FDA 审计指南
U.S. Food and Drug AdministrationProtecting and Promoting Your Health Inspection GuidesWe have recently redesigned the FDA Web Site. As a result, some Web links (URLs) embedded within guidance documents are no longer valid. If you find a link that does not work, please try searching for the document using the document title. For more assistance, go to Contact FDA.(/AboutFDA/ContactFDA/default.htm)Guide to Inspections of:•Biotechnology•Computer Issues•Devices•Drugs•Foods Cosmetics•MiscellaneousNote: These documents are reference material for investigators and other FDA personnel. The documents do not bind FDA and do not confer any rights, privileges, benefits or immunities for or on any person(s). An alternative approach may be used if such an approach satisfies the applicable statutes, regulations or both.Page Updated: 2006-05-25Biotechnology•Biotechnology Inspection Guide (11/91)(/ICECI/Inspections/InspectionGuides/ucm074181.htm)Computer Issues•Computerized Systems in Drug Establishments (2/83)(/ICECI/Inspections/InspectionGuides/ucm074869.htm)•Computerized Systems in Food Processing Industry(/ICECI/Inspections/InspectionGuides/ucm074871.htm)•Glossary of Computer System Software Development Terminology (8/95)(/ICECI/Inspections/InspectionGuides/ucm074875.htm)Devices•Quality Systems(/ICECI/Inspections/InspectionGuides/ucm074883.htm)•Electromagnetic Compatibility Aspects of Medical Device Quality Systems(/ICECI/Inspections/InspectionGuides/ucm074885.htm)•Bioresearch Monitoring Inspections in Vitro Diagnostics Devices(/ICECI/Inspections/InspectionGuides/ucm074893.htm)•Mammography Quality Standards Act Auditor's Guide(/ICECI/Inspections/InspectionGuides/ucm074895.htm)•Medical Device Manufacturers(/ICECI/Inspections/InspectionGuides/ucm074899.htm)Drugs•High Purity Water System (7/93)(/ICECI/Inspections/InspectionGuides/ucm074905.htm)•Lyophilization of Parenteral (7/93)(/ICECI/Inspections/InspectionGuides/ucm074909.htm)•Microbiological Pharmaceutical Quality Control Labs (7/93)(/ICECI/Inspections/InspectionGuides/ucm074914.htm)•Pharmaceutical Quality Control Labs (7/93)(/ICECI/Inspections/InspectionGuides/ucm074918.htm)•Validation of Cleaning Processes (7/93)(/ICECI/Inspections/InspectionGuides/ucm074922.htm)•Dosage Form Drug Manufacturers cGMPs (10/93)(/ICECI/Inspections/InspectionGuides/ucm074927.htm)•Oral Solid Dosage Forms Pre/Post Approval Issues (1/94)(/ICECI/Inspections/InspectionGuides/ucm074928.htm)•Sterile Drug Substance Manufacturers (7/94)(/ICECI/Inspections/InspectionGuides/ucm074930.htm)•Topical Drug Products (7/94)(/ICECI/Inspections/InspectionGuides/ucm074933.htm)•Oral Solutions and Suspensions (8/94)(/ICECI/Inspections/InspectionGuides/ucm074935.htm)Foods & Cosmetics•Allergy Inspection Guide (4/01)(/ICECI/Inspections/InspectionGuides/ucm074944.htm)•Aseptic Processing and Packaging for the Food Industry(/ICECI/Inspections/InspectionGuides/ucm074946.htm)•Nutritional Labeling and Education Act (NLEA) Requirements (8/94 - 2/95)(/ICECI/Inspections/InspectionGuides/ucm074948.htm)•Computerized Systems in the Food Processing Industry(/ICECI/Inspections/InspectionGuides/ucm074955.htm)•Grain Product Manufacturers(/ICECI/Inspections/InspectionGuides/ucm074958.htm)•Guide to Produce Farm Investigations (11/05)(/ICECI/Inspections/InspectionGuides/ucm074962.htm)•Interstate Carriers and Support Facilities (4/95)(/ICECI/Inspections/InspectionGuides/ucm074964.htm)•Dairy Product Manufacturers (4/95)(/ICECI/Inspections/InspectionGuides/ucm074974.htm)•Miscellaneous Food Products - Vol. 1 (5/95)(/ICECI/Inspections/InspectionGuides/ucm074967.htm)•Miscellaneous Food Products - Vol. 2 (9/96)(/ICECI/Inspections/InspectionGuides/ucm074988.htm)•Low Acid Canned Food Manufacturers Part 1 - Adminstrative Procedures/Scheduled Processes (/ICECI/Inspections/InspectionGuides/ucm074992.htm)•Low Acid Canned Food Manufacturers Part 2 - Processes/Procedures (/ICECI/Inspections/InspectionGuides/ucm074995.htm)•Low Acid Canned Food Manufacturers Part 3 - Container/Closures (11/98)(/ICECI/Inspections/InspectionGuides/ucm074999.htm)•Acidified Food Manufacturers (/ICECI/Inspections/InspectionGuides/ucm075003.htm)•Guide to Traceback of Fresh Fruit and Vegetables Implicated in Epidemiological Investigations (/ICECI/Inspections/InspectionGuides/ucm075005.htm)•Samonella Enteritidis (SE) Guide to Traceback in Eggs (7/03)(/ICECI/Inspections/InspectionGuides/ucm075011.htm)[ARCHIVED]Miscellaneous•Foreign Medical Device Manufacturers (9/95)(/ICECI/Inspections/InspectionGuides/ucm075017.htm)•Foreign Pharmaceutical Manufacturers (5/96)(/ICECI/Inspections/InspectionGuides/ucm075021.htm)Inspection Technical Guides (/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/default.htm)More in Inspection Guides (/ICECI/Inspections/InspectionGuides/default.htm)。
FDA现场检查行业指南(中英文对照)
FDA行业指南-药品现场检查中被认为是延迟、否认、限制或拒绝的情形一、介绍2012年7月9日，《美国食品和药物管理局安全及创新法案》（FDASIA）被签署成为法律。
FDASIA章节707添加了501（j）到《食品、药品和化妆品法令》（FD&C Act），认为“任何从事生产、加工、包装或持有的生产企业、库房造成现场检查的延迟、否认、限制或拒绝的情况均被认为该产品为假劣药品”。
该指南的目的是对“延迟、否认、限制或拒绝”的情形进行定义。
二、定义1、延迟A、检查计划安排的延迟FDA将会根据当地的情况对检查计划进行适当的调整，例如天气、安保、节假日、其他非工作日、企业的生产计划等。
以下延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●企业不同意建议的检查日期，但没有合理的解释。
●在检查安排后，企业要求延迟检查日期，但没有合理的解释。
●企业不能回答为什么FDA联系不上企业指定的联系人。
下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业没有正在生产，例如每个月只生产一次，企业要求检查日期另定，以便FDA检查时生产正在进行中。
B、检查期间的延迟以下检查期间的延迟情况将会被认为产品是假劣药品，包括但不仅限于：●企业不允许FDA检查官进入某个区域直至一段时间过去之后，即使这个区域是正在进行操作的并且是FDA有权检查的区域，对于这种行为没有合理的解释。
●企业长时间把FDA检查官单独撂在会议室，没有相应的文件或责任人供审查和询问，从而干扰检查官完成其相应的检查。
下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业不允许FDA检查官进入无菌工艺区域，直至检查官能满足企业的无菌更衣程序要求。
C、记录提供延迟以下记录提供延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●在检查期间，FDA检查官要求在合理的时间内提供其有权查看的文件和记录，但是企业不能按时提供，且没有合理的解释。
FDA检查的注意事项
General considerations总体考虑
3. 总是陪同在审计官身边！ Always escort the inspector!
General considerations总体考虑
An inspector is someone who arrives after the battle and bayonets all the wounded ： 4. 有时检查官也会处于特殊情况下。他可能问自己这些问题 Consider that also the inspector is in an exceptional situation. He might ask himself the questions:
不希望引起审计官关注的事项 Unwanted attention 在车间和实验室里的行为 Behavior for the shop floor and laboratory 每个员工的行为 Behavior for everybody
General considerations总体考虑
1. 审计期间，对人际关系的应对。如果审计官不喜欢或喜 欢我们团队中的某一主要人员时，我们需要做一些内部 调整。如果审计官不喜欢你，你也不要生气或者觉得是 对自己的一种冒犯，团队会对人员做适当调整。 React to interpersonal relationships during the inspection. If the inspector dislikes / likes a key player of your team take appropriate internal actions. Don„t be offended if the inspector doesn't like you!
美国FDA分析方法验证指南中英文对照因文章太多平台分批发送
美国FDA分析方法验证指南中英文对照因文章太多平台分批发送I. INTRODUCTIONThis guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.1. 绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。
This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications.本指南旨在帮助申请者收集资料，递交样品并资料以支持分析方法。
这些建议适用于NDA，ANDA，BLA，PLA及其它们的补充中所涉及的原料药和制剂。
fda审计模型的六大内容
fda审计模型的六大内容FDA审计模型的六大内容引言随着食品和药物监管的不断深入以及对产品质量和安全的追求，FDA（美国食品药品监管局）审计模型成为了重要的工具。
本文将介绍FDA审计模型的六大内容，以帮助读者更好地了解和应用该模型。
1. 管理责任•组织管理：审计将关注食品和药物监管局的管理系统，包括结构和流程，以确保其有效性和透明度。
•风险管理：审计将评估企业对产品质量和安全风险的识别和管理程度，以及相关的预防、纠正措施。
2. 质量系统•质量政策：审计将确保企业有明确的质量政策，并且已经将其传达给所有员工。
•质量计划：审计将评估企业的质量计划，包括质量目标和相关的资源分配。
3. 设备、设施和环境•设备管理：审计将关注企业对设备的有效管理，包括校准、维修和保养等方面。
•设施和环境：审计将评估企业的生产环境是否符合相关要求，以及是否能够保证产品质量和安全。
4. 生产和过程控制•过程验证：审计将关注企业对生产过程的验证和确认，以确保产品符合标准。
•变更管理：审计将评估企业对生产过程变更的管理和控制程度。
5. 文档与记录•文件管理：审计将评估企业的文件管理系统，包括记录的创建、审查、批准和管理等方面。
•产品标识：审计将关注产品标识和标签的准确性和合规性。
6. 不合格品管理•不合格品处理：审计将评估企业对不合格品的处理和管理流程，包括不合格品的确认、隔离和处置等方面。
•报告和追踪：审计将关注企业对不合格品的报告和追踪，以及相关的改进措施。
结论FDA审计模型的六大内容为企业提供了一个全面评估和改进产品质量和安全的框架。
通过遵守和应用这些内容，企业能够有效管理质量风险，提高产品的标准和合规性。
因此，深入了解和掌握这些内容对于企业的持续发展至关重要。
FDA审计注意事项和技巧
识水平太差了，欠缺培训。
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审计须遵守的“十要”
要将你所提供的回应，全部整理归纳；
要做你或部门需作的事，讲你或部门所需讲的； 要确保所提供的资料或数据，在出示之前已被审核确认过； 要及时地给出正确的资料或信息； 要确保你及部门的区域干净整洁； 要及时解决和处理细小的问题，在检查员知道之前； 如果你没听懂所问的问题，首先要弄清楚问题再回答；
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文件和记录
仅提供检查员要看的文件资料；
所有递交给检查人员的文件，事先一定要尽可能经部门负责人快速检 查一遍（以免有纸条夹带或其他错误如漏签名等现象）； 慎重回答检查员对原始数据和各种记录所提出的问题（以免使检查员 产生有“程中人员注意事项
在检查人员到来之前，所有相关人员必须提前就位；
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办公场所迎检准备
严禁杂乱的记录、文件散放于桌面；
非受控及其他不可出示记录或文件需清理，受控文件需为现行版并有 目录，经整理后可存放至文件夹归档； 已开启的电脑桌面需进行清理，部分文件可备份至U盘后清除； 整理个人电脑桌面的私人邮箱或工作邮箱，不得呈开启状态，需加密 后关闭； 办公抽屉尽量减少或不存放与工作无关的私人物品。 保持办公墙面整洁，仅可悬挂日历等与工作无直接关联的物品。
在开始生产之前，对生产区和设备的卫生进行检查；
产品和物料要有防止微生物和其它污染源污染的措施； 进入生产区人数受控、使用物品受控，偏差受控制，中间过程受控制； 计算产量和收率，不一致的地方则要调查并解释； 签字确认关键步骤； 包装物或设备进入生产区之前，清除其上不适当的标签； 环境检测；
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各部门指定负责回答问题的人员要求
FDA：关于数据完整性指南十八问和实验室审计缺陷案例分析
FDA：关于数据完整性指南十八问和实验室审计缺陷案例分析2018年年底，FDA关于《数据完整性及CGMP合规指南》完成了定稿发布。
本指南澄清了数据完整性在21CFR210,211和212中所要求的现行药品生产质量管理规范中的作用，它提供了关于按照CGMP要求创建和处理数据的机构看法。
一般情况下，FDA指南文件不具有规定依法强制执行责任,它充许企业使用灵活和基于风险的策略预防和检测数据完整性问题。
本指南是实验室数据完整性的一个重要参考文献。
无论是官方认证、检查，还是客户审计，用它来指导实验室的准备工作可以更深入、更全面。
作为实验室人员，对于这份指南的理解也决定了技术人员掌握数据完整性和CGMP合规的程度。
本文摘录了这份指南的18个问题，具体的回答在原指南中可以查阅。
同时我们根据这份定稿的指南分析了FDA近两年检查的8个案例中关于实验室部分的缺陷，以飨读者，限于笔者水平有限，意见仅供参考。
FDA关于行业指南：数据完整性与药品CGMP合规的18个问题：1请澄清以下术语在用于CGMP记录时的含义。
2.什么时候允许宣布一个CGMP结果无效并在判定批合格时排除该结果？3.是否需要对计算机系统中的每个CGMP工作流均进行验证？4.应如何限制对CGMP计算机系统的访问？5.为什么FDA会关切使用共用计算机系统登录账号？6.空白表格要如何受控？7.审计追踪应由谁审核？8.审计追踪应多久审核一次？9.电子副本是否可用作电子或纸质记录的准确复制本？10.是否可以将单机版计算机化实验室仪器，如FT/R仪器中的原始电子记录保存为纸质打印件或静态记录？11.主生产和检验记录中是否可使用电子签名替代手动签名？12.电子数据何时成为一份CGMP记录？13.为什么FDA在警告信中将“系统适用性”或检测、准备或系统平衡运行中使用实际样品作为缺陷？14.是否可以只保存重新处理后的实验室色谱图得到的最终结果？15.是否可以在书面CGMP质量体系以外以非正式方式处理内部提醒或关于质量问题的信息,如潜在数据造假问题？16.是否要将防止和发现数据完整性问题培训作为常规CGMP培训计划的一部分？17.是否应允许FDA查看电子记录？18.FDA建议如何解决数据完整性问题？案例1公司：BayerPharmaAG地点：德国检查官：JustinA.BoydQC缺陷一：没有保存和复核所有的检测记录。
FDA审计指南
21CFR Part 11
Clause #
Question
Yes
No
Comments
11.10 (a)
Is the system validated?
11.10 (a)
Is it possible to distinguish invalid or altered records?
System Assessment Report
<System Name>
Position
Signature
Date
Position
Signature
Date
Result
Review Performed by
Pass / Fail *
Pass / Fail *
* Circle as appropriate
11.300 (b)
Are procedures in place to ensure that the validity of identification codes is periodically checked?
11.300 (b)
Do passwords expire and need to be revised?
11.300 (b)
Is there a procedure for electronically recalling identification codes and passwords if a person leaves or is transferred?
4.Electronic Signatures (General)
FDA审计注意事项和技巧
严禁杂乱的记录、文件散放于桌面；
非受控及其他不可出示记录或文件需清理，受控文件需为现行版并有 目录，经整理后可存放至文件夹归档； 已开启的电脑桌面需进行清理，部分文件可备份至U盘后清除； 整理个人电脑桌面的私人邮箱或工作邮箱，不得呈开启状态，需加密 后关闭； 办公抽屉尽量减少或不存放与工作无关的私人物品。 保持办公墙面整洁，仅可悬挂日历等与工作无直接关联的物品。
仅就问题而答，只要拿所需资料；
要非常熟悉你的现场和档案资料； 要快速提供关键的文件档案。
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审计须遵守的“十不要”
1、不要猜测。如果你不是最适合的人选，你就不要回答；
2、不要胡聊。确保你的回答简明而正确； 3、不要被检查人员干扰，保持平静和有序的心态完成； 4、不要显得没有信心，吞吞吐吐； 5、不要说谎或回避； 6、不要给出不可能获得支持的承诺； 7、不要首先申辩而后回应； 8、不要提供虚假的数据或信息； 9、不要违反SOP， 同时也不许检查人员违反； 10、不要提供与本次认证无关的同类资料给检查人员。
液相、气相等工作站的电脑在不使用时需要锁屏，可以设置自动锁屏
。
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质量体系迎检关注点
产品年度回顾及时完整、总结具有条理性，对不良趋势进行论述；
审计：GMP自检，对供应商的审计和药政部门按规定检查的资料及 整改报告； 变更控制； 投诉； 偏差管理； 产品放行； 返工、再加工管理； SOP 管理； 各级人员资质、培训。
避免交叉污染，定期有效的检查，SOP及相关记录；
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生产现场检查时关注点
避免灰尘产生和传播，通风或净化措施的处理； 生产前要经过批准（有生产指令）；
中间产品和待包装品：储存条件符合，标识和标签齐全；
fda临床试验现场审计流程
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FDA QC实验室审计
U.S. Food and Drug AdministrationProtecting and Promoting Your Health Pharmaceutical Quality Control Labs (7/93)GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIESNote: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, orimmunities for or on any person(s).1. INTRODUCTIONThe pharmaceutical quality control laboratory serves one of the most important functions in pharmaceutical production and control. A significant portion of the CGMP regulations (21 CFR 211) pertain to the quality control laboratory and product testing. Similar concepts apply to bulk drugs.This inspection guide supplements other inspectional information contained in other agency inspectional guidance documents. For example, Compliance Program 7346.832 requiring pre-approval NDA/ANDA inspections contains general instructions to conduct product specific NDA/ANDA inspection audits to measure compliance with the applications and CGMP requirements. This includes pharmaceutical laboratories used for in-process and finished product testing.2. OBJECTIVEThe specific objective will be spelled out prior to the inspection. The laboratory inspection may be limited to specific issues, or the inspection may encompass a comprehensive evaluation of the laboratory's compliance with CGMP's. As a minimum, each pharmaceutical quality control laboratory should receive a comprehensive GMP evaluation each two years as part of the statutory inspection obligation.In general these inspections may include- the specific methodology which will be used to test a new product- a complete assessment of laboratory's conformance with GMP's- a specific aspect of laboratory operations3. INSPECTION PREPARATIONFDA Inspection Guides are based on the team inspection approach and our inspection of a laboratory is consistent with this concept. As part of our effort to achieve uniformity and consistency in laboratory inspections, we expect that complex, highly technical and specialized testing equipment, procedures and data manipulations, as well as scientific laboratory operations will be evaluated by an experienced laboratory analyst with specialized knowledge in such matters.District management makes the final decision regarding the assignment of personnel to inspections. Nevertheless, we expect investigators, analysts and others to work as teams and to advise management when additional expertise is required to complete a meaningful inspection.Team members participating in a pre-approval inspection must read and be familiar with Compliance Program 7346.832, Pre-Approval Inspections/Investigations. Relevant sections of the NDA or ANDA should be reviewed prior to the inspection; but if the application is not available from any other source, this review will have to be conducted using the company's copy of the application.Team members should meet, if possible, prior to the inspection to discuss the approach to the inspection, to define the roles of the team members, and to establish goals for completion of the assignment. Responsibilities for development of all reports should also be established prior to the inspection. This includes the preparation of the FDA 483.The Center for Drug Evaluation and Research (CDER) may have issued deficiency letters listing problems that the sponsor must correct prior to the approval of NDA/ANDA's and supplements. The inspection team is expected to review such letters on file at the district office, and they are expected to ask the plant for access to such letters. The team should evaluate the replies to these letters to assure that the data are accurate and authentic. Complete the inspection even though there has been no response to these letters or when the response is judged inadequate.4. INSPECTION APPROACHA. GeneralIn addition to the general approach utilized in a drug CGMP inspection, the inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with CGMP's and to specifically carry out the commitments in an application or DMF. When conducting a comprehensive inspection of a laboratory, all aspects of the laboratory operations will be evaluated. Laboratory records and logs represent a vital source of information that allows a complete overview of the technical ability of the staff and of overall quality control procedures. SOPs should be complete and adequate and the operations of the laboratories should conform to the written procedures. Specifications and analytical procedures should be suitable and, as applicable, in conformance with application commitments and compendial requirements. Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipment,including maintenance and calibration, and methods validation data to determine the overall quality of the laboratory operation and the ability to comply with CGMP regulations. Examine chromatograms and spectra for evidence of impurities, poor technique, or lack of instrument calibration.Most manufacturers use systems that provide for the investigation of laboratory test failures. These are generally recorded in some type of log. Ask to see results of analyses for lots of product that have failed to meet specifications and review the analysis of lots that have been retested, rejected, or reworked. Evaluate the decision to release lots of product when the laboratory results indicate that the lot failed to meet specifications and determine who released them.B. Pre-ApprovalDocuments relating to the formulation of the product, synthesis of the bulk drug substance, product specifications, analysis of the product, and others are examined during the review process in headquarters. However, these reviews and evaluations depend on accurate and authentic data that truly represents the product.Pre-approval inspections are designed to determine if the data submitted in an application are authentic and accurate and if the procedures listed in the application were actually used to produce the data contained in the application. Additionally, they are designed to confirm that plants (including the quality control laboratory) are in compliance with CGMP regulations. The analytical sections of drug applications usually contain only test results and the methods used to obtain them. Sponsors are not required to file all the test data because such action would require voluminous submissions and would often result in filing redundant information. Sponsors may deliberately or unintentionally select and report data showing that a drug is safe and effective and deserves to be approved. The inspection team must decide if there is valid and scientific justification for the failure to report data which demonstrates the product failed to meet its predetermined specifications.Coordination between headquarters and the field is essential for a complete review of the application and the plant. Experienced investigators and analysts may contact the review chemist (with appropriate supervisory concurrence) when questions concerning specifications and standards arise.Inspections should compare the results of analyses submitted with results of analysis of other batches that may have been produced. Evaluate the methods and note any exceptions to the procedures or equipment actually used from those listed in the application and confirm that it is the same method listed in the application. The analyst is expected to evaluate raw laboratory data for tests performed on the test batches (biobatches and clinical batches) and to compare this raw data to the data filed in the application.5. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTSEvaluate the company's system to investigate laboratory test failures. These investigations represent a key issue in deciding whether a product may be released or rejected and form the basis for retesting, and resampling.In a recent court decision the judge used the term "out-of-specification" (OOS) laboratory result rather than the term "product failure" which is more common to FDA investigators and analysts. He ruled that an OOS result identified as a laboratory error by a failure investigation or an outlier test. The court provided explicit limitations on the use of outlier tests and these are discussed in a later segment of this document., or overcome by retesting. The court ruled on the use of retesting which is covered in a later segment of this document. is not a product failure. OOS results fall into three categories:- laboratory error- non-process related or operator error- process related or manufacturing process errorA. LABORATORY ERRORSLaboratory errors occur when analysts make mistakes in following the method of analysis, use incorrect standards, and/or simply miscalculate the data. Laboratory errors must be determined through a failure investigation to identify the cause of the OOS. Once the nature of the OOS result has been identified it can be classified into one of the three categories above. The inquiry may vary with the object under investigation.B. LABORATORY INVESTIGATIONSThe exact cause of analyst error or mistake can be difficult to determine specifically and it is unrealistic to expect that analyst error will always be determined and documented. Nevertheless, a laboratory investigation consists of more than a retest. The inability to identify an error's cause with confidence affects retesting procedures, not the investigation inquiry required for the initial OOS result.The firm's analyst should follow a written procedure, checking off each step as it is completed during the analytical procedure. We expect laboratory test data to be recorded directly in notebooks; use of scrap paper and loose paper must be avoided. These common sense measures enhance the accuracy and integrity of data.Review and evaluate the laboratory SOP for product failure investigations. Specific procedures must be followed when single and multiple OOS results are investigated. For the single OOS result the investigation should include the following steps and these inquiries must be conducted before there is a retest of the sample:- the analyst conducting the test should report the OOS result to the supervisor- the analyst and the supervisor should conduct an informal laboratory investigation which addresses the following areas:1. discuss the testing procedure2. discuss the calculation3. examine the instruments4. review the notebooks containing the OOS resultAn alternative means to invalidate an initial OOS result, provided the failure investigation proves inconclusive, is the "outlier" test. However, specific restrictions must be placed on the use of this test.1. Firms cannot frequently reject results on this basis.2. The USP standards govern its use in specific cases only.3. The test cannot be used for chemical testing results. An initial content uniformity test was OOS followed by a passing retest. The initial OOS result was claimed the result of analyst error based on a statistical evaluation of the data. The court ruled that the use of an outlier test is inappropriate in this case..4. It is never appropriate to utilize outlier tests for a statistically based test, i.e., content uniformity and dissolution.Determine if the firm uses an outlier test and evaluate the SOP.Determine that a full scale inquiry has been made for multiple OOS results. This inquiry involves quality control and quality assurance personnel in addition to laboratory workers to identify exact process or non process related errors.When the laboratory investigation is inconclusive (reason for the error is not identified) the firm:1. Cannot conduct 2 retests and base release on average of three tests2. Cannot use outlier test in chemical tests3. Cannot use a re-sample to assume a sampling or preparation error4. Can conduct a retest of different tablets from the same sample when a retest is considered appropriate (see criteria elsewhere)C. FORMAL INVESTIGATIONSFormal investigations extending beyond the laboratory must follow an outline with particular attention to corrective action. The company must:1. State the reason for the investigation2. Provide summation of the process sequences that may have caused the problem3. Outline corrective actions necessary to save the batch and prevent similar recurrence4. List other batches and products possibly affected, the results of investigation of these batches and products, and any corrective action. Specifically:- examine other batches of product made by the errant employee or machine- examine other products produced by the errant process or operation5. Preserve the comments and signatures of all production and quality control personnel who conducted the investigation and approved any reprocessed material after additional testing D. INVESTIGATION DOCUMENTATIONAnalyst's mistakes, such as undetected calculation errors, should be specified with particularity and supported by evidence. Investigations along with conclusions reached must be preserved with written documentation that enumerates each step of the investigation. The evaluation, conclusion and corrective action, if any, should be preserved in an investigation or failure report and placed into a central file.E. INVESTIGATION TIME FRAMESAll failure investigations should be performed within 20 business days of the problem's occurrence and recorded and written into a failure or investigation report.6. PRODUCT FAILURESAn OOS laboratory result can be overcome (invalidated) when laboratory error has been documented. However, non-process and process related errors resulting from operators making mistakes, equipment (other than laboratory equipment) malfunctions, or a manufacturing process that is fundamentally deficient, such as an improper mixing time, represent product failures.Examine the results of investigations using the guidance in section 5 above and evaluate the decision to release, retest, or rework products.7. RETESTINGEvaluate the company's retesting SOP for compliance with scientifically sound and appropriate procedures. A very important ruling in one recent court decision sets forth a procedure to govern the retesting program.This district court ruling provides an excellent guide to use in evaluating some aspects of a pharmaceutical laboratory, but should not be considered as law, regulation or binding legal precedent. The court ruled that a firm should have a predetermined testing procedure and it should consider a point at which testing ends and the product is evaluated. If results are not satisfactory, the product is rejected. Additionally, the company should consider all retest results in the context of the overall record of the product. This includes the history of the product. The court ordered a recall of one batch of product on the basis of an initial content uniformity failure and no basis to invalidate the test result and on a history of content uniformity problems with the product., type of test performed, and in-process test results. Failing assay results cannot be disregarded simply on the basis of acceptable content uniformity results.The number of retests performed before a firm concludes that an unexplained OOS result is invalid or that a product is unacceptable is a matter of scientific judgment. The goal of retesting is to isolate OOS results but retesting cannot continue ad infinitum.In the case of nonprocess and process-related errors, retesting is suspect. Because the initial tests are genuine, in these circumstances, additional testing alone cannot contribute to product quality. The court acknowledged that some retesting may precede a finding of nonprocess or process-based errors. Once this determination is made, however, additional retesting for purposes of testing a product into compliance is not acceptable.For example, in the case of content uniformity testing designed to detect variability in the blend or tablets, failing and non-failing results are not inherently inconsistent and passing results on limited retesting do not rule out the possibility that the batch is not uniform. As part of the investigation firms should consider the record of previous batches, since similar or related failures on different batches would be a cause of concern.Retesting following an OOS result is ruled appropriate only after the failure investigation is underway and the failure investigation determines in part whether retesting is appropriate. It is appropriate when analyst error is documented or the review of analyst's work is "inconclusive" , but it is not appropriate for known and undisputed non-process or process related errors. The court ruled that retesting:- must be done on the same, not a different sample- may be done on a second aliquot from the same portion of the sample that was thesource of the first aliquot- may be done on a portion of the same larger sample previously collected for laboratory purposes8. RESAMPLINGFirms cannot rely on resampling. The court ordered the recall of one batch of product after having concluded that a successful resample result alone cannot invalidate an initial OOS result. to release a product that has failed testing and retesting unless the failure investigation discloses evidence that the original sample is not representative or was improperly prepared. Evaluate each resampling activity for compliance with this guidance.9. AVERAGING RESULTS OF ANALYSISAveraging can be a rational and valid approach when the object under consideration is total product assay, but as a general rule this practice should be avoided. The court ruled that the firm must recall a batch that was released for content uniformity on the basis of averaged test results. because averages hide the variability among individual test results. This phenomenon is particularly troubling if testing generates both OOS and passing individual results which when averaged are within specification. Here, relying on the average figure without examining and explaining the individual OOS results is highly misleading and unacceptable. Content uniformity and dissolution results never should be averaged to obtain a passing value. In the case of microbiological turbidimetric and plate assays an average is preferred by the USP. In this case, it is good practice to include OOS results in the average unless an outlier test (microbiological assays) suggests the OOS is an anomaly.10. BLEND SAMPLING AND TESTINGThe laboratory serves a vital function in blend testing which is necessary to increase the likelihood of detecting inferior batches. Blend uniformity testing cannot be waived in favor of total reliance on finished product testing because finished product testing is limited.One court has ruled that sample size influences ultimate blend test results and that the sample size should resemble the dosage size. Any other practice would blur differences in portions of the blend and defeat the object of the test. If a sample larger than the unit must be taken initially, aliquots which resemble the dosage size should be carefully removed for the test, retests, and reserve samples. Obviously, the initial larger sample should not be subjected to any additional mixing or manipulation prior to removing test aliquots as this may obscure non-homogeneity.Multiple individual blend uniformity samples taken from different areas cannot be composited. However when variation testing is not the object of assay testing, compositing is permitted. If firms sample product from sites other than the blender, they must demonstrate through validation that their sampling technique is representative of all portions and concentrations of the blend. This means that the samples must be representative of those sites that might be problems; e.g. weak or hot spots in the blend.11. MICROBIOLOGICALThe review of microbiological data on applicable dosage forms is best performed by the microbiologist (analyst). Data that should be reviewed include preservative effectiveness testing, bioburden data, and product specific microbiological testing and methods. Review bioburden (before filtration and/or sterilization) from both an endotoxin and sterility perspective. For drug substance labs evaluate methods validation and raw data for sterility, endotoxin testing, environmental monitoring, and filter and filtration validation. Also, evaluate the methods used to test and establish bioburdens.Refer to the Microbiological Inspection Guide for additional information concerning the inspection of microbiological laboratories.12. SAMPLINGSamples will be collected on pre-approval inspections. Follow the sampling guidelines in CP 7346.832, Part III, pages 5 and 6.13. LABORATORY RECORDS AND DOCUMENTATIONReview personal analytical notebooks kept by the analysts in the laboratory and compare them with the worksheets and general lab notebooks and records. Be prepared to examine all records and worksheets for accuracy and authenticity and to verify that raw data are retained to support the conclusions found in laboratory results.Review laboratory logs for the sequence of analysis versus the sequence of manufacturing dates. Test dates should correspond to the dates when the sample should have been in the laboratory. If there is a computer data base, determine the protocols for making changes to the data. There should be an audit trail for changes to data.We expect raw laboratory data to be maintained in bound, (not loose or scrap sheets of paper), books or on analytical sheets for which there is accountability, such as prenumbered sheets. For most of those manufacturers which had duplicate sets of records or "raw data", non-numbered loose sheets of paper were employed. Some companies use discs or tapes as raw data and for the storage of data. Such systems have also been accepted provided they have been defined (with raw data identified) and validated.Carefully examine and evaluate laboratory logs, worksheets and other records containing the raw data such as weighings, dilutions, the condition of instruments, and calculations. Note whether raw data are missing, if records have been rewritten, or if correction fluid has been used to conceal errors. Results should not be changed without explanation. Cross reference the data that has been corrected to authenticate it. Products cannot be "tested into compliance" by arbitrarily labeling out-of-specification lab results as "laboratory errors" without an investigation resulting in scientifically valid criteria.Test results should not have been transcribed without retention of the original records, nor should test results be recorded selectively. For example, investigations have uncovered the use of loose sheets of paper with subsequent selective transcriptions of good data to analyst worksheets and/or workbooks. Absorbance values and calculations have even been found on desk calendars.Cut charts with injections missing, deletion of files in direct data entry systems, indirect data entry without verification, and changes to computerized programs to override program features should be carefully examined. These practices raise questions about the overall quality of data. The firm should have a written explanation when injections, particularly from a series are missing from the official work-sheets or from files and are included among the raw data. Multiple injections recorded should be in consecutive files with consecutive injection times recorded. Expect to see written justification for the deletion of all files. Determine the adequacy of the firm's procedures to ensure that all valid laboratory data are considered by the firm in their determination of acceptability of components, in-process, finished product, and retained stability samples. Laboratory logs and documents when cross referenced may show that data has been discarded by company officials who decided torelease the product without a satisfactory explanation of the results showing the product fails to meet the specifications. Evaluate the justification for disregarding test results that show the product failed to meet specifications.14. LABORATORY STANDARD SOLUTIONSAscertain that suitable standards are being used (i.e. in-date, stored properly). Check for the reuse of stock solutions without assuring their stability. Stock solutions are frequently stored in the laboratory refrigerator. Examine the laboratory refrigerators for these solutions and when found check for appropriate identification. Review records of standard solution preparation to assure complete and accurate documentation. It is highly unlikely that a firm can "accurately and consistently weigh" to the same microgram. Therefore data showing this level of standardization or pattern is suspect and should be carefully investigated.15. METHODS VALIDATIONInformation regarding the validation of methods should be carefully evaluated for completeness, accuracy and reliability. In particular, if a compendial method exists, but the firm chooses to use an alternate method instead, they must compare the two and demonstrate that the in-house method is equivalent or superior to the official procedure. For compendial methods firms must demonstrate that the method works under the actual conditions of use. Methods can be validated in a number of ways. Methods appearing in the USP are considered validated and they are considered validated if part of an approved ANDA. Also a company can conduct a validation study on their method. System suitability data alone is insufficient for and does not constitute method validation.In the review of method validation data, it is expected that data for repetitive testing be consistent and that the varying concentrations of test solutions provide linear results. Many assay and impurity tests are now HPLC, and it is expected that the precision of these assays be equal or less than the RSD's for system suitability testing. The analytical performance parameters listed in the USP XXII, <1225>, under the heading of Validation of Compendial Methods, can be used as a guide for determining the analytical parameters (e.g., accuracy, precision, linearity, ruggedness, etc.) needed to validate the method.16. EQUIPMENTLaboratory equipment usage, maintenance, calibration logs, repair records, and maintenance SOPs also should be examined. The existence of the equipment specified in the analytical methods should be confirmed and its condition noted. Verify that the equipment was present and in good working order at the time the batches were analyzed. Determine whether equipment is being used properly.In addition, verify that the equipment in any application was in good working order when it was listed as used to produce clinical or biobatches. One would have to suspect the data that are generated from a piece of equipment that is known to be defective. Therefore, continuing to use and release product on the basis of such equipment represents a serious violation of CGMP's.17. RAW MATERIAL TESTINGSome inspections include the coverage of the manufacturer of the drug substance. The safety and efficacy of the finished dosage form is largely dependent on the purity and quality of the bulk active drug substance. Examine the raw data reflecting the analysis of the drug substance including purity tests, charts, etc.。