卫生组织
WHO Technical Report Series, No. 961, 2011世界卫生组织技术报告系列，编号961，2011年Annex 2 附录2
WHO good practices for pharmaceutical microbiology laboratories
世界卫生组织药品微生物实验室管理规范
目录
Background 背景 (2)
Introduction and scope of document 文件介绍和范围 (2)
Glossary 术语表 (3)
1. Personnel 人员 (5)
2. Environment 环境 (6)
2.1 Premises 房屋 (6)
2.3 Cleaning, disinfection and hygiene 清洁、消毒和卫生 (8)
2.4 Sterility test facilities 无菌试验设施 (8)
3. Validation of test methods 检验方法的验证 (10)
4. Equipment 设备 (10)
4.1 Maintenance of equipment 设备维护 (11)
4.2 Qualification 验证 (11)
4.3 Calibration, performance verification and monitoring of use 校准、性能确认和使用的监控 (11)
4.3.3 Temperature measurement devices 温度测量装置 (11)
4.3.4 Incubators, water-baths and ovens 培养箱、水浴和烘箱 (11)
4.3.5 Autoclaves, including media preparators 高压灭菌锅，包括培养基制备器 (12)
4.3.6 Weights and balances 砝码和天平 (13)
4.3.7 Volumetric equipment 测定体积的设备 (13)
4.3.8 Other equipment 其他设备 (13)
5. Reagents and culture media 试剂和培养基 (14)
5.1 Reagents 试剂 (14)
5.2 Media 培养基 (14)
5.3 Labelling 贴签 (16)
5.4 Organism resuscitation 微生物复苏 (16)
6. Reference materials and reference cultures 标准物质和标准菌株 (16)
6.1 International standards and pharmacopoeial reference substances 国际标准和药典标准品 (16)
6.2 Reference cultures 标准菌株 (17)
7. Sampling取样 (18)
8. Sample handling and identification 样品处理和鉴定 (18)
9. Disposal of contaminated waste污染废物的处理 (19)
10. Quality assurance of results and quality control of performance结果的质量保证和性能的质量控制 (19)
10.1 Internal quality control内部质量控制 (19)
11. Testing procedures检验程序 (20)
12. Test reports检验报告 (20)
References参考文件 (20)
Further reading 补充书目 (21)
Appendix 1 附件1 (22)
Examples of zones in which operations could be carried out可进行操作的区域的例子 (22)
Appendix 2 附件2 (23)
Examples of maintenance of equipment设备维护的例子 (23)
Appendix 3 附件3 (24)
Examples of calibration checks and intervals for different laboratory equipment不同实验室设备校准检查和间隔的例子 (24)
Appendix 4 附件4 (25)
Examples of equipment qualification and monitoring设备验证和监控的例子 (25)
Appendix 5 附件5 (27)
General use of reference cultures 标准菌株的一般用途 (27)
Background 背景
The WHO Expert Committee on Specifications for Pharmaceutical Preparations adopted in 2009 a revised version of the Good practices for pharmaceutical quality control laboratories (1).
世界卫生组织制剂产品的质量标准专家委员会在2009年通过了药品质量控制实验室管理规范的修订版本(1)。

During the inspections carried out when prequalifying laboratories, the inspectors had noticed that some of the texts of these guidelines might benefit from additional guidance, with a special focus on microbiology.
在预验证实验室时所进行的检查过程中，检查官注意到这些指导原则的部分内容可能受益于附加的特别关注微生物的指导原则。

In light of the above, the Expert Committee recommended that the WHO Secretariat initiate the process of developing a new text on good practices for pharmaceutical microbiology laboratories.
鉴于以上，专家委员会建议世界卫生组织秘书处启动撰写新的药品微生物实验室管理规范的程序。

The following text is proposed to cover this specific type of laboratory.
提出下文以包含这种特殊类型的实验室。

Introduction and scope of document 文件介绍和范围
Pharmaceutical microbiology laboratories may be involved in:
药品微生物实验室可涉及到：
— sterility testing; 无菌试验；
—detection, isolation, enumeration and identification of microorganisms (bacteria, yeast and moulds) and testing for bacterial endotoxins in different materials (e.g. starting materials, water), products, surfaces, garments and the environment; and
—在不同物料（如原辅料、水）、产品、表面、外衣和环境中的微生物（细菌、酵母菌和霉菌）的检测、分离、计数和鉴别，以及细菌内毒素的检验；
—assay using microorganisms as part of the test system.
—使用微生物作为检验系统的一部分进行含量测定。

These guidelines relate to all microbiology laboratories involved in the above-mentioned testing activities, whether they are independent or a department or unit of a pharmaceutical manufacturing
facility.
这些指导原则有关于所有在上述检验活动中涉及的微生物实验室，无论它们是独立的或是药品生产厂的一个部门或单位。

These guidelines are based on and supplement the requirements described in Good practices for pharmaceutical quality control laboratories(1); General guidelines for the establishment, maintenance and distribution of chemical reference substances. Revision(2); The International Pharmacopoeia, Fourth Edition (3); First Supplement to The International Pharmacopoeia, Fourth Edition (4); and ISO/IEC 17025 (5).
这些指导原则是建立在以下规定的要求的基础上的，并对其进行补充：药品质量控制实验室管理规范(1)；建立、维护和分发化学标准品的通用指导原则(2)；国际药典，第四版(3)；国际药典的第一附录，第四版(4)；和ISO/IEC 17025 (5)。

Glossary 术语表
calibration 校准
The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.
在规定条件下建立一台测量（特别是称量）、记录和控制的设备或系统所显示的值，或一个实物量具所代表的值和相应的标准品的值之间关系的一套操作。

应建立测量结果的可接受限度。

certified reference material 检定合格的标准物质
Reference material, characterized by a metrologically valid procedure for one or more specified properties, accompanied by a certificate that provides the value of the specified property, its associated uncertainty and a statement of metrological traceability. 标准物质，通过度量衡有效的程序对一个或多个指定属性进行性质确证，具有提供指定属性的值、其相关不确定度和对度量衡可追溯性的说明的证书。

limit of detection 检测限
The lowest number of microorganisms that can be detected, but in numbers that cannot be estimated accurately.
可被检测出、但在数量上不能被准确估算的微生物的最低数量。

precision 精密度
The degree of agreement among individual results.
单个结果之间一致的程度。

quantitation limit (limit of quantitation) 定量限
Applied to quantitative microbiological tests. The lowest number of microorganisms within a defined variability that may be counted under the experimental conditions of the method under evaluation.
适用于定量微生物试验。

在被评估的方法的试验条件下，在规定的变异性之内，可被计数的微生物的
最低数量。

reference cultures 标准菌株
Collective term for reference strain and reference stocks.
参考菌株和参考原株的总称。

reference material 标准物质
Material sufficiently homogeneous and stable with respect to one or more specified properties, which has been established to be fit for its intended use in a measurement process.
具有足够均一和稳定的一个或多个指定属性的物质，建立该物质以适合于其在测量过程中的预期用途。

reference method 参考方法
A method which has been validated as being fit for purpose, with which an alternative method may be compared.
经过验证证明适合于目的的方法，将替代性的方法与之相比较。

reference stocks 参考原株
A set of separate identical cultures obtained by a single subculture from the reference strain (6).
从参考菌株进行一次继代培养所获得的一套独立的完全相同的培养物(6)。

reference strains 参考菌株
Microorganisms defined at least to the genus and species level, catalogued and described according to its characteristics and preferably stating its origin (6). Normally obtained from a recognized national or international collection.
根据其性质至少规定到种属级别的分类和描述的微生物，最好说明其来源(6)。

通常从认可的国家或国际保藏处获得。

repeatability 重复性
Closeness of the agreement between the results of successive measurements of the same measure and under the same conditions of measurement (adapted from ISO).
同一被测物在相同的测量条件下连续多次测量结果之间相一致的紧密程度。

reproducibility 重现性
Reproducibility expresses precision between laboratories.
重现性表示不同实验室之间的精密度。

robustness (or ruggedness) 耐用性
The ability of the procedure to provide analytical results of acceptable accuracy and precision under a variety of conditions.
程序在不同条件下提供具有可接受的准确度和精密度的分析结果的能力。

sensitivity 灵敏度
The fraction of the total number of positive cultures or colonies correctly assigned in the presumptive inspection (7).
在假定检验中正确指定的阳性培养物或菌落的总数中的部分(7)。

specificity (selectivity) 专属性（选择性）
The ability of the method to detect the required range of microorganisms that might be present in the test sample.
方法能够检测出可能存在于被检样品中的微生物的必需范围的能力。

validation 验证
Action of proving, in accordance with the principles of good practice quality guidelines and regulations (GxP), that any procedure, process, equipment (including the software or hardware used), material, activity or system actually and consistently leads to the expected results.
根据质量管理规范指导原则和法规（GxP）的原则，证明任何程序、工艺、设备（包括所用的软件或硬件）、物料、行为或系统真正能够始终产生预期结果的行动。

verification 确认
The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with GxP principles.
除了监控之外，应用方法、程序、检验和其他评估来确定符合GxP原则。

working culture 工作菌株
A primary subculture from a reference stock (6).
从参考原株处得到的主要继代培养物(6)。

1. Personnel 人员
1.1 Microbiological testing should be performed and supervised by an experienced person,
qualified in microbiology or equivalent. Staff should have basic training in microbiology and relevant practical experience before being allowed to perform work covered by the scope of testing.
应由有经验的、具备微生物或相等资质的人员进行和指导微生物检验。

在被允许进行检验范围所包含的工作之前，员工应接受基本的微生物和相关实践经验的培训。

1.2 Current job descriptions for all personnel involved in tests and/ or calibrations, validations and
verifications should be maintained. The laboratory should also maintain records of all technical
personnel, describing their qualifications, training and experience.
应保存在检验和/或校准、验证和确认中涉及的所有人员的现行职务说明书。

实验室还应保存所有技术人员的记录，描述他们的资质、培训和经验。

1.3 If the laboratory includes opinions and interpretations of test results in reports, this should be
done by authorized personnel with suitable experience and relevant knowledge of the specific application including, for example, regulatory and technological requirements and acceptability criteria.
若实验室包括对报告中检验结果的意见和解释，应由具备具体应用的合适经验和相关知识的获得授权的人员来进行，具体应用包括，例如法规和技术要求和可接受标准。

1.4 The laboratory management should ensure that all personnel have received adequate
training for the competent performance of tests and operation of equipment. This should include training in basic techniques, e.g. plate pouring, counting of colonies, aseptic technique, media preparation, serial dilutions, and basic techniques in identification, with acceptability determined using objective criteria where relevant. Personnel may only perform tests on samples if they are either recognized as competent to do so, or if they do so under adequate supervision.
Competence should be monitored continuously with provision for retraining where necessary.
Where a method or technique is not in regular use, the competency of the personnel to perform the test should be verified before testing is undertaken. In some cases it is acceptable to relate competence to a general technique or instrument being used rather than to particular methods.
实验室管理层应保证所有人员受到了充分的培训，以胜任检验和设备操作。

这将包括基本技术的培训，例如平皿倾灌、菌落计数、无菌技术、培养基制备、连续稀释和鉴别的基本技术，以及使用相关的客观标准决定可接受性。

人员仅在被认可能够胜任，或在充分监督下才能进行样品检验。

应不断监控其能力，必要时进行再培训。

若不定时使用某方法或技术，应在承担检验之前确认进行检验的人员的能力。

在有些情况下，将能力与普通技术或在用仪器而非特殊方法关联起来，是可以接受的。

1.5 Personnel should be trained in necessary procedures for containment of microorganisms
within the laboratory facility.
人员应接受实验室设施内微生物防范的必要程序的培训。

1.6 Personnel should be trained in safe handling of microorganisms.
人员应接受安全处理微生物的培训。

2. Environment 环境
2.1 Premises 房屋
2.1.1 Microbiology laboratories and certain support equipment (e.g. autoclaves and glassware)
should be dedicated and separated from other areas, especially from production areas.
微生物实验室和支持性设备（如高压灭菌器和玻璃器皿）应是专用的，并独立于其他区域，特别是独立于生产区域。

2.1.2 Microbiology laboratories should be designed to suit the operations to be carried out in
them. There should be sufficient space for all activities to avoid mix ups, contamination and cross-contamination. There should be adequate suitable space for samples, reference organisms, media (if necessary, with cooling), testing and records. Due to the nature of some materials (e.g.
sterile media versus reference organisms or incubated cultures), separate storage locations may be necessary.
微生物实验室的设计应与在其中所进行的操作相称。

应有充足的所有活动的空间，以避免混淆、污染和交叉污染。

应有样品、参考有机体、培养基（必要时进行冷却）、检验和记录的足够的合适空间。

鉴于一些物料（如无菌培养基和参考有机体或培养菌株）的性质，单独的储存位置可能是必要的。

2.1.3 Laboratories should be appropriately designed and should take into account the suitability of construction materials to enable appropriate cleaning, disinfection and minimize the risks of contamination.
实验室应有合适的设计，并应考虑到建筑材料的适宜性，能够进行合适的清洁、消毒，尽量降低污染的风险。

2.1.4 There should be separate air supply to laboratories and production areas. Separate air-handling units and other provisions, including temperature and humidity controls where required, should be in place for microbiological laboratories. The air supplied to the laboratory should be of appropriate quality and should not be a source of contamination.
实验室和生产区域应有独立的供风。

应有微生物实验室的独立的空气处理机组和其他供应装备，包括所需的温湿度控制。

供给给实验室的空气应有适宜的质量，不得成为污染源。

2.1.5 Access to the microbiological laboratory should be restricted to authorized personnel. Personnel should be made aware of:
仅限获得授权的人员进入微生物实验室。

人员应了解：
—the appropriate entry and exit procedures including gowning;
—适当的进出规程，包括更衣；
—the intended use of a particular area; 特殊区域的预期用途；
—the restrictions imposed on working within such areas;
—在这些区域内工作的限制条件；
— the reasons for imposing such restrictions; and 这些限制条件的原因；
— the appropriate containment levels. 适当的防范等级。

2.1.6 Laboratory activities, such as sample preparation, media and equipment preparation and enumeration of microorganisms, should be segregated by space or at least in time, so as to minimize risks of cross-contamination, false-positive results and false-negative results. Where non-dedicated areas are used, risk management principles should be applied. Sterility testing should always be performed in a dedicated area.
实验室活动，例如样品制备、培养基和设备准备、微生物计数，应通过空间或至少通过时间进行隔离，以尽量降低交叉污染、假阳性结果和假阴性结果的风险。

若使用非专用区域，应使用风险管理原则。

在专用区域内应始终进行无菌试验。

2.1.7 Consideration should be given to designing appropriate classified areas for the operations to be performed within the microbiology laboratory. The classification should be based on the criticality of the product and the operation being carried out in the area. Sterility testing should be performed under the same class as used for sterile/aseptic manufacturing operations. Appendix 1 shows recommendations for zone classifications.
应为微生物实验室内所进行的操作考虑设计适当分类的区域。

应根据产品和区域内所进行的操作的危急程度来划分类别。

进行无菌试验的级别应与用于无菌洁净生产操作的级别相同。

附件1为区域分类的建议。

2.1.8 In general, laboratory equipment should not routinely be moved between areas of different cleanliness class, to avoid accidental cross-contamination. Laboratory equipment used in the
microbiology laboratory should not be used outside the microbiology area, unless there are specific precautions in place to prevent cross-contamination.
总之，通常实验室设备不得在不同洁净级别的区域之间移动，以避免意外的交叉污染。

微生物实验室内使用的实验室设备不得在微生物区域外使用，除非有具体的防范措施防止交叉污染。

2.2 Environmental monitoring in the laboratory 实验室内的环境监控
2.2.1 Where necessary and appropriate (e.g. in areas for sterility testing) an environmental
monitoring programme should be in place which covers, for example, use of active air monitoring, air settling or contact plates, temperature and pressure differentials. Alert and action limits should be defined. Trending of environmental monitoring results should be carried out.
必要和适当时（如在无菌试验区域内），应有环境监控计划包括，例如，使用活性空气监控、空气沉降或接触平皿、温度和压差。

应规定警报限和行动限。

应进行环境监控结果的趋势分析。

2.3 Cleaning, disinfection and hygiene 清洁、消毒和卫生
2.3.1 There should be a documented cleaning and disinfection programme. Results of
environmental monitoring should be considered where relevant.
应有书面清洁和消毒计划。

应在相关时考虑环境监控结果。

2.3.2 There should be a procedure for dealing with spillages.
应有处理泄漏的规程。

2.3.3 Adequate hand-washing and hand-disinfection facilities should be available.
应有足够的手部清洗和消毒的设施。

2.4 Sterility test facilities 无菌试验设施
2.4.1 Sterility test facilities have specific environmental requirements to ensure the integrity of tests carried out. WHO good manufacturing practices (GMP) for sterile pharmaceutical products(8) requires that sterility testing should be carried out and specifies requirements for sterility testing. This section details the clean-room requirements for a sterility test facility.
无菌试验设施有专门的环境要求，以保证所进行的试验的完整性。

世界卫生组织无菌药品的生产质量管理规范(GMP) (8)要求应进行无菌试验，并规定了无菌试验的要求。

这一章节详细规定了无菌试验设施的洁净室要求。

2.4.2 Sterility testing should be performed under aseptic conditions, which should be equivalent to air quality standards required for the aseptic manufacture of pharmaceutical products. The premises, services and equipment should be subject to the appropriate qualification process.
应在无菌条件下进行无菌试验，该条件应与无菌生产制剂产品所要求的空气质量标准相等。

应有适当的确认程序来管理厂房、服务和设备。

2.4.3 The sterility testing should be carried out within a Grade A unidirectional airflow protected zone or a biosafety cabinet (if warranted), which should be located within a clean room with a Grade B background. Alternatively, the testing can be carried out within a barrier isolator. Care should be taken with the design of the facility layout and room airflow patterns, to ensure that the unidirectional airflow patterns are not disrupted.
无菌试验应在位于B级背景下的洁净室内的A级单向气流保护的区域或生物安全柜（若获得批准）内进行。

或者在屏障隔离器中进行该实验。

应小心设计设施布局和房间气流模式，以保证不破坏单向气流
模式。

2.4.4 The clean-room classification and air-handling equipment of the sterility test facilities should be requalified at least annually by a competent person or contractor. The environment should comply with the non-viable and viable limits, and verification of high efficiency particulate air (HEPA) filter integrity and room airflows should be performed. However, an alternative frequency of the monitoring may be justified based on quality risk management (QRM). Mapping locations for sample points for routine monitoring should be documented, as well as exposure duration, and frequency of all types of microbiological environmental monitoring should be specified in written procedures.
应由有能力的人员或承包商至少每年对无菌试验设施的洁净室级别和空气处理设备进行再确认。

环境应符合死亡微生物和活微生物限度，并应确认高效空气粒子（HEPA）过滤器的完整性和房间气流。

但应在质量风险管理（QRM）的基础上论证供选择的监控频次。

应记录日常监控的样品点的绘图位置，以及暴露时间，应在书面规程中规定所有类型的微生物环境监控的频次。

2.4.5 Air supplied to Grade A and B zones should be via terminal HEPA filters.
供应给A级和B级区域的空气应经过终端高效过滤器。

2.4.6 Appropriate airflow alarms and pressure differentials and indication instruments should be provided (GMP: Heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms (8); and GMP for sterile pharmaceutical products (8).
应提供适宜的气流警报、压差和指示仪器（GMP：非无菌制剂的加热通风和空调系统）(8)；和无菌制剂的GMP(8)。

2.4.7 Room pressure readings should be taken and recorded from externally mounted gauges unless a validated continuous monitoring system is installed. As a minimum, readings should be taken prior to entry of the operator to the test suite. Pressure gauges should be labelled to indicate the area served and the acceptable specification.
除非安装了经过验证的持续监控系统，否则应从外部安装的气压表上读取和记录房间压力读数。

操作员至少应在进入试验房间之前读取读数。

气压表应贴签，标识所服务的区域和可接受标准。

2.4.8 Entry to the clean room should be via a system of airlocks and a change room where operators are required to don suitable clean-room garments. The final change room should be under “at rest” conditions of the same grade as the room it serves. Change rooms should be of adequate size for ease of changing. There should be clear demarcation of the different zones.
应通过气闸室和更衣间进入洁净房间，要求操作人员在其中穿上合适的洁净室工作服。

最终更衣室应处于与它服务的房间相同级别的“静止”状态下。

更衣室应足够大，以便于更衣。

不同区域应有清晰的划分。

2.4.9 Garments for the sterility test operator should comply with the principles of section 10 of WHO GMP for sterile pharmaceutical products (8). Operators should be trained and certified in gowning procedures with training records maintained.
无菌试验操作人员的工作服应符合世界卫生组织无菌药品的生产质量管理规范(8)第10节的原则。

应对操作人员进行更衣规程的培训和认证，保存培训记录。

2.4.10 The fittings and finishes of the premises should comply with section 11 of WHO GMP for sterile pharmaceutical products (8).
厂房的配件和表面材料应符合世界卫生组织无菌药品的生产质量管理规范(8)第11节。

2.4.11 Environmental microbiological monitoring should reflect the facility used (room or isolator) and include a combination of air and surface sampling methods appropriate to the facility, such as: 环境微生物监控应反映所用的设施（房间或隔离器），还包括适于设施的空气和表面取样方法的组合，例如：
— active air sampling; 活性空气取样；
— settle (exposure) plates; 沉降（暴露）平皿；
—surface contact — replicate organism detection and counting (RODAC) plates, swabs or flexible films;
—表面接触—复制微生物检测和计数（RORAC）平皿、涂抹棒或柔韧性薄膜；
—operators’ glove prints. 操作员的手套印花。

Microbial environmental monitoring of the sterility test zone should be performed during every work session under operational (dynamic) conditions.
应在操作（动态）状态下的每个工作进程中监控无菌试验区域的微生物环境。

There should be written specifications, including appropriate alert and action limits for microbial contamination. Limits for microbiological environmental monitoring are given in the WHO GMP for sterile pharmaceutical products (8).
应有书面质量标准，包括适当的微生物污染的警报和行动限。

世界卫生组织无菌药品的生产质量管理规范(8)中给出了微生物环境监控的限度。

3. Validation of test methods 检验方法的验证
3.1 Standard (pharmacopoeial) test methods are considered to be validated. However, the
specific test method to be used by a specific laboratory for testing of a specific product needs to be shown to be suitable for use in recovering bacteria, yeast and mould in the presence of the specific product. The laboratory should demonstrate that the performance criteria of the standard test method can be met by the laboratory before introducing the test for routine purposes
(method verification) and that the specific test method for the specific product is suitable (test method suitability including positive and negative controls).
标准（药典）检验方法被视为是经过验证的。

但特定实验室检验具体产品所用的具体检验方法需要证明在存在具体产品时适于用于再生细菌、酵母菌和霉菌。

实验室在引入常规目的（方法确认）的检验之前应证实实验室能够满足标准检验方法的性能标准，并且具体产品的具体检验方法是合适的（检验方法适用性包括阳性和阴性对照）。

3.2 Test methods not based on compendial or other recognized references should be validated
before use. The validation should comprise, where appropriate, determining accuracy, precision, specificity, limit of detection, limit of quantitation, linearity and robustness. Potentially inhibitory effects from the sample should be taken into account when testing different types of sample. The results should be evaluated with appropriate statistical methods, e.g. as described in the national, regional or international pharmacopoeias.
非药典或其他认可的参考的检验方法应在使用前进行验证。

在适当的情况下，验证应包括测定准确度、精密度、专属性、检测限、定量限、线性和耐用性。

在检验不同类型样品时，应考虑来自样品的潜在抑制作用。

应使用适当的统计学方法评估结果，如在国家、地区或国际药典中描述的方法。

4. Equipment 设备
Each item of equipment, instrument or other device used for testing, verification and calibration should be uniquely identified.
每台用于检验、确认和校准的仪器、设备或其它装置应有唯一的标识。

As part of its quality system, a laboratory should have a documented programme for the qualification, calibration, performance verification, maintenance and a system for monitoring the use of its equipment.
作为其质量体系的一部分，实验室应有书面的验证、校准、性能确认和维护计划，以及监控它的设备使用的体系。

4.1 Maintenance of equipment 设备维护
4.1.1 Maintenance of essential equipment should be carried out at predetermined intervals in
accordance with a documented procedure. Detailed records should be kept. (For examples of maintenance of equipment and intervals see Appendix 2.)
应依照书面规程在预定间隔对重要设备进行维护。

应保存详细的记录。

（设备维护及间隔的例子见附件2。

）
4.2 Qualification 验证
4.2.1 For qualification of equipment see sections 8 and 12 in Good practices for pharmaceutical
quality control laboratories (1).
设备验证见药品质量控制实验室管理规范(1)第8节和第12节。

4.3 Calibration, performance verification and monitoring of use 校准、性能确认和使用的监控
4.3.1 The date of calibration and servicing and the date when recalibration is due should be
clearly indicated on a label attached to the instrument.
应在仪器上所贴的标签上明确标识校准和服务日期、再校准日期。

4.3.2 The frequency of calibration and performance verification will be determined by
documented experience and will be based on need, type and previous performance of the equipment. Intervals between calibration and verification should be shorter than the time the equipment has been found to take to drift outside acceptable limits. (For examples of calibration checks and intervals for different laboratory equipment, see Appendix 3; and for equipment qualification and monitoring, see Appendix 4.) The performance of the equipment should conform to predefined acceptance criteria.
应由记录的经验，并根据需要、设备类型和之前的性能来决定校准和性能确认的频率。

校准和确认之间的间隔应短于发现设备开始漂移出可接受限度之外的时间。

（不同实验室设备的校准检查和间隔的例子见附件3；设备验证和监控的例子见附件4。

）设备性能应符合预定的可接受标准。

4.3.3 Temperature measurement devices 温度测量装置
4.3.3.1 Where temperature has a direct effect on the result of an analysis or is critical for the
correct performance of equipment, temperature measuring devices should be of appropriate quality to achieve the accuracy required (e.g. liquid-in-glass thermometers, thermocouples and platinum resistance thermometers (PRTs) used in incubators and autoclaves).
若温度对分析结果有直接影响，或对正确的设备性能来说是关键的，温度测量装置应有适当的质量，来达到所要求的准确度（如培养箱和高压灭菌锅里所用的玻管液体温度计、热电偶和铂电阻温度计（PRTs））。

4.3.3.2 Calibration of devices should be traceable to national or international standards for
temperature.
装置的校准应追溯到温度的国家或国际标准。

4.3.4 Incubators, water-baths and ovens 培养箱、水浴和烘箱
The stability of temperature, uniformity of temperature distribution and time required to achieve equilibrium conditions in incubators, water-baths, ovens and temperature-controlled rooms
should be established initially and documented, in particular with respect to typical uses (for example, position, space between, and height of, stacks of Petri dishes). The constancy of the characteristics recorded during initial validation of the equipment should be checked and recorded after each significant repair or modification. The operating temperature of this type of equipment should be monitored and records retained. The use of the equipment should be considered when determining what temperature controls are required.
应首先建立和记录培养箱、水浴、烘箱和温控房间内温度的稳定性、温度分布的均匀性、达到平衡条件所需的时间，特别是有关典型用途（例如培养皿的位置、之间的空间和高度和堆叠）。

应在每次大修或改造后检查和记录设备初始验证期间所记录的性质的恒久性。

应监控这种设备的运行温度，并保存记录。

在决定需要哪些温度控制时，应考虑设备的用途。

4.3.5 Autoclaves, including media preparators 高压灭菌锅，包括培养基制备器
4.3.
5.1 Autoclaves should be capable of meeting specified time and temperature tolerances;
monitoring pressure alone is not acceptable. Sensors used for controlling or monitoring operating cycles require calibration and the performance of timers should be verified.
高压灭菌锅应能够满足规定的时间和温度容限；只监控压力是不可以接受的。

用于控制或监督运行周期的探头需要校准，并应确认计时器的性能。

4.3.
5.2 Initial validation should include performance studies (spatial temperature distribution
surveys) for each operating cycle and each load configuration used in practice. This process must be repeated after any significant repair or modification (e.g. replacement of thermoregulator probe or programmer, change to loading arrangements or operating cycle) or where indicated by the results of quality control checks on media or risk assessment. Sufficient temperature sensors should be positioned within the load (e.g. in containers filled with liquid/medium) to enable location differences to be demonstrated. In the case of media preparators, where uniform heating cannot be demonstrated by other means, the use of two sensors, one adjacent to the control probe and one remote from it, would generally be considered appropriate. Validation and revalidation should consider the suitability of come-up and come-down times as well as time at sterilization temperature.
初始验证应包括实践中所用的每个运行周期和每个负载构型的性能研究（立体空间温度分布调查）。

在任何大修或改造后（如替换温度调节器探头或程序设计员，更改负载安排或运行周期），或对培养基的质量控制检查或风险评估的结果表明需要时，必须重复此过程。

应在负载内（如在充满液体/介质的容器内）安置足够的温度探头，使具有待证实的位置间差异。

若使用培养基制备器，若不能通过其他方法确定均匀的加热，使用两个探头，一个靠近控制探头，一个远离它，通常被视为是合适的。

验证和在验证应考虑向上和向下时间的适用性，以及停留在消毒温度的时间。

4.3.
5.3 Clear operating instructions should be provided based on the heating profiles
determined for typical uses during validation/revalidation. Acceptance/rejection criteria should be established and records of autoclave operations, including temperature and time, maintained for every cycle.
应根据确定用于验证/再验证其间的典型用途的加热特征来提供明确的操作指令。

应建立可接受/拒绝标准，并保存每个周期的高压灭菌锅的运行记录，包括温度和时间。

4.3.
5.4 Monitoring may be achieved by one of the following: 可通过下列方法中的一种来进行监
控：
—using a thermocouple and recorder to produce a chart or printout;
使用热电偶和记录器来生成图表或打印出的资料；
—direct observation and recording of maximum temperature achieved and time at that temperature.。