洛施德GMP咨询 - FDA行业指南 - 药品生产中OOS结果的调查中文版.pdf

Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 1 页 / 共 22 页 , Soltoris Management Consultants, Inc. Guidance for Industry 行业指南行业指南 Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production 药品生产中药品生产中 OOS 结果的调查结果的调查 Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 2 页 / 共 22 页 , Soltoris Management Consultants, Inc. Content 目录目录 1 INTRODUCTION 介绍介绍 . 3 2 BACKGROUND 背景背景. 4 3 IDENTIFYING AND ASSESSING OOS TEST RESULTS 界定和评价界定和评价 OOS 检验结果检验结果 . 6 A. Responsibility of the Analyst 化验员职责 . 7 B. Responsibilities of the Laboratory Supervisor 化验室主管职责 . 8 4 INVESTIGATING OOS TEST RESULTS 对对 OOS 结果的调查结果的调查 . 10 A. Review of Production 生产情况审核 . 10 B. Additional Laboratory Testing 附加化验室测试 . 12 C. Reporting Testing Results 报告测试结果 . 14 5 CONCLUDING THE INVESTIGATION 调查结论调查结论 . 19 A. Interpretation of Investigation Results 调查结果解释 . 19 B. Cautions 注意事项 . 20 C. Field Alert Reports 现场警示报告 . 21 Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 3 页 / 共 22 页 , Soltoris Management Consultants, Inc. GUIDANCE FOR INDUSTRY1 行业指南行业指南 Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production 药物生产中不合格结果的调查 This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 本指南代表 FDA 对本专题现行的想法。它没有给任何人创造或者赋予他们任何的权利，而且也不会束缚FDA 或公众的操作。如果有替代的方法能满足法律法规的要求，你可以使用一个替代的方法。如果你要讨论一个替代的方法，请联系负责实施本指南的 FDA 工作人员。如果你不能够识别适当的 FDA 工作人员，请拨打本指南封面页上的适当电话。 1 INTRODUCTION 介绍介绍 This guidance for industry provides the Agencys current thinking on how to evaluate out-of-specification (OOS) test results. For purposes of this document, the term OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.2 本指南旨在表达当局对如何评价 OOS 结果的最新想法。本文件中 OOS 结果这个术语包括所有不符合质量标准，或经由药品申请、DMF 文件、官方药典及生产商所确立的可接受标准的检测结果。这个术语也适用于所有不符合已建立标准的中控化验室检测结果。 This guidance applies to chemistry-based laboratory testing of drugs regulated by CDER. It is directed toward traditional drug testing and release methods. These laboratory tests are performed on active pharmaceutical ingredients, excipients and other components, in-process materials, and finished drug products3 to the extent that current good manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211) and the Federal Food, Drug, and Cosmetic Act (the Act) (section 501(a)(2)(B) apply. The principles in this guidance also apply to in-house testing of drug product components that are purchased by a firm. This guidance can also be used by contract firms performing production and/or laboratory testing responsibilities. Specifically, the guidance discusses how to investigate 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. 本指南适用于由 CDER 管理的药品类别的化学实验室。它直接针对传统的药品测试和放行方法。这些实验室检测项目是对活性药物成份、赋形剂和其它组件、中控材料和制剂成品，这些就是 CGMP 法规Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 4 页 / 共 22 页 , Soltoris Management Consultants, Inc. （21CFR210 部分和 211 部分）和联邦食品药品和化妆品法案（501(a)(2)(B)）所适用的范围。本指南的公司采购的用于制剂成品的组件在公司内的检测。本指南也能用于承担生产和/或实验室测试的合同公司，尤其是， 指南讨论如何调查 OOS 结果时， 包括实验室人员职责， 化验室调查阶段、 可能需要的附加测试、何时扩大调查至化验室之外，和所有检测结果的最终评价。 The Agency, in accordance with its August 2002 “Pharmaceutical CGMPs for the 21st Century” initiative, encourages modern approaches to manufacturing, monitoring, and control to enhance process predictability and efficiency. Process Analytical Technology (PAT) takes a different approach to quality assurance by using process controls and in-process data as the release specification instead of relying on single laboratory determinations to make batch acceptability decisions. This guidance is not intended to address PAT approaches, as routine in-process use of these methods might include other considerations. For information on timely in-process testing, see the CGMP guidance entitled PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. 官方机构，按照 2002 年 8 月“21 世纪药品 CGMPS”倡导的，鼓励采用现代方法制造、监测和控制以提高工艺可预测性和效率。工艺分析技术（PAT）采用了不同的质量保证方法，即采用工艺控制和制程数据作为放行标准而不仅信赖于单一的化验室检测来作出批放行决定。由于这些方法的用于常规制程可能还有其它考虑，本指南并准备对 PAT 方法进行探讨。关于即时制程检测，参见 CGMP 指南 PAT-药品研发、生产和质量保证框架。 FDAs guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. FDA 的指南文件， 包括本指南， 并不具备法规强制性。 指南仅是用于表述当局的目前对某个问题的看法，应该当作一种推荐来采纳，除非在其中引用了特定的法规要求。在官方指南中，SHOULD 表示建议或推荐的方法，并非必须。 2 BACKGROUND 背景背景 Laboratory testing, which is required by the CGMP regulations ( 211.160 and 211.165), is necessary to confirm that components, containers and closures, in-process materials, and finished products conform to specifications, including stability specifications. cGMP 法规（211 章第 160 部分和 211 章第 165 部分）要求化验室对药品的成分、包装材料、过程控制及成品进行检测，确保其达到既定的标准要求，包括稳定性标准要求。 Testing also supports analytical and process validation efforts.4 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, 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. Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 5 页 / 共 22 页 , Soltoris Management Consultants, Inc. 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 FDAs 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。 1 This guidance has been prepared by the Office of Compliance/Division of Manufacturing and Product Quality in the Center for Drug Evaluation and Research (CDER). 本指南由药品评审中心 CDER 生产和产品质量分部法规符合办公室起草。 2 In certain instances, in-process testing is done solely for purposes of triggering real time equipment or system adjustments to prevent process drift. This guidance does not address these situations. 在特定情况下，中控检测的目的仅仅是触发实时设备和体系调节以防止工艺偏差。本指南不适用于这种情况。 3 Chemistry-based laboratory testing of biotechnology products that are under the jurisdiction of CDER are within the scope of this guidance. However, this guidance is not intended to address biological assays (e.g., in vivo, immunoassays). 由 CDER 负责的生物技术产品的化学检测项目在本指南范围内。但本指南不适用于生物含量检测（例如体内免疫检测）。 4 Specifications must be scientifically sound and appropriate ( 211.160(b), test procedures must be validated as to their accuracy, sensitivity, specificity, and reproducibility ( 211.165(e), and the suitability of the test procedures under actual conditions of use must be documented ( 211.194(a)(2). For products that are the subjects of new drug applications (NDAs), abbreviated new drug applications (ANDAs), or Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 6 页 / 共 22 页 , Soltoris Management Consultants, Inc. investigational new 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 http:/www.fda.gov/cder/guidance/index.htm 访问 CDER 指南页。 3 IDENTIFYING AND ASSESSING OOS TEST RESULTS 界定和评价界定和评价 OOS 检验结果检验结果 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).1 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 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 laboratorys 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 firms 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Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 7 页 / 共 22 页 , Soltoris Management Consultants, Inc. 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。 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Soltoris Management Consultants, Inc. 洛施德企业管理咨询（上海）有限公司 第 8 页 / 共 22 页 , Soltoris Management Consultants, Inc. 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