CDER1998行业指南：药品检测结果OOS调查指南.doc

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 ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)September 1998CP #TABLE OF CONTENTS目录I. INTRODUCTION 序言. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1II. BACKGROUND . 背景. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1III. IDENTIFYING AND ASSESSING OOS TEST RESULTS OOS检验结果的判断和评估. . . 2A. Responsibility of the Analyst 检验员的责任. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2B. Responsibilities of the Supervisor主管的责任. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3IV. INVESTIGATING OOS TEST RESULTS OOS 检验结果的调查. . . . . . . . . . . . . . . . . . . . 5A. General Investigational Principles . . 一般调查原则. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5B. Laboratory Phase of an Investigation . 实验室的调查阶段 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6V. CONCLUDING THE INVESTIGATION . .调查结论 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10A. Interpretation of Investigation Results . 调查结果的解释 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10B. Reporting . . .报告 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11This 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 Agencys 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.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 INDUSTRY1Investigating Out of Specification (OOS) Test Resultsfor Pharmaceutical Production行业指南：药品检验结果OOS的调查I. INTRODUCTION 序言This guidance for industry provides the Agencys 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。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.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.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.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).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 laboratorys 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. 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.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.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.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.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 supervisors 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.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 supervisors 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。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.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.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.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.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.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.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.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 RESULTSOOS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.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。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 。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。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.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.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 additi