药品检验结果OOS的调查
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2006年11月8日
Guidance for Industry，Investigating Out of Specification
(OOS) Test Results for Pharmaceutical Production
行业指南：
药品检验结果OOS的调查
DRAFT GUIDANCE
指南草案
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
, 百拇医药
September 1998
CP #
TABLE OF CONTENTS目录
I. INTRODUCTION 序言. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . .. . . .. . . 1
II. BACKGROUND . 背景. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . 1
III. IDENTIFYING AND ASSESSING OOS TEST RESULTS OOS检验结果的判断和评估. . .. 2
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A.Responsibility of the Analyst 检验员的责任. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2
B. Responsibilities of the Supervisor主管的责任. . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . .. . . . .3
IV. INVESTIGATING OOS TEST RESULTS OOS 检验结果的调查. . . . . . . . . . . . . . . . . . . .. 5
A. General Investigational Principles . . 一般调查原则. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
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B. Laboratory Phase of an Investigation . 实验室的调查阶段 . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . 6
V. CONCLUDING THE INVESTIGATION . .调查结论 . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . 10
A. Interpretation of Investigation Results . 调查结果的解释 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
B. Reporting . . .报告 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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This guidance has been prepared by the Office of Compliance/Division of Manufacturing and Product
Quality, Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. This guidance document represents the Agency’s current thinking on evaluating OOS test results. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
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本指南由FDA的CDER的达标办公室/制造、产品、质量分部起草，本指南阐明了机构关于评估OOS检验结果的现行的想法。它不会创造或赠与任何人任何权力，也不会约束FDA或公众。如果其他可选择的相接近的指南能满足适用的法令和法规的要求，也可以使用。
GUIDANCE FOR INDUSTRY1
Investigating Out of Specification (OOS) Test Results
for Pharmaceutical Production
行业指南：药品检验结果OOS的调查
I. INTRODUCTION
序言
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This guidance for industry provides the Agency’s current thinking on how to evaluate suspect, or out of specification (OOS), test results. For purposes of this document, the term OOS results includes all suspect results that fall outside the specifications or acceptance criteria established in new drug applications, official compendia, or by the manufacturer.
本行业指南反应了FDA关于如何评估怀疑的或OOS检验结果的现行想法，本指南的目的，OOS结果包括超出了新药申请材料、法定标准、生产商建立的可接受标准或规格的所有可疑的结果。
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This guidance applies to laboratory testing during the manufacture of active pharmaceutical ingredients, excipients, and other components and the testing of finished products to the extent that current good manufacturing practices (CGMP) regulations apply (21 CFR parts 210 and 211). Specifically, the guidance discusses how to investigate suspect, or OOS test results, including the responsibilities of laboratory personnel, the laboratory phase of the investigation, additional testing that may be necessary, when to expand the investigation outside the laboratory, and the final evaluation of all test results.
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本指南适用于API、赋形剂和其它组分生产的实验室检验和CGMP法规应用的成品检验。特别的，指南讨论了如何调查可疑的或OOS检验结果，包括了实验室人员的责任、实验室阶段调查、必须的额外试验，何时进行实验室范围外的调查和对所有检验结果的最终评估。
II. BACKGROUND 背景
FDA considers the integrity of laboratory testing and documentation records to be of fundamental importance during drug manufacturing. Laboratory testing, which is required by the CGMP regulations (§ 211.165), is necessary to confirm that components, containers and closures, inprocess materials, and finished products conform to specifications, including stability. Testing Specifications must be scientifically sound and appropriate (21 CFR 211.160(b)), and test procedures must be validated as to their accuracy, reliability, and suitability under actual conditions of use (21 CFR 211.194(a)(2)). For products that are the subjects of NDAs, ANDAs, or INDs, specifications are contained in the application. Specifications for non-application products may be found in official compendia, or established by the manufacturer.
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FDA认为在药品生产中实验室检验和文件记录的完整性是基本重要的。CGMP要求的实验室检验，必须确定成分、容器和封口材料、生产用辅料、成品符合标准要求，包括稳定性。检验标准必须是科学正确和适当的(1 CFR 211.160(b)，检验方法必须验证现行使用条件下的正确性、线性和适应性(21 CFR 211.194(a)(2))，如果是用于NDAs, ANDAs, 或 INDs申请的产品，申请材料中应包括标准。 如果是非申请产品的质量标准，可以在法定标准中找到或由企业自已建立。
Although the subject of this document is OOS results, much of the guidance may be useful for examining results that are out of trend. also supports analytical and process validation efforts. General CGMP regulations covering laboratory 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 and containers of drug products conform to the established standards. Section 211.165(f) of the CGMP regulations specifies that products that fail to meet established standards and other relevant quality control criteria will be rejected.
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尽管本指南的目的是OOS结果，其中许多部分对于调查超出趋势以外的结果也是有用的，对分析和工艺验证也有用。有关实验室操作一般性CGMP法规可以在211部分，分目I (实验室控制)和分目 J (报告和记录)找到。这些法规规定了科学正确和适当的用于保证制剂的成分和容器符合建立标准的规格、标准和检验方法的建立。CGMP的211.165(f)章节规定不符合既定标准和其它相关质量控制标准的产品不得放行。
III. IDENTIFYING AND ASSESSING OOS TEST RESULTS
OOS检验结果的判断和评估
FDA regulations require that an investigation be conducted whenever an OOS test result is obtained. The purpose of the investigation is to determine the cause of the OOS. 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 of the investigation and follow-up (211.192).
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FDA法规要求当OOS检验结果出现时应该进行调查，调查的目的是确定引起OOS的原因。即使因OOS结果判断了不合格批，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。法规要求对调查包括调查结论和随后采取的措施进行记录(211.192)。
To be meaningful, the investigation should be thorough, timely, unbiased, well-documented, and scientifically defensible. The first phase of such an investigation should include an initial assessment of the accuracy of the laboratory's data, before test solutions are discarded, whenever possible. This way, hypotheses regarding laboratory error or instrument malfunctions may be tested using the same test solutions. If this initial assessment indicates that no errors were made in the analytical process used to arrive at the data, a complete failure investigation should follow.
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更有意义的，调查必须是完全的，及时的，不带有任何偏见的，记录是完整的和经得起科学推敲的。调查的最初阶段应该在试验溶液丢弃前，对实验室数据正确性进行最初评估，这样，假定认为是实验室错误或仪器故障，可以用原溶液测定。如果最初的评估评估显示在得到该数据的分析过程中没有发生错误，必须立即开展一个完全的不合格调查。
A.Responsibility of the Analyst
检验员的责任
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 OOS results.
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从事测试的检验员的首要责任是取得正确实验室检验结果。检验员应该意识到在实验过程中可能发生的潜在的问题和应该注意可能产生OOS结果的问题。
In accordance with the CGMP regulations (§ 211.160 (b)(4)), the analyst should ensure that only those instruments meeting established specifications are used and that all instruments are properly calibrated.
Certain analytical methods have system suitability requirements, and systems not meeting such 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 corrected before a decision is made whether to use any data prior to the suspect period.
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依据CGMP (§ 211.160 (b)(4))，检验员应该保证只有符合既定标准的仪器才能使用和所有的仪器都经过的校正。某些分析方法有系统适应性要求，不符合要求的系统不能使用。例如：在色谱系统中，在进行色谱检测期间内间隔一段时间进样对照品溶液去测定漂移、噪声和重复性。如果对照品响应值显示该系统功能不正常，在可疑的时间内收集的所有数据应该被适当标识并不能使用。在决定是否使用可疑期间之前的数据前，应鉴别故障的原因并予以纠正。
Before discarding test preparations or standard preparations, analysts should check the data for compliance with specifications. When unexpected results are obtained and no obvious explanation exists, test preparations should be retained and the analyst should inform the supervisor. An assessment of the accuracy of the results should be started immediately.
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在丢弃样品制备液和标准制备液之前，检验员应该核查数据对标准的符合性。当获得意想不到的结果且没有明显的理由时，应该保留样品制备液且检验员应该通知主管。应该立即开始评估检验结果的正确性。
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). These same responsibilities extend to analysts at contract testing laboratories.
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如果错误是明显的，如：样品溶液有洒出或样品成分的未完全转移，检验员应该立即记录所发生的情况。检验员不应该有意的继续这无效的分析(也就是，当明显的错误发生了，不应该带着会得出什么结果的目的去完成分析)。这些相同的责任适用于合同实验室的检验员。
B.Responsibilities of the Supervisor
主管的责任
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 may 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 would allow more credibility to be given to laboratory error theories.
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一旦OOS结果被确定，主管应该客观的和及时的进行评估。不应该对OOS结果的原因进行预想的假定。应该迅速评估数据以确定结果是否属于实验室错误，或该结果是否显示是生产过程的问题。立即的评估应该包括重新检测原溶液、测试的单位、玻璃器具和溶液制备过程，这样可以进一步证实对OOS结果属于实验室错误的假设。
The following steps should be taken as part of the supervisor's assessment:
下面是作为主管应评估的部分步骤：
1. Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct procedure.
与检验员讨论检测方法；确认检验员知道并执行了正确的程序。
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2. Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect information.
检查分析的原始数据，包括色谱和光谱，并识别出反常或可疑的信息。
3. Confirm the performance of the instruments.
确认仪器性能
4. Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they meet quality control specifications.
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确定使用了合适的参照标准品、溶媒、试剂和其它溶液，并且它们符合质量控制标准。
5. Evaluate the performance of the testing method to ensure that it is performing according to the standard expected based on method validation data.
评估检验方法的执行情况，以保证是按照标准执行并有方法验证数据。
6. Document and preserve evidence of this assessment.
记录并保存评估的证据。
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) can be tested. Examination of the retained solutions can be performed as part of the laboratory investigation.
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如果及时检测了所保留的样品制备液，会极大的促进OOS结果原因的确定。可以对所发生的事情的假设(如：稀释错误、仪器故障)进行检测。对被留的溶液的检验可以作为实验室调查的一部分。
Examples:
例如! Solutions can be re-injected as part of an investigation where a transient equipment malfunction is suspected. This could occur if bubbles were introduced during an injection on a chromatographic system, which other tests indicated was performing properly. Such theories are difficult to prove. However, a reinjection can provide strong evidence that the problem should be attributed to the instrument, rather than the sample or its preparation.
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如果怀疑设备瞬间的故障，那么调查可以重新进样该溶液。如果在色谱系统一次进样期间引入了气泡，而其它的试验进行正常，这是可能发生的。这样的推测很困难去证明。但是，重新进样能有力的证明问题与仪器有关，而不是与样品或样品的准备有关。! For release rate testing of certain specialized dosage forms, where possible, examination of the dosage unit tested might determine whether it was damaged in a way that affected its performance. Such damage would provide evidence to invalidate the OOS test result, and a retest would be indicated.
对于某一特定制剂的放行检验，如果可能，检查一下被测的这份制剂可以确定是否在什么方面被损坏而影响了其性能。这样的损坏能提供证据使OOS检验结果无效，这样就可以进行重新检验。! Further extraction of a dosage unit 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.
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对一份制剂做进一步提取以确定在初次检验期间是否被充分的提取了。不完全的提取能使检验结果无效，将导致检验方法验证的问题。
It is important that each step in the investigation be fully documented. The supervisor should ascertain not only the reliability of the individual value obtained, but also the significance these OOS results represent in the overall quality assurance program.
在调查的每一步都应做充分的记录，这是很重要的。主管不仅应该确定获得的个别值的可靠性，也应该确定在整个质量保证程序中阐明的OOS结果的重要性。
Supervisors should be especially alert to developing trends.
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主管应该特别警惕发展趋势。
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 laboratory error is identified, the firm should determine the source of that error and take corrective action to ensure that it does not occur again. To ensure full compliance with the CGMP regulations, the manufacturer also should maintain adequate documentation of the corrective action.
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In summary, when clear evidence of laboratory error exists, laboratory testing results should be invalidated. When evidence of laboratory error remains unclear, a failure investigation should be conducted to determine what caused the unexpected results. It should not be assumed that failing test results are attributable to analytical error without performing and documenting an investigation. Both the initial laboratory assessment and the following failure investigation should be documented fully.
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实验室错误应该是极少发生的。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。如果实验室错误被确定了，企业应该确定错误的来源并采取纠正措施去保证错误不再发生。为保证完全符合CGMP,生产商应该保持充分的纠正措施的记录。总之，当实验室错误的证据已经存在，实验室检验结果应该作废。当实验室错误的证据仍然不清楚，应该进行不合格结果的调查以确定引起意外结果的原因。在没有进行调查及调查文件确定之前不应该假定失败的检验结果属于检验错误。最初的实验室评估和下面的不合格结果的调查应该被充分的记录。
IV. INVESTIGATING OOS TEST RESULTS
OOS结果调查
When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale failure investigation using a predefined procedure should be conducted. The objective of such an investigation should be to identify the source of the OOS result. Varying test results could indicate problems in the manufacturing process, or result from sampling problems. Such investigations present a challenge both to employees and to management and should be given the highest priority.
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如果最初的评估不能确定是实验室错误造成了OOS结果且实验结果是正确的，应按照预先确定的程序进行全方位的不合格调查。这样调查的目的是确定OOS结果的来源，变化的试验结果可能显示是生产工艺的问题或取样问题导致的结果。这样的调查是对员工和管理者的挑战应给予极高度的重视。
The investigation should be conducted by the quality control unit and should involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering. Other potential problems should be identified and investigated.
调查应该由质量控制部门和所有其它相关的部门完成，包括生产部门，工艺研发部门，维护保养和工程部门。其它的潜在问题也应该被确定和调查。
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The records and documentation of the manufacturing process should be fully investigated to determine the possible cause of the OOS results.
应该充分调查生产过程的记录和文件以判断引起OOS结果的可能原因。
A.General Investigational Principles
一般调查原则
A failure investigation should consist of a timely, thorough, and well-documented review.
一个不合格结果的调查在于及时，彻底，和完善的记录审核 。
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The written record should reflect that the following general steps have been taken.
记录应该反映通常采取的下列步骤：
1. The reason for the investigation has been clearly identified.
调查的原因被清楚的确定。
2. The manufacturing process sequences that may have caused the problem should be summarized.
对可能引起问题的生产工艺流程进行了总结。
, http://www.100md.com 3. Results of the documentation review should be provided with the assignment of actual or probable cause.
文件审核的结果提供了实际的或可能的原因。
4. A review should be made to determine if the problem has occurred previously.
审核并判断是否以前发生过这类问题。
5. Corrective actions taken should be described.
应该描述采取的纠正措施
The general review should include a list of other batches and products possibly affected and any required corrective actions taken including any comments and signatures of appropriate production and quality control personnel regarding any material that may have been reprocessed after additional testing.
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一般性审核应该包括可能受影响的其它批和产品的列表，任何必须的纠正行为包括对复检后进行返工的物料的适宜的生产和质量控制人员的评论和签名。
B. Laboratory Phase of an Investigation 实验室阶段的调查
A number of practices are used during the laboratory phase of an investigation. These include: (1) retesting a portion of the original sample, (2) testing a specimen from the collection of a new sample from the batch, (3) resampling testing data, and (4) using outlier testing.
, 百拇医药 在实验室阶段的一系列调查包括：(1)最初样品一部分的再检验，(2)从该批中重新取样样品的检验，(3)重新取样的检验数据，(4)逸出值的检验
1. Retesting
重新检验
Part of the investigation may involve retesting of a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid it may be an additional weighing from the same sample composite that had been prepared by the analyst.
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调查部分工作包括最初检验样品的再检验。用于再检验的样品应该是最初收集检验的、出现OOS结果的样品均质物料的一部分。如果是液体，可以是液体成品的原始单位或液体成品的混合物。如果是固体，可以是检验员制备的相同混合物的额外的称量。
Situations where retesting is indicated include investigating testing instrument malfunctions or to identify a possible sample handling integrity problem, for example, a suspected dilution error. Generally, retesting is neither specified nor prohibited by approved applications or by the compendia. Decisions to retest should be based on the objectives of the testing and sound scientific judgment. Retesting should be performed by an analyst other than the one who performed the original test.
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再检验的情况标明包括检验仪器故障的调查或判断样品处理完整性。例如：一个可疑的溶解错误。一般地，在批准的申请中或药典中既没有限定也没有禁止，应该依据客观的检验和正确科学的判断决定再检验。再检验应该是另一检验员完成而不是最初检验人员。
The CGMP regulations require the establishment of specifications, standards, sampling plans, test procedures, and other laboratory control mechanisms (§ 211.160). The establishment of such control mechanisms for examination of additional specimens，for commercial or regulatory compliance testing must be in accordance with "predetermined guidelines or sampling strategies" (USP 23, General Notices and Requirements, p.9).
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CGM法规要求建立规格、标准、取样计划、检验程序和其它的实验室控制机制(§ 211.160)。符加样品的检验、商业或调整的依从性试验的控制机制的建立必须依据预先确定指南或取样策略。
Some firms have used a strategy of repeated testing until a passing result is obtained (testing into compliance), then disregarding the OOS results without scientific justification. Testing into compliance is objectionable under the CGMPs. The number of retests to be performed on a sample should be specified in advance by the firm in the SOP.
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许多企业使用重复的检验直到获得满意的结果的策略，然后没有科学的理由就忽视了OOS结果。重复的检验直到获得满意的结果，CGMP是不允许的。样品的再检验次数应该在企业的SOP中被预先限定。
The number may vary depending upon the variability of the particular test method employed, but should be based on scientifically sound, supportable principles. The number should not be adjusted depending on the results obtained. The firm's predetermined testing procedures should contain a point at which the testing ends and the product is evaluated. If, at this point, the results are unsatisfactory, the batch is suspect and must be rejected or held pending further investigation(§ 211.165(f)).
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检验次数可以根据使用的检验方法的可变性决定，但必须依据科学正确和可支持的原则。检验次数不能依据结果进行判断。企业预先确定的检验程序应该包括何时检验结束和进行产品评估。如果，就这一点，结果是不满意的，这批产品就是可疑的，必须批准不合格或进一步调查后再作决定(§ 211.165(f)).。
In the case of a clearly identified laboratory error, the retest results would substitute for the original test results. The original results should be retained, however, and an explanation recorded. This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments.
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在明确确定了实验室错误的情况下，再检验结果将取代最初检验结果，应该保留最初结果和一个解释记录，这个记录应该有相关人员人员的签名、注上日期，并应包括对错误的讨论、主管的注释。
If no laboratory or statistical errors are identified in the first test, there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported and considered in batch release decisions.
如果不能确定是首次的试验是实验室或统计错误，就没有为了让产品通过复检而废除最初OOS结果的科学基础。所有检验结果，不论是通过的和可疑的，都应该报告并供批放行结论中考虑。
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2. Resampling
再取样
While retesting refers to analysis of the original sample, resampling involves analyzing a specimen from the collection of a new sample from the batch. The establishment of control mechanisms for examination of additional specimens for commercial or regulatory compliance testing should be in accordance with predetermined procedures and sampling strategies (§ 211.165(c)).
涉及最初样品分析的再检验，再取样包括从该批产品抽取新的样品。应该按照预先制定的程序和取样策略来建立为符合商业或法规的试验的目的而对额外样品进行检验的控制机制。
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In some cases, when all data have been examined, it may be concluded that the original sample was prepared improperly and was therefore not representative of the batch (§ 211.160(b)(3)). A resampling of the batch should be conducted if the investigation shows that the original sample was not representative of the batch. This would be indicated, for example, by widely varied results obtained from several aliquots of the original composite (after determining there was no error in the performance of the analysis). Resampling should be performed by the same qualified, validated methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was in error, a new accurate sampling method must be developed, qualified, and documented (§§ 211.160 and 165(c)).
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在某些情况下，当已对所有的数据进行检查，可能会得出结论，即最初的样品没有正确制备因此不能代表该批产品(§ 211.160(b)(3))。如果调查显示最初的样品不能代表批产品，可以进行该批产品的再取样。这可以通过最初成分的几次分取样品分析获得差异较大的结果来表明(在确定检验操作没有错误之后)。重新取样应采用最初取样所采用的相同合格的、经过验证的方法进行。但是，如果调查确定最初取样方法是错误的，应该研究一个新的正确的取样方法并进行确认、并形成文件(§§ 211.160 and 165(c))。
3. Averaging
平均法
Averaging test data can be a valid approach, but its use depends upon the sample and its purpose. For example, in an optical rotation test, several discrete measurements are averaged to determine the optical rotation for a sample, and this average is reported as the test result. If the sample can be assumed to be homogeneous (i.e., an individual sample preparation designed to be homogeneous), using averages can provide a more accurate result. In the case of microbiological assays, the USP prefers the use of averages because of the innate variability of the biological test system.
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将检验数据平均是一个有效的方法，对其使用应依据样品和其目的。例如：在旋光度测试中，将几次不连续的测定结果进行平均以确定样品的旋光度，这个平均值可以作为检验结果。如果样品是均质的，使用平均值能提供更准确的结果。在微生物测定试验中，因为微生物测定系统的固有的可变性，USP更希望用平均值。
Reliance on averages has the disadvantage of hiding variability among individual test results. For this reason, unless averaging is specified by the test method or adequate written investigation procedures, all individual test results should be reported. In some cases, a statistical treatment of the variability of results should be reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is also reported.
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依赖平均值有隐藏各单独的检验结果中变异性的不利一面。因此，除非分析方法或适宜的调查程序指定了用平均值，所有的单独试验结果都应该报告。在某些情况下，结果可变性的统计处理方法也应该报告。G例如：在制剂含量均一性检验中、标准偏差(或相对标准偏差)也应报告。
Averaging also can conceal variations in the different portions of the sample. For example, the use of averages is inappropriate when performing powder blend/mixture uniformity or dosage form content uniformity determinations. In these cases, the testing is intended to measure variability within the product, and the individual results should be reported.
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平均法也会隐藏样品不同部分的差异性。例如：当进行粉末混和/混合物的均匀性检测或制剂含量均匀性检验，使用平均法是不合适的。在这些情况下，检测是为了测量产品内的差异性的，因此应该使用各单独测试结果。
It should be noted that a test might consist of replicates to arrive at a result. For instance,an HPLC assay result may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation (usually 2 or 3). The assay result would be calculated using the peak response average. This determination is considered one test and one result. This is a distinct difference from the analysis of different portions from a lot, intended to determine variability within the lot. The use of replicates should be included in the written, approved, test methodology. Unexpected variation in replicate determinations should trigger investigation and documentation requirements (21 CFR 211.192).
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应该注意一个检验结果可能是反复测定得出的。实例：一个HPLC分析结果可能是对相同样品溶液几次连续、反复的进样(2-3次)所得峰的响应值的平均而确定的。含量测试结果应使用峰响应值的平均值来计算。这个确定被认为是一次试验和一个结果，这与同一批产品的不同部分的分析以判断一批产品的可变性是明显不同的。重复测定应该收载在书面的、经批准的检验方法里。重复测定结果的意外变更应引起调查并进行记录(21 CFR 211.192)。
In some cases, a series of assay results may be a part of the test procedure. If some of the results are OOS and some are within specification and all are within the documented variation of the method, the passing results should be given no more credence than the failing results, in the absence of documented evidence that analytical error had occurred.
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在某些情况下，一系列的测试结果可以是分析过程的一部分。如果其中一些结果是OOS结果而有一些在标准之内而且所有结果都在该方法的变异范围之内，在没有能文件证明存在检验错误的情况下，合格的结果并不比失败的结果有更高的可信度。
Relying on test data averaging in such a case can be particularly misleading. For example, in an assay with a given range of 90 to 110 percent, test results of 89 percent, 89 percent, and 92 percent would produce an average of 90 percent even though two of the assay values represent failing results.
依据对检验结果的平均在某些方面能产生特别的误导，例如：一个含量标准范围是90%-110%，检验结果是：89%、89%、92%，尽管两个含量值表明不合格，其平均值却为得到90%。
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To use averaged results for assay reporting, all test results should conform to specifications. Although the above average of 90 percent may be useful in terms of an overall assessment of process capabilities, the individual assay results indicate nonconformance because two of the three results are outside of the range. A low assay value should also trigger concerns that the batch was not formulated properly because the batch must be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient (21 CFR 211.101(a)). The above example does not necessarily require the manufacturer to fail the batch, but indicates that an immediate investigation should be conducted for batch disposition decisions.
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要应使用平均结果作为含量测定结果，所有的检验结果都必须符合标准。尽管上面的平均值90%可以用于生产能力的全面评估，因为3个结果中的2个在范围之外，单独的含量测定结果就标明产品不符合要求。一个低的含量值应引起注意 ：因为一批产品应该按照能提供不低于100%标示量或确定数量的原料的标准来制备(21 CFR 211.101(a))，因此该批没有正确配制。上面的例子并不一定要求企业把此批作为不合格批，但是表明应该对此批立即进行调查以确定对该批的处置方法。
4. Outlier Tests
逸出值的检验
The CGMP regulations require that statistically valid quality control criteria include appropriate acceptance and/or rejection levels (§ 211.165(d)). On rare occasions, a value may be obtained that is markedly different from the others in a series obtained using a validated method. Such a value may qualify as a statistical outlier. An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is error in the testing procedure, rather than inherent variability in the sample being tested.
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CGMP法规要求统计的有效质量控制标准包括合适的可接受的和/或不合格水平(§ 211.165(d))。在极少情况下，用一个用验证过的方法获得的一个值会明显的不同于得到的一系列值，这样的一个值应该作为一个统计的逸出值，一个逸出值可以是规定检验方法的偏差的结果，或是样品存在差异的结果。决不能将出现逸出值的原因假定为检验操作的错误，而不认为被检验样品存在固有的差异。
Outlier testing is a statistical procedure for identifying from an array those data that are extreme. The possible use of outlier tests should be determined in advance. This should be written into SOPs for data interpretation and be well documented. The SOPs should include the specific outlier test to be applied with relevant parameters specified in advance. The SOPs should specify the minimum number of results required to obtain a statistically significant assessment from the specified outlier test.
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逸出值检验是从一组数据中识别出极端数据中的统计方法。逸出值检验的可能使用应该事先确定。对这中使用应该写入用来解释数据的SOP里并做好记录。SOP应该包括特定的逸出值适用于预先指定的相关参数。该SOP应该规定用于从特定的逸出值测试中获得统计学上有意义的评估结果的最少的检测结果数量。
For biological assays having a high variability, an outlier test may be an appropriate statistical analysis to identify those results that are statistically extreme observations. The USP describes outlier tests in the section on Design and Analysis of Biological Assays (USP 23, p. 1705). In these cases, the outlier observation is omitted from calculations. The USP also states that "arbitrary rejection or retention of an apparently aberrant response can be a serious source of bias. . .the rejection of observations solely on the basis of their relative magnitudes is a procedure to be used sparingly" (USP 23, p. 1705).
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生物制剂含量测定有更高的变异性，逸出值测试可能是判断这些极端结果的适当的统计分析。USP在生物制剂设计和分析章节描述了逸出值。在这些情况下，逸出值在计算时被省略。USP也规定了“对明显的异常值的任意拒绝或保留可能是发生偏差的重要原因. . . . . .仅依靠相对重要性来拒绝观测值是一个应谨慎使用的方法”
For validated chemical tests with relatively small variance, and if the sample being tested can be considered homogeneous (for example, an assay of composited dosage form to determine strength), an outlier test is only a statistical analysis of the data obtained from testing and retesting. It will not identify the cause of an extreme observation and ,therefore, should not be used to invalidate the data. An outlier test may be useful as part of the evaluation of the significance of that result for batch evaluation, along with other data.
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对于验证过的相对变化较小的化学测试来说，如果被检验的样品是均质的(例如，测定一复方制剂的浓度)，逸出值测试仅仅是对检验和再检验数据的统计分析。不能确定出现极端观察值的原因，因此，不能用来决定使数据无效。逸出值测试与其它数据一起用于评估批产品。
Outlier tests have no applicability in cases where the variability in the product is what is being assessed, such as for content uniformity, dissolution, or release rate determinations. In these applications, a value perceived to be an outlier may in fact be an accurate result of a nonuniform product.
逸出值测试在正是要评估产品的变异性的情况下不适用，如含量均一性，溶解度，释放率测定。在这些情况下，一个感觉是逸出值的数值实际上可能是不均匀产品的真实结果。
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V. CONCLUDING THE INVESTIGATION
调查结论
To conclude the investigation, the results should be evaluated, the batch quality should be determined, and a release decision should be made. The SOPs should be followed in arriving at this point. Once a batch has been rejected, there is no limit to further testing to determine the cause of the failure so that a corrective action can be taken.
对调查作结论，应该评估结果，确定批产品质量，才能做出放行决定。必须按照SOP要求开展这些工作。一旦产品被判为了不合格，对于进一步检验以判断不合格的原因是没有限制的，以便可以采取纠正措施。
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A. Interpretation of Investigation Results
调查结果的解释
An OOS result does not necessarily mean the subject batch fails and must be rejected. The OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection (§ 211.165).
一个OOS结果不一定就意味着批产品不合格和必须拒绝使用。应该对OOS结果进行调查，调查的结果包括再检验结果，应该被解释去评估批产品并得出放行或拒绝的结论(§ 211.165)。
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In those instances where an investigation has revealed a cause, and the suspect result is invalidated, the result should not used to evaluate the quality of the batch or lot. Invalidation of a discrete test result may be done only upon the observation and documentation of a test event that can reasonably be determined to have caused the OOS result.
在调查揭示出了原因，且可疑结果被作废的情况下，检验结果不应该用于评估批产品的质量。只有依据观察资料和测试过程的记录能合理地确定是试验操作造成了OOS结果时，才能做出分离的检验结果无效的决定。
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In those cases where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch's rejection, in accordance with § 211.165(f), and proper disposal.
在调查标明OOS结果是由影响批产品质量的因素引起的情况下(即，OOS结果得到确认)，检测结果应该应用于评估批产品质量，得到确认的OOS 结果标明了批产品不符合建立的标准或规格，应该依据211.165(f)确定批产品不合格，并做合适的处理。
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For inconclusive investigations — in cases where an investigation (1) does not reveal a cause for the OOS test result and (2) does not confirm the OOS result — the OOS result should be retained in the record and given full consideration in the batch or lot disposition decision.
对非决定性调查――在调查(1)没有揭示引起OOS结果的原因 (2)没有对OOS 结果确认的情况下-----OOS结果应该保留在记录中，对批处理决定做出充分的考虑。
Statistical treatments of data should not be used to invalidate a discrete chemical test result. In very rare occasions and only after a full investigation has failed to reveal the cause of the OOS result, a statistical analysis may be valuable as one assessment of the probability of the OOS result as discordant, and for providing perspective on the result in the overall evaluation of the quality of the batch.
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不应该用数据的统计处理方法来确定分离的化学检验结果无效。在极少情况下和只有在经过了充分的调查也没有揭示出OOS结果的原因时，统计分析可以作为对OOS结果可能性的一种评估方法和对该批产品质量的全面评估结果提供看法。
Records must be kept of complete data derived from all tests performed to ensure compliance with established specifications and standards.
必须保持为确认符合既定的指标和标准所做的测试而得到的所有数据的记录(21 CFR 211.194)。
B. Reporting
报告
For those products that are the subject of applications, regulations require submitting within three working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii). OOS test results not invalidated on distributed batches or lots for this class of products are considered to be one kind of “information concerning any failure” described in this regulation. This includes OOS results that are considered to be discordant and of low value in batch quality evaluation. In these cases, an FAR should be submitted.
对用于上市申请所涉及的所有产品，法规要求在三个工作日内递交有关已销售批不符合申请中制定的标准的区域警惕报告(21 CFR 314.81(b)(1)(ii)。已销售的批产品的没有作废的OOS结果被认为是本规则中描述的一类“涉及不合格内容的信息”。这包括被认为是不和谐的OOS结果和批产品质量评估中的近低限值。在这些情况下，应递交FAR。, http://www.100md.com(佚名)
(OOS) Test Results for Pharmaceutical Production
行业指南：
药品检验结果OOS的调查
DRAFT GUIDANCE
指南草案
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
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September 1998
CP #
TABLE OF CONTENTS目录
I. INTRODUCTION 序言. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . .. . . .. . . 1
II. BACKGROUND . 背景. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . 1
III. IDENTIFYING AND ASSESSING OOS TEST RESULTS OOS检验结果的判断和评估. . .. 2
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A.Responsibility of the Analyst 检验员的责任. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2
B. Responsibilities of the Supervisor主管的责任. . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . .. . . . .3
IV. INVESTIGATING OOS TEST RESULTS OOS 检验结果的调查. . . . . . . . . . . . . . . . . . . .. 5
A. General Investigational Principles . . 一般调查原则. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
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B. Laboratory Phase of an Investigation . 实验室的调查阶段 . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . 6
V. CONCLUDING THE INVESTIGATION . .调查结论 . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . 10
A. Interpretation of Investigation Results . 调查结果的解释 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
B. Reporting . . .报告 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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This guidance has been prepared by the Office of Compliance/Division of Manufacturing and Product
Quality, Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. This guidance document represents the Agency’s current thinking on evaluating OOS test results. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
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本指南由FDA的CDER的达标办公室/制造、产品、质量分部起草，本指南阐明了机构关于评估OOS检验结果的现行的想法。它不会创造或赠与任何人任何权力，也不会约束FDA或公众。如果其他可选择的相接近的指南能满足适用的法令和法规的要求，也可以使用。
GUIDANCE FOR INDUSTRY1
Investigating Out of Specification (OOS) Test Results
for Pharmaceutical Production
行业指南：药品检验结果OOS的调查
I. INTRODUCTION
序言
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This guidance for industry provides the Agency’s current thinking on how to evaluate suspect, or out of specification (OOS), test results. For purposes of this document, the term OOS results includes all suspect results that fall outside the specifications or acceptance criteria established in new drug applications, official compendia, or by the manufacturer.
本行业指南反应了FDA关于如何评估怀疑的或OOS检验结果的现行想法，本指南的目的，OOS结果包括超出了新药申请材料、法定标准、生产商建立的可接受标准或规格的所有可疑的结果。
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This guidance applies to laboratory testing during the manufacture of active pharmaceutical ingredients, excipients, and other components and the testing of finished products to the extent that current good manufacturing practices (CGMP) regulations apply (21 CFR parts 210 and 211). Specifically, the guidance discusses how to investigate suspect, or OOS test results, including the responsibilities of laboratory personnel, the laboratory phase of the investigation, additional testing that may be necessary, when to expand the investigation outside the laboratory, and the final evaluation of all test results.
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本指南适用于API、赋形剂和其它组分生产的实验室检验和CGMP法规应用的成品检验。特别的，指南讨论了如何调查可疑的或OOS检验结果，包括了实验室人员的责任、实验室阶段调查、必须的额外试验，何时进行实验室范围外的调查和对所有检验结果的最终评估。
II. BACKGROUND 背景
FDA considers the integrity of laboratory testing and documentation records to be of fundamental importance during drug manufacturing. Laboratory testing, which is required by the CGMP regulations (§ 211.165), is necessary to confirm that components, containers and closures, inprocess materials, and finished products conform to specifications, including stability. Testing Specifications must be scientifically sound and appropriate (21 CFR 211.160(b)), and test procedures must be validated as to their accuracy, reliability, and suitability under actual conditions of use (21 CFR 211.194(a)(2)). For products that are the subjects of NDAs, ANDAs, or INDs, specifications are contained in the application. Specifications for non-application products may be found in official compendia, or established by the manufacturer.
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FDA认为在药品生产中实验室检验和文件记录的完整性是基本重要的。CGMP要求的实验室检验，必须确定成分、容器和封口材料、生产用辅料、成品符合标准要求，包括稳定性。检验标准必须是科学正确和适当的(1 CFR 211.160(b)，检验方法必须验证现行使用条件下的正确性、线性和适应性(21 CFR 211.194(a)(2))，如果是用于NDAs, ANDAs, 或 INDs申请的产品，申请材料中应包括标准。 如果是非申请产品的质量标准，可以在法定标准中找到或由企业自已建立。
Although the subject of this document is OOS results, much of the guidance may be useful for examining results that are out of trend. also supports analytical and process validation efforts. General CGMP regulations covering laboratory 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 and containers of drug products conform to the established standards. Section 211.165(f) of the CGMP regulations specifies that products that fail to meet established standards and other relevant quality control criteria will be rejected.
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尽管本指南的目的是OOS结果，其中许多部分对于调查超出趋势以外的结果也是有用的，对分析和工艺验证也有用。有关实验室操作一般性CGMP法规可以在211部分，分目I (实验室控制)和分目 J (报告和记录)找到。这些法规规定了科学正确和适当的用于保证制剂的成分和容器符合建立标准的规格、标准和检验方法的建立。CGMP的211.165(f)章节规定不符合既定标准和其它相关质量控制标准的产品不得放行。
III. IDENTIFYING AND ASSESSING OOS TEST RESULTS
OOS检验结果的判断和评估
FDA regulations require that an investigation be conducted whenever an OOS test result is obtained. The purpose of the investigation is to determine the cause of the OOS. 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 of the investigation and follow-up (211.192).
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FDA法规要求当OOS检验结果出现时应该进行调查，调查的目的是确定引起OOS的原因。即使因OOS结果判断了不合格批，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。法规要求对调查包括调查结论和随后采取的措施进行记录(211.192)。
To be meaningful, the investigation should be thorough, timely, unbiased, well-documented, and scientifically defensible. The first phase of such an investigation should include an initial assessment of the accuracy of the laboratory's data, before test solutions are discarded, whenever possible. This way, hypotheses regarding laboratory error or instrument malfunctions may be tested using the same test solutions. If this initial assessment indicates that no errors were made in the analytical process used to arrive at the data, a complete failure investigation should follow.
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更有意义的，调查必须是完全的，及时的，不带有任何偏见的，记录是完整的和经得起科学推敲的。调查的最初阶段应该在试验溶液丢弃前，对实验室数据正确性进行最初评估，这样，假定认为是实验室错误或仪器故障，可以用原溶液测定。如果最初的评估评估显示在得到该数据的分析过程中没有发生错误，必须立即开展一个完全的不合格调查。
A.Responsibility of the Analyst
检验员的责任
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 OOS results.
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从事测试的检验员的首要责任是取得正确实验室检验结果。检验员应该意识到在实验过程中可能发生的潜在的问题和应该注意可能产生OOS结果的问题。
In accordance with the CGMP regulations (§ 211.160 (b)(4)), the analyst should ensure that only those instruments meeting established specifications are used and that all instruments are properly calibrated.
Certain analytical methods have system suitability requirements, and systems not meeting such 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 corrected before a decision is made whether to use any data prior to the suspect period.
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依据CGMP (§ 211.160 (b)(4))，检验员应该保证只有符合既定标准的仪器才能使用和所有的仪器都经过的校正。某些分析方法有系统适应性要求，不符合要求的系统不能使用。例如：在色谱系统中，在进行色谱检测期间内间隔一段时间进样对照品溶液去测定漂移、噪声和重复性。如果对照品响应值显示该系统功能不正常，在可疑的时间内收集的所有数据应该被适当标识并不能使用。在决定是否使用可疑期间之前的数据前，应鉴别故障的原因并予以纠正。
Before discarding test preparations or standard preparations, analysts should check the data for compliance with specifications. When unexpected results are obtained and no obvious explanation exists, test preparations should be retained and the analyst should inform the supervisor. An assessment of the accuracy of the results should be started immediately.
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在丢弃样品制备液和标准制备液之前，检验员应该核查数据对标准的符合性。当获得意想不到的结果且没有明显的理由时，应该保留样品制备液且检验员应该通知主管。应该立即开始评估检验结果的正确性。
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). These same responsibilities extend to analysts at contract testing laboratories.
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如果错误是明显的，如：样品溶液有洒出或样品成分的未完全转移，检验员应该立即记录所发生的情况。检验员不应该有意的继续这无效的分析(也就是，当明显的错误发生了，不应该带着会得出什么结果的目的去完成分析)。这些相同的责任适用于合同实验室的检验员。
B.Responsibilities of the Supervisor
主管的责任
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 may 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 would allow more credibility to be given to laboratory error theories.
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一旦OOS结果被确定，主管应该客观的和及时的进行评估。不应该对OOS结果的原因进行预想的假定。应该迅速评估数据以确定结果是否属于实验室错误，或该结果是否显示是生产过程的问题。立即的评估应该包括重新检测原溶液、测试的单位、玻璃器具和溶液制备过程，这样可以进一步证实对OOS结果属于实验室错误的假设。
The following steps should be taken as part of the supervisor's assessment:
下面是作为主管应评估的部分步骤：
1. Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct procedure.
与检验员讨论检测方法；确认检验员知道并执行了正确的程序。
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2. Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect information.
检查分析的原始数据，包括色谱和光谱，并识别出反常或可疑的信息。
3. Confirm the performance of the instruments.
确认仪器性能
4. Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they meet quality control specifications.
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确定使用了合适的参照标准品、溶媒、试剂和其它溶液，并且它们符合质量控制标准。
5. Evaluate the performance of the testing method to ensure that it is performing according to the standard expected based on method validation data.
评估检验方法的执行情况，以保证是按照标准执行并有方法验证数据。
6. Document and preserve evidence of this assessment.
记录并保存评估的证据。
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) can be tested. Examination of the retained solutions can be performed as part of the laboratory investigation.
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如果及时检测了所保留的样品制备液，会极大的促进OOS结果原因的确定。可以对所发生的事情的假设(如：稀释错误、仪器故障)进行检测。对被留的溶液的检验可以作为实验室调查的一部分。
Examples:
例如! Solutions can be re-injected as part of an investigation where a transient equipment malfunction is suspected. This could occur if bubbles were introduced during an injection on a chromatographic system, which other tests indicated was performing properly. Such theories are difficult to prove. However, a reinjection can provide strong evidence that the problem should be attributed to the instrument, rather than the sample or its preparation.
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如果怀疑设备瞬间的故障，那么调查可以重新进样该溶液。如果在色谱系统一次进样期间引入了气泡，而其它的试验进行正常，这是可能发生的。这样的推测很困难去证明。但是，重新进样能有力的证明问题与仪器有关，而不是与样品或样品的准备有关。! For release rate testing of certain specialized dosage forms, where possible, examination of the dosage unit tested might determine whether it was damaged in a way that affected its performance. Such damage would provide evidence to invalidate the OOS test result, and a retest would be indicated.
对于某一特定制剂的放行检验，如果可能，检查一下被测的这份制剂可以确定是否在什么方面被损坏而影响了其性能。这样的损坏能提供证据使OOS检验结果无效，这样就可以进行重新检验。! Further extraction of a dosage unit 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.
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对一份制剂做进一步提取以确定在初次检验期间是否被充分的提取了。不完全的提取能使检验结果无效，将导致检验方法验证的问题。
It is important that each step in the investigation be fully documented. The supervisor should ascertain not only the reliability of the individual value obtained, but also the significance these OOS results represent in the overall quality assurance program.
在调查的每一步都应做充分的记录，这是很重要的。主管不仅应该确定获得的个别值的可靠性，也应该确定在整个质量保证程序中阐明的OOS结果的重要性。
Supervisors should be especially alert to developing trends.
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主管应该特别警惕发展趋势。
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 laboratory error is identified, the firm should determine the source of that error and take corrective action to ensure that it does not occur again. To ensure full compliance with the CGMP regulations, the manufacturer also should maintain adequate documentation of the corrective action.
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In summary, when clear evidence of laboratory error exists, laboratory testing results should be invalidated. When evidence of laboratory error remains unclear, a failure investigation should be conducted to determine what caused the unexpected results. It should not be assumed that failing test results are attributable to analytical error without performing and documenting an investigation. Both the initial laboratory assessment and the following failure investigation should be documented fully.
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实验室错误应该是极少发生的。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。如果实验室错误被确定了，企业应该确定错误的来源并采取纠正措施去保证错误不再发生。为保证完全符合CGMP,生产商应该保持充分的纠正措施的记录。总之，当实验室错误的证据已经存在，实验室检验结果应该作废。当实验室错误的证据仍然不清楚，应该进行不合格结果的调查以确定引起意外结果的原因。在没有进行调查及调查文件确定之前不应该假定失败的检验结果属于检验错误。最初的实验室评估和下面的不合格结果的调查应该被充分的记录。
IV. INVESTIGATING OOS TEST RESULTS
OOS结果调查
When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale failure investigation using a predefined procedure should be conducted. The objective of such an investigation should be to identify the source of the OOS result. Varying test results could indicate problems in the manufacturing process, or result from sampling problems. Such investigations present a challenge both to employees and to management and should be given the highest priority.
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如果最初的评估不能确定是实验室错误造成了OOS结果且实验结果是正确的，应按照预先确定的程序进行全方位的不合格调查。这样调查的目的是确定OOS结果的来源，变化的试验结果可能显示是生产工艺的问题或取样问题导致的结果。这样的调查是对员工和管理者的挑战应给予极高度的重视。
The investigation should be conducted by the quality control unit and should involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering. Other potential problems should be identified and investigated.
调查应该由质量控制部门和所有其它相关的部门完成，包括生产部门，工艺研发部门，维护保养和工程部门。其它的潜在问题也应该被确定和调查。
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The records and documentation of the manufacturing process should be fully investigated to determine the possible cause of the OOS results.
应该充分调查生产过程的记录和文件以判断引起OOS结果的可能原因。
A.General Investigational Principles
一般调查原则
A failure investigation should consist of a timely, thorough, and well-documented review.
一个不合格结果的调查在于及时，彻底，和完善的记录审核 。
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The written record should reflect that the following general steps have been taken.
记录应该反映通常采取的下列步骤：
1. The reason for the investigation has been clearly identified.
调查的原因被清楚的确定。
2. The manufacturing process sequences that may have caused the problem should be summarized.
对可能引起问题的生产工艺流程进行了总结。
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文件审核的结果提供了实际的或可能的原因。
4. A review should be made to determine if the problem has occurred previously.
审核并判断是否以前发生过这类问题。
5. Corrective actions taken should be described.
应该描述采取的纠正措施
The general review should include a list of other batches and products possibly affected and any required corrective actions taken including any comments and signatures of appropriate production and quality control personnel regarding any material that may have been reprocessed after additional testing.
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一般性审核应该包括可能受影响的其它批和产品的列表，任何必须的纠正行为包括对复检后进行返工的物料的适宜的生产和质量控制人员的评论和签名。
B. Laboratory Phase of an Investigation 实验室阶段的调查
A number of practices are used during the laboratory phase of an investigation. These include: (1) retesting a portion of the original sample, (2) testing a specimen from the collection of a new sample from the batch, (3) resampling testing data, and (4) using outlier testing.
, 百拇医药 在实验室阶段的一系列调查包括：(1)最初样品一部分的再检验，(2)从该批中重新取样样品的检验，(3)重新取样的检验数据，(4)逸出值的检验
1. Retesting
重新检验
Part of the investigation may involve retesting of a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid it may be an additional weighing from the same sample composite that had been prepared by the analyst.
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调查部分工作包括最初检验样品的再检验。用于再检验的样品应该是最初收集检验的、出现OOS结果的样品均质物料的一部分。如果是液体，可以是液体成品的原始单位或液体成品的混合物。如果是固体，可以是检验员制备的相同混合物的额外的称量。
Situations where retesting is indicated include investigating testing instrument malfunctions or to identify a possible sample handling integrity problem, for example, a suspected dilution error. Generally, retesting is neither specified nor prohibited by approved applications or by the compendia. Decisions to retest should be based on the objectives of the testing and sound scientific judgment. Retesting should be performed by an analyst other than the one who performed the original test.
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再检验的情况标明包括检验仪器故障的调查或判断样品处理完整性。例如：一个可疑的溶解错误。一般地，在批准的申请中或药典中既没有限定也没有禁止，应该依据客观的检验和正确科学的判断决定再检验。再检验应该是另一检验员完成而不是最初检验人员。
The CGMP regulations require the establishment of specifications, standards, sampling plans, test procedures, and other laboratory control mechanisms (§ 211.160). The establishment of such control mechanisms for examination of additional specimens，for commercial or regulatory compliance testing must be in accordance with "predetermined guidelines or sampling strategies" (USP 23, General Notices and Requirements, p.9).
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CGM法规要求建立规格、标准、取样计划、检验程序和其它的实验室控制机制(§ 211.160)。符加样品的检验、商业或调整的依从性试验的控制机制的建立必须依据预先确定指南或取样策略。
Some firms have used a strategy of repeated testing until a passing result is obtained (testing into compliance), then disregarding the OOS results without scientific justification. Testing into compliance is objectionable under the CGMPs. The number of retests to be performed on a sample should be specified in advance by the firm in the SOP.
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许多企业使用重复的检验直到获得满意的结果的策略，然后没有科学的理由就忽视了OOS结果。重复的检验直到获得满意的结果，CGMP是不允许的。样品的再检验次数应该在企业的SOP中被预先限定。
The number may vary depending upon the variability of the particular test method employed, but should be based on scientifically sound, supportable principles. The number should not be adjusted depending on the results obtained. The firm's predetermined testing procedures should contain a point at which the testing ends and the product is evaluated. If, at this point, the results are unsatisfactory, the batch is suspect and must be rejected or held pending further investigation(§ 211.165(f)).
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检验次数可以根据使用的检验方法的可变性决定，但必须依据科学正确和可支持的原则。检验次数不能依据结果进行判断。企业预先确定的检验程序应该包括何时检验结束和进行产品评估。如果，就这一点，结果是不满意的，这批产品就是可疑的，必须批准不合格或进一步调查后再作决定(§ 211.165(f)).。
In the case of a clearly identified laboratory error, the retest results would substitute for the original test results. The original results should be retained, however, and an explanation recorded. This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments.
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在明确确定了实验室错误的情况下，再检验结果将取代最初检验结果，应该保留最初结果和一个解释记录，这个记录应该有相关人员人员的签名、注上日期，并应包括对错误的讨论、主管的注释。
If no laboratory or statistical errors are identified in the first test, there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported and considered in batch release decisions.
如果不能确定是首次的试验是实验室或统计错误，就没有为了让产品通过复检而废除最初OOS结果的科学基础。所有检验结果，不论是通过的和可疑的，都应该报告并供批放行结论中考虑。
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2. Resampling
再取样
While retesting refers to analysis of the original sample, resampling involves analyzing a specimen from the collection of a new sample from the batch. The establishment of control mechanisms for examination of additional specimens for commercial or regulatory compliance testing should be in accordance with predetermined procedures and sampling strategies (§ 211.165(c)).
涉及最初样品分析的再检验，再取样包括从该批产品抽取新的样品。应该按照预先制定的程序和取样策略来建立为符合商业或法规的试验的目的而对额外样品进行检验的控制机制。
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In some cases, when all data have been examined, it may be concluded that the original sample was prepared improperly and was therefore not representative of the batch (§ 211.160(b)(3)). A resampling of the batch should be conducted if the investigation shows that the original sample was not representative of the batch. This would be indicated, for example, by widely varied results obtained from several aliquots of the original composite (after determining there was no error in the performance of the analysis). Resampling should be performed by the same qualified, validated methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was in error, a new accurate sampling method must be developed, qualified, and documented (§§ 211.160 and 165(c)).
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在某些情况下，当已对所有的数据进行检查，可能会得出结论，即最初的样品没有正确制备因此不能代表该批产品(§ 211.160(b)(3))。如果调查显示最初的样品不能代表批产品，可以进行该批产品的再取样。这可以通过最初成分的几次分取样品分析获得差异较大的结果来表明(在确定检验操作没有错误之后)。重新取样应采用最初取样所采用的相同合格的、经过验证的方法进行。但是，如果调查确定最初取样方法是错误的，应该研究一个新的正确的取样方法并进行确认、并形成文件(§§ 211.160 and 165(c))。
3. Averaging
平均法
Averaging test data can be a valid approach, but its use depends upon the sample and its purpose. For example, in an optical rotation test, several discrete measurements are averaged to determine the optical rotation for a sample, and this average is reported as the test result. If the sample can be assumed to be homogeneous (i.e., an individual sample preparation designed to be homogeneous), using averages can provide a more accurate result. In the case of microbiological assays, the USP prefers the use of averages because of the innate variability of the biological test system.
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将检验数据平均是一个有效的方法，对其使用应依据样品和其目的。例如：在旋光度测试中，将几次不连续的测定结果进行平均以确定样品的旋光度，这个平均值可以作为检验结果。如果样品是均质的，使用平均值能提供更准确的结果。在微生物测定试验中，因为微生物测定系统的固有的可变性，USP更希望用平均值。
Reliance on averages has the disadvantage of hiding variability among individual test results. For this reason, unless averaging is specified by the test method or adequate written investigation procedures, all individual test results should be reported. In some cases, a statistical treatment of the variability of results should be reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is also reported.
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依赖平均值有隐藏各单独的检验结果中变异性的不利一面。因此，除非分析方法或适宜的调查程序指定了用平均值，所有的单独试验结果都应该报告。在某些情况下，结果可变性的统计处理方法也应该报告。G例如：在制剂含量均一性检验中、标准偏差(或相对标准偏差)也应报告。
Averaging also can conceal variations in the different portions of the sample. For example, the use of averages is inappropriate when performing powder blend/mixture uniformity or dosage form content uniformity determinations. In these cases, the testing is intended to measure variability within the product, and the individual results should be reported.
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平均法也会隐藏样品不同部分的差异性。例如：当进行粉末混和/混合物的均匀性检测或制剂含量均匀性检验，使用平均法是不合适的。在这些情况下，检测是为了测量产品内的差异性的，因此应该使用各单独测试结果。
It should be noted that a test might consist of replicates to arrive at a result. For instance,an HPLC assay result may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation (usually 2 or 3). The assay result would be calculated using the peak response average. This determination is considered one test and one result. This is a distinct difference from the analysis of different portions from a lot, intended to determine variability within the lot. The use of replicates should be included in the written, approved, test methodology. Unexpected variation in replicate determinations should trigger investigation and documentation requirements (21 CFR 211.192).
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应该注意一个检验结果可能是反复测定得出的。实例：一个HPLC分析结果可能是对相同样品溶液几次连续、反复的进样(2-3次)所得峰的响应值的平均而确定的。含量测试结果应使用峰响应值的平均值来计算。这个确定被认为是一次试验和一个结果，这与同一批产品的不同部分的分析以判断一批产品的可变性是明显不同的。重复测定应该收载在书面的、经批准的检验方法里。重复测定结果的意外变更应引起调查并进行记录(21 CFR 211.192)。
In some cases, a series of assay results may be a part of the test procedure. If some of the results are OOS and some are within specification and all are within the documented variation of the method, the passing results should be given no more credence than the failing results, in the absence of documented evidence that analytical error had occurred.
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在某些情况下，一系列的测试结果可以是分析过程的一部分。如果其中一些结果是OOS结果而有一些在标准之内而且所有结果都在该方法的变异范围之内，在没有能文件证明存在检验错误的情况下，合格的结果并不比失败的结果有更高的可信度。
Relying on test data averaging in such a case can be particularly misleading. For example, in an assay with a given range of 90 to 110 percent, test results of 89 percent, 89 percent, and 92 percent would produce an average of 90 percent even though two of the assay values represent failing results.
依据对检验结果的平均在某些方面能产生特别的误导，例如：一个含量标准范围是90%-110%，检验结果是：89%、89%、92%，尽管两个含量值表明不合格，其平均值却为得到90%。
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To use averaged results for assay reporting, all test results should conform to specifications. Although the above average of 90 percent may be useful in terms of an overall assessment of process capabilities, the individual assay results indicate nonconformance because two of the three results are outside of the range. A low assay value should also trigger concerns that the batch was not formulated properly because the batch must be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient (21 CFR 211.101(a)). The above example does not necessarily require the manufacturer to fail the batch, but indicates that an immediate investigation should be conducted for batch disposition decisions.
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要应使用平均结果作为含量测定结果，所有的检验结果都必须符合标准。尽管上面的平均值90%可以用于生产能力的全面评估，因为3个结果中的2个在范围之外，单独的含量测定结果就标明产品不符合要求。一个低的含量值应引起注意 ：因为一批产品应该按照能提供不低于100%标示量或确定数量的原料的标准来制备(21 CFR 211.101(a))，因此该批没有正确配制。上面的例子并不一定要求企业把此批作为不合格批，但是表明应该对此批立即进行调查以确定对该批的处置方法。
4. Outlier Tests
逸出值的检验
The CGMP regulations require that statistically valid quality control criteria include appropriate acceptance and/or rejection levels (§ 211.165(d)). On rare occasions, a value may be obtained that is markedly different from the others in a series obtained using a validated method. Such a value may qualify as a statistical outlier. An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is error in the testing procedure, rather than inherent variability in the sample being tested.
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CGMP法规要求统计的有效质量控制标准包括合适的可接受的和/或不合格水平(§ 211.165(d))。在极少情况下，用一个用验证过的方法获得的一个值会明显的不同于得到的一系列值，这样的一个值应该作为一个统计的逸出值，一个逸出值可以是规定检验方法的偏差的结果，或是样品存在差异的结果。决不能将出现逸出值的原因假定为检验操作的错误，而不认为被检验样品存在固有的差异。
Outlier testing is a statistical procedure for identifying from an array those data that are extreme. The possible use of outlier tests should be determined in advance. This should be written into SOPs for data interpretation and be well documented. The SOPs should include the specific outlier test to be applied with relevant parameters specified in advance. The SOPs should specify the minimum number of results required to obtain a statistically significant assessment from the specified outlier test.
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逸出值检验是从一组数据中识别出极端数据中的统计方法。逸出值检验的可能使用应该事先确定。对这中使用应该写入用来解释数据的SOP里并做好记录。SOP应该包括特定的逸出值适用于预先指定的相关参数。该SOP应该规定用于从特定的逸出值测试中获得统计学上有意义的评估结果的最少的检测结果数量。
For biological assays having a high variability, an outlier test may be an appropriate statistical analysis to identify those results that are statistically extreme observations. The USP describes outlier tests in the section on Design and Analysis of Biological Assays (USP 23, p. 1705). In these cases, the outlier observation is omitted from calculations. The USP also states that "arbitrary rejection or retention of an apparently aberrant response can be a serious source of bias. . .the rejection of observations solely on the basis of their relative magnitudes is a procedure to be used sparingly" (USP 23, p. 1705).
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生物制剂含量测定有更高的变异性，逸出值测试可能是判断这些极端结果的适当的统计分析。USP在生物制剂设计和分析章节描述了逸出值。在这些情况下，逸出值在计算时被省略。USP也规定了“对明显的异常值的任意拒绝或保留可能是发生偏差的重要原因. . . . . .仅依靠相对重要性来拒绝观测值是一个应谨慎使用的方法”
For validated chemical tests with relatively small variance, and if the sample being tested can be considered homogeneous (for example, an assay of composited dosage form to determine strength), an outlier test is only a statistical analysis of the data obtained from testing and retesting. It will not identify the cause of an extreme observation and ,therefore, should not be used to invalidate the data. An outlier test may be useful as part of the evaluation of the significance of that result for batch evaluation, along with other data.
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对于验证过的相对变化较小的化学测试来说，如果被检验的样品是均质的(例如，测定一复方制剂的浓度)，逸出值测试仅仅是对检验和再检验数据的统计分析。不能确定出现极端观察值的原因，因此，不能用来决定使数据无效。逸出值测试与其它数据一起用于评估批产品。
Outlier tests have no applicability in cases where the variability in the product is what is being assessed, such as for content uniformity, dissolution, or release rate determinations. In these applications, a value perceived to be an outlier may in fact be an accurate result of a nonuniform product.
逸出值测试在正是要评估产品的变异性的情况下不适用，如含量均一性，溶解度，释放率测定。在这些情况下，一个感觉是逸出值的数值实际上可能是不均匀产品的真实结果。
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V. CONCLUDING THE INVESTIGATION
调查结论
To conclude the investigation, the results should be evaluated, the batch quality should be determined, and a release decision should be made. The SOPs should be followed in arriving at this point. Once a batch has been rejected, there is no limit to further testing to determine the cause of the failure so that a corrective action can be taken.
对调查作结论，应该评估结果，确定批产品质量，才能做出放行决定。必须按照SOP要求开展这些工作。一旦产品被判为了不合格，对于进一步检验以判断不合格的原因是没有限制的，以便可以采取纠正措施。
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A. Interpretation of Investigation Results
调查结果的解释
An OOS result does not necessarily mean the subject batch fails and must be rejected. The OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection (§ 211.165).
一个OOS结果不一定就意味着批产品不合格和必须拒绝使用。应该对OOS结果进行调查，调查的结果包括再检验结果，应该被解释去评估批产品并得出放行或拒绝的结论(§ 211.165)。
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In those instances where an investigation has revealed a cause, and the suspect result is invalidated, the result should not used to evaluate the quality of the batch or lot. Invalidation of a discrete test result may be done only upon the observation and documentation of a test event that can reasonably be determined to have caused the OOS result.
在调查揭示出了原因，且可疑结果被作废的情况下，检验结果不应该用于评估批产品的质量。只有依据观察资料和测试过程的记录能合理地确定是试验操作造成了OOS结果时，才能做出分离的检验结果无效的决定。
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In those cases where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch's rejection, in accordance with § 211.165(f), and proper disposal.
在调查标明OOS结果是由影响批产品质量的因素引起的情况下(即，OOS结果得到确认)，检测结果应该应用于评估批产品质量，得到确认的OOS 结果标明了批产品不符合建立的标准或规格，应该依据211.165(f)确定批产品不合格，并做合适的处理。
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For inconclusive investigations — in cases where an investigation (1) does not reveal a cause for the OOS test result and (2) does not confirm the OOS result — the OOS result should be retained in the record and given full consideration in the batch or lot disposition decision.
对非决定性调查――在调查(1)没有揭示引起OOS结果的原因 (2)没有对OOS 结果确认的情况下-----OOS结果应该保留在记录中，对批处理决定做出充分的考虑。
Statistical treatments of data should not be used to invalidate a discrete chemical test result. In very rare occasions and only after a full investigation has failed to reveal the cause of the OOS result, a statistical analysis may be valuable as one assessment of the probability of the OOS result as discordant, and for providing perspective on the result in the overall evaluation of the quality of the batch.
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不应该用数据的统计处理方法来确定分离的化学检验结果无效。在极少情况下和只有在经过了充分的调查也没有揭示出OOS结果的原因时，统计分析可以作为对OOS结果可能性的一种评估方法和对该批产品质量的全面评估结果提供看法。
Records must be kept of complete data derived from all tests performed to ensure compliance with established specifications and standards.
必须保持为确认符合既定的指标和标准所做的测试而得到的所有数据的记录(21 CFR 211.194)。
B. Reporting
报告
For those products that are the subject of applications, regulations require submitting within three working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii). OOS test results not invalidated on distributed batches or lots for this class of products are considered to be one kind of “information concerning any failure” described in this regulation. This includes OOS results that are considered to be discordant and of low value in batch quality evaluation. In these cases, an FAR should be submitted.
对用于上市申请所涉及的所有产品，法规要求在三个工作日内递交有关已销售批不符合申请中制定的标准的区域警惕报告(21 CFR 314.81(b)(1)(ii)。已销售的批产品的没有作废的OOS结果被认为是本规则中描述的一类“涉及不合格内容的信息”。这包括被认为是不和谐的OOS结果和批产品质量评估中的近低限值。在这些情况下，应递交FAR。, http://www.100md.com(佚名)