Guidance for Industry 行业指南

Investigating Out-of-Specification (OOS)

Test Results for Pharmaceutical Production

药品生产中OOS结果的调查

Additional copies are available from: 本文件可自以下途径得到

Office of Training and Communication 培训和交流办公室

Division of Drug Information HFD-240 药品信息分部

Center for Drug Evaluation and Research 药品审评中心

Food and Drug Administration 食品药品管理局

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services 美国卫生和福利部

Food and Drug Administration 食品药品管理局

Center for Drug Evaluation and Research(CDER) 药品审评中心

October 2006

TABLE OF CONTENTS 目录

I. INTRODUCTION 介绍

II. BACKGROUND 背景

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

A. Responsibility of the Analyst 化验员职责

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

IV.INVESTIGATING OOS TEST RESULTS 对OOS结果的调查— PHASE II: FULL-SCALE OOS INVESTIGATION 第二步：全面OOS调查

A. Review ofProduction 生产情况审核

B. Additional Laboratory Testing 附加化验室测试

C. Reporting Testing Results 报告测试结果

V. CONCLUDINGTHE INVESTIGATION 调查结论

A.Interpretation of Investigation Results 调查结果解释

B. Cautions 注意事项

C. Field Alert Reports 现场警示报告.

GUIDANCE FOR INDUSTRY [1] 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 Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bindFDA 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 forimplementing 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。

I.INTRODUCTION 介绍

This guidance for industry provides the Agency’s 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 alsoapplies 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 products [3] to the extent that current good manufacturing practice (CGMP) regulations (21 CFRparts 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（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 guidanceis not intended to address PAT approaches, as routine in-process use of thesemethods 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。

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should beviewed 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。

II. BACKGROUND 背景

Laboratory testing, which is required by the CGMP regulations (§§211.160 and 211.165), is necessary to confirm that components, containers andclosures, 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 andprocess 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 thatcomponents, containers and closures, in-process materials, and finished drug products conform to the established standards. Section 211.165(f) of the CGMP regulations specifies that finished drug products that fail to meet established standards, specifications, or other relevant quality control criteria will be rejected.

检验亦应支持方法验证和工艺验证。通用CGMP规范包括化验室操作，在211部分章节 I (化验室控制) 和J (记录和报告)可以查阅到。这些法规用于建立科学合理和适当的质量规格、标准和检验方法，用于保证组件、容器和密闭器材、中控材料和制剂成品符合既定标准。CGMP法规211部分165（f）指出制剂成品不符合既定标准、规格或其它相应质量控制标准时应拒绝放行。

Both finished pharmaceuticals and active pharmaceutical ingredients (APIs) are to be manufactured in accordance with current good manufacturing practice under section

制剂成品和原料药（APIs）生产均应符合现行GMP对应条款下的要求。

501(a)(2)(B) of the Act. Current good manufacturing practice for APIs includes the performance of scientifically sound raw material testing, in-process monitoring, release and stabilitytesting, process validation, and adequate investigations of any OOS result obtained from such testing. All citations to part 211 in this document pertain to finished pharmaceuticals, but these referenced regulatory requirements are also consistent with Agency guidance on CGMPs for APIs with respect to laboratory controls, which include out-of-specification investigations. See FDA’s guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A)for specific recommendations. [5]

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

The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of amanufacturing 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] Incertain 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 investigational new drugapplications (INDs), specifications are contained in the application or DMF. Specifications for non application products may be found in official compendiaor 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 ofa guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm.

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