FDA化验室OOS指南中英文_Guidance_for_Industry_OOS_CHEN

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operations can be found in part 211, subparts I (Laboratory Controls) and J (Records and Reports). These regulations provide for the establishment of scientifically sound and appropriate specifications, standards, and test procedures that are designed to ensure that components, containers and closures, in-process materials, and finished drug products conform to the established standards. Section 211.165(f) of the CGMP regulations specifies that finished drug products that fail to meet established standards, specifications, or other relevant quality control criteria will be rejected. 检验亦应支持方法验证和工艺验证。通用CGMP规范包括化验室操作，在211部分章节 I (化验室控制) 和J (记录和报告)可以查阅到。这些法规用于建立科学合理和适当的质量规格、标准和检验方法，用于保证组件、容器和密闭器材、中控材料和制剂成品符合既定标准。CGMP法规211部分165（f）指出制剂成品不符合既定标准、规格或其它相应质量控制标准时应拒绝放行。 Both finished pharmaceuticals and active pharmaceutical ingredients (APIs) are to be manufactured in

accordance with current good manufacturing practice under section 制剂成品和原料药（APIs）生产均应符合现行GMP对应条款下的要求。

501(a)(2)(B) of the Act. Current good manufacturing practice for APIs includes the performance of scientifically sound raw material testing, in-process monitoring, release and stability testing, process validation, and adequate investigations of any OOS result obtained from such testing. All citations to part 211 in this document pertain to finished pharmaceuticals, but these referenced regulatory requirements are also consistent with Agency guidance on CGMPs for APIs with respect to laboratory controls, which include out-of-specification investigations. See FDA’s guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical

Ingredients (ICH Q7A) for specific recommendations.5 法案的501（a）(2)(B)中对原料药（API）的CGMP包括科学合理的原料检测、中控监测、放行和稳定性测试、工艺验证和对任何来自于这些测试的OOS结果的充分的调查。本文中所有对CFR211章的引用都涉及制剂产品，但这些相关法规要求也与当局对原料药实验室控制方面的要求一致，其中包括OOS调查。参见FDA行业指南：Q7A活性药物成份优良生产规范指南（ICH Q7A）特定推荐.

The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm. 对合同化验室的要求与对生产公司的化验室要求相同。

III. IDENTIFYING AND ASSESSING OOS TEST RESULTS界定和评价OOS检验结果— PHASE I: LABORATORY INVESTIGATION第一步：化验室调查

FDA regulations require that an investigation be conducted whenever an OOS test result is obtained (§

211.192).6 The purpose of the investigation is to determine the cause of the OOS result. The source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the

drug applications (INDs), specifications are contained in the application or DMF. Specifications for

nonapplication products may be found in official compendia or established by the manufacturer. 制订的标准应科

学合理并恰当（211章第160部分b），检测方法应经过验证，验证应包括准确度、灵敏度、专属性及重复性（211章165部分e），测试时所做的系统适用性试验数据应记录（211章194部分a（2））。对于新药申请（NDA）、仿制新药申请（ANDA）和研究用新药申请（IND）的药品，其质量标准应包括在申报文件或DMF文件中。非申请项目的药品的质量标准应为公定标准或生产厂商自建标准。

5

We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page

at http://www.fda.gov/cder/guidance/index.htm. 我们定期更新各指南。为保证使用最新版本的指南，请至

http://www.fda.gov/cder/guidance/index.htm 访问CDER指南页。 6

Although the subject of this document is OOS results, much of the guidance may be useful for examining results that are out of trend.虽然本文的主题是OOS结果，指南内许多内容对于检查偏离趋势结果亦有帮助。

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manufacturing process. Even if a batch is rejected based on an OOS result, the investigation is necessary to determine if the result is associated with other batches of the same drug product or other products. Batch

rejection does not negate the need to perform the investigation. The regulations require that a written record of the investigation be made, including the conclusions and follow-up (§ 211.192). FDA法规要求当发现OOS结果时应立即展开调查。调查的目的是确定引起OOS的原因。应确定是检验过程的异常还是生产工艺异常导致的OOS结果。即使因OOS结果判定了不合格的批，仍必须进行调查以确定该结果是否影响到同种产品其它批号或其它产品，一批不合格也不能否定调查的必要。法规(§ 211.192)要求要有调查的书面记录，包括结论和跟进措施。

To be meaningful, the investigation should be thorough, timely, unbiased, well-documented, and scientifically sound. The first phase of such an investigation should include an initial assessment of the accuracy of the

laboratory's data. Whenever possible, this should be done before test preparations (including the composite or the homogenous source of the aliquot tested) are discarded. This way, hypotheses regarding laboratory error or

instrument malfunctions can be tested using the same test preparations. If this initial assessment indicates that no meaningful errors were made in the analytical method used to arrive at the data, a full-scale OOS investigation should be conducted. For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s quality control unit (QCU), who should then initiate the full-scale OOS investigation. 为了使调查有意义，调查应是彻底的，及时的，没有偏见的，形成文件并经得起科学推敲。调查的第一阶段应包括对实验室数据的准确性的初步评价。如果可能，这应在丢弃试验溶液（包括被测样品复合的或同质的来源）之前进行。这样，假定是实验室错误或仪器故障，可以使用原溶液测定。如果初步评估显示在得到该数据的分析过程中没有生错误，应进行全面的OOS调查。如果OOS结果出自合同化验室，化验室应将数据、所有发现和支持性文件提交生产商的质量部门，以便其展开全面的OOS调查。

A. Responsibility of the Analyst 化验员职责

The first responsibility for achieving accurate laboratory testing results lies with the analyst who is performing the test. The analyst should be aware of potential problems that could occur during the testing process and should watch for problems that could create inaccurate results. 得到精确的化验结果的责任首先是在做检验的化验员身上。化验员应明白检验过程中可能会产生的问题，对可能会导致不准确结果的问题应特别注意。 In accordance with the CGMP regulations in § 211.160 (b)(4), the analyst should ensure that only those instruments meeting established performance specifications are used and that all instruments are properly

calibrated. 依照第211章160部分（b）（4）中cGMP的要求，化验员应确认只使用那些符合性能要求并经过正确校正的仪器。

Certain analytical methods have system suitability requirements, and systems not meeting these requirements should not be used. For example, in chromatographic systems, reference standard solutions may be injected at intervals throughout chromatographic runs to measure drift, noise, and repeatability. If reference standard responses indicate that the system is not functioning properly, all of the data collected during the suspect time period should be properly identified and should not be used. The cause of the malfunction should be identified and, if possible, corrected before a decision is made whether to use any data prior to the suspect period. 特定的分析方法有系统适用性要求，如果系统不符合这些要求则不能用于该检验。例如，在色谱系统中，对照液可能在色谱运行过程中进针以测试其飘移、噪声和重复性。如果对照品响应显示系统功能不适用，所有在可疑时间段收集的数据应适当鉴别且不能采用。故障原因应该查出，并且如果可能的话，在决定是否采用可疑时间段之前的任何数据前应采取纠正措施。

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Analysts should check the data for compliance with test specifications before discarding test preparations or standard preparations. When unexpected results are obtained and no obvious explanation exists, test preparations should be retained, if stable, and the analyst should inform the supervisor. An assessment of the accuracy of the results should be started immediately. 分析员在丢弃供试样和标准样前，应该检查数据是否符合检测标准。如果出现结果不在预期内，且没有明显的解释，如果供试液稳定的话应该保留，分析员应该通知主管。对结果准确性的评估应立即开始。

If errors are obvious, such as the spilling of a sample solution or the incomplete transfer of a sample composite, the analyst should immediately document what happened. Analysts should not knowingly continue an analysis they expect to invalidate at a later time for an assignable cause (i.e., analyses should not be completed for the sole purpose of seeing what results can be obtained when obvious errors are known). 如果错误是明显的，例如样品溶液溅出或样品成分转移不完全，分析员应立即记录下发生的事情。分析员在明知这类错误的前提下，不应继续分析过程，而在后来将结果根据该可归结的原因判定无效（即如果有已知明显错误存在时，不应该仅为了看看会出来什么结果而继续检验）。

B. Responsibilities of the Laboratory Supervisor化验室主管职责

Once an OOS result has been identified, the supervisor's assessment should be objective and timely. There should be no preconceived assumptions as to the cause of the OOS result. Data should be assessed promptly to ascertain if the results might be attributed to laboratory error, or whether the results could indicate problems in the manufacturing process. An immediate assessment could include re-examination of the actual solutions, test units, and glassware used in the original measurements and preparations, which might provide more credibility for laboratory error hypotheses. 对OOS结果进行确认，主管对可能的原因进行客观及时的评估，不应预先假想OOS结果的原因。应迅速评价数据以确定结果是因为实验室错误，还是表明了生产工艺有问题。直接的评估可以包括对目前溶液，检验单位，最初测量和准备使用的玻璃器具的复验。复验可能提供对实验室错误假定的更多的可信性。

The following steps should be taken as part of the supervisor's assessment: 主管的评估应包括以下步骤 1. Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct

procedure. 与化验员讨论检验方法，确认化验员的经验和能正确使用方法的能力 2. Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify

anomalous or suspect information. 检查原始分析中得到的记录，包括谱图等，确定有无异常和可疑信息。 3. Verify that the calculations used to convert raw data values into a final test result are scientifically sound,

appropriate, and correct; also determine if unauthorized or unvalidated changes have been made to

automated calculation methods. 确认原始数据计算方法的科学合理性、恰当性和正确性，确认自动计算方法是否有被擅自改动。 4. Confirm the performance of the instruments. 检查仪器的性能；

5. Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that

they met quality control specifications. 检查标准品、试剂、溶剂和其它用到的溶液，应满足质量控制的要求。

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6. Evaluate the performance of the test method to ensure that it is performing according to the standard

expected based on method validation data and historical data. 对检验方法的性能进行评价以保证其性能符合基于方法验证数据和历史数据而期望得到的表现。 7. Fully document and preserve records of this laboratory assessment. 保存该化验室评价的所有文件和记

录。 The assignment of a cause for OOS results will be greatly facilitated if the retained sample preparations are examined promptly. Hypotheses regarding what might have happened (e.g. dilution error, instrument malfunction) should be tested. Examination of the retained solutions should be performed as part of the

laboratory investigation.如果马上检查保留的样品，将会使OOS结果原因的陈述容易得多，可验证可能发生事故的假设（如稀释错误、设备故障等）检查保留的溶液应作为实验室调查的一部分。例：

Examples: 例如

Solutions can be re-injected as part of an investigation where a transient equipment malfunction is

suspected. Such hypotheses are difficult to prove. However, reinjections can provide strong evidence that the problem should be attributed to the instrument, rather than the sample or its preparation. 如果怀疑是瞬时的仪器故障，作为调查的一部分，可以重新进样。很难证明这些假想。尽管如此，再次进样强有力的证明了是仪器的原因而不是样本或其它的制备的原因。 For release rate testing of certain specialized dosage form drugs that are not destroyed during testing, where possible, examination of the original dosage unit tested might determine whether it was damaged during laboratory handling in a way that affected its performance. Such damage would provide evidence to invalidate the OOS test result, and a retest would be indicated. 对于特定剂型的药物，在检验中没有破坏的释放速率的试验，如果可能，对最初检验的剂量单位的检查，可能确定它是否在实验室处理中以影响它性能的方式被破坏了。这样的破坏能够证明OOS检验结果无效，表明应复验。 Further extraction of a dosage unit, where possible, can be performed to determine whether it was fully extracted during the original analysis. Incomplete extraction could invalidate the test results and

should lead to questions regarding validation of the test method. 如果可能，对一个剂量单位进一步提取，以确定在最初分析时是否提取完全。不完全提取可能使检验结果无效，也可导致检验方法无效的问题。

It is important that each step in the investigation be fully documented. Laboratory management should ascertain not only the reliability of the individual value obtained, but also the significance these OOS results represent to the laboratory quality assurance program. Laboratory management should be especially alert to developing trends. As part of an effective quality system, a firm’s upper management should appropriately monitor these trends and ensure that any problematic areas are addressed. 调查的每一步都全部存档非常重要。实验室主管应确定，不仅个别数值的可靠性，这些OOS结果也代表了对实验室质量保证的程序的重大意义。实验室主管应特别注意发展趋势。作为有效质量体系的一部分，一个公司的上层管理应适当的监控这些趋势，并确保提出有问题的地方。

Laboratory error should be relatively rare. Frequent errors suggest a problem that might be due to inadequate training of analysts, poorly maintained or improperly calibrated equipment, or careless work. Whenever

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laboratory error is identified, the firm should determine the source of that error and take corrective action to prevent recurrence. To ensure full compliance with the CGMP regulations, the manufacturer also should maintain adequate documentation of the corrective action. 实验室错误相对来说不应太多，频繁的错误暗示一个问题，那就是检验员培训不充分，设备维护保养不善或没有得到正确校正，或工作粗心。只要确定是实验室错误，公司应确定错误的来源，并采取改正措施以防再次发生。为了确保完全符合CGMP，制造商应持有改正措施的足够的文件。

In summary, when clear evidence of laboratory error exists, laboratory testing results should be invalidated. When evidence of laboratory error remains unclear, a full-scale OOS investigation should be conducted by the manufacturing firm to determine what caused the unexpected results. It should not be assumed that OOS test results are attributable to analytical error without performing and documenting an investigation. Both the initial laboratory assessment and the following OOS investigation should be documented fully. 总之，当有实验室错误的确切证据时，实验室检验结果应是无效的。当实验室错误的证据不够确切时，应有生产公司进行全面的OOS调查，以确定是什么引起了意外的结果。在没有进行调查和存档的情况下，不应假定OOS检验结果是由于分析错误。最初的实验室评估和以下的OOS调查都应全部存档。 IV. INVESTIGATING OOS TEST RESULTS 对OOS结果的调查—

PHASE II: FULL-SCALE OOS INVESTIGATION 第二步：全面OOS调查

When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale OOS investigation using a predefined procedure should be conducted. This investigation may consist of a production process review and/or additional laboratory work. The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective and preventative action.7 A full-scale investigation should include a review of production and sampling procedures, and will often include additional laboratory testing. Such investigations should be given the highest priority. Among the elements of this phase is evaluation of the impact of OOS result(s) on already distributed batches. 如果初步评估表明不是实验室错误引起的OOS结果，结果又不正确的话，就要按事先规定的程序进行全面的OOS调查。该调查可能包括生产工艺回顾和／或附加的实验室工作。调查的目的的应是确定引起OOS结果的根本原因并采取适当的改正和预防措施。一个全面的调查应包括对生产和取样程序的回顾，并且经常包括附加的实验室检验。这样的调查有最高的优先权。在这一阶段的内容中，是评估OOS结果对已销售批次的影响。

A. Review of Production 生产情况审核

The investigation should be conducted by the QCU and should involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering. In cases where

manufacturing occurs off-site (i.e., performed by a contract manufacturer or at multiple manufacturing sites), all sites potentially involved should be included in the investigation. Other potential problems should be identified and investigated. 调查应由质量管理部门执行，应包括所有涉及的部门，包括生产，工艺发展，维护和工程。如果生产不在当地（也就是由签约生产商生产或在多个生产地生产）调查应包括所有可能的生产地 7

Please note that § 211.192 requires a thorough investigation of any discrepancy, including documentation of conclusions and follow-up. Implicit in this requirement for investigation is the need to implement corrective and preventative actions. Corrective and preventive action is consistent with the FDA’s requirements under 21 CFR part 820, subpart J, pertaining to medical devices, as well as the 2004 draft guidance entitled Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, which, when finalized, will represent the

Agency’s current thinking on this topic. 请注意§ 211.192 要求所有不符都要有一个彻底的调查，包括结论和跟踪的记录

文件。此要求对调查而言即是需要实施纠正与预防措施，这些纠正与预防措施与FDA在21CFR 820部分章节J中涉及到医疗器械的要求是一致的，同时2004年起草的指南，名为药品CGMP质量体系方法，最终定稿时将代表当局在此问题上当前的想法。