FDA 审计指南
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
fda临床试验现场审计流程下载温馨提示:该文档是我店铺精心编制而成，希望大家下载以后，能够帮助大家解决实际的问题。
文档下载后可定制随意修改，请根据实际需要进行相应的调整和使用，谢谢!并且，本店铺为大家提供各种各样类型的实用资料，如教育随笔、日记赏析、句子摘抄、古诗大全、经典美文、话题作文、工作总结、词语解析、文案摘录、其他资料等等，如想了解不同资料格式和写法，敬请关注!Download tips: This document is carefully compiled by theeditor. I hope that after you download them,they can help yousolve practical problems. The document can be customized andmodified after downloading,please adjust and use it according toactual needs, thank you!In addition, our shop provides you with various types ofpractical materials,such as educational essays, diaryappreciation,sentence excerpts,ancient poems,classic articles,topic composition,work summary,word parsing,copy excerpts,other materials and so on,want to know different data formats andwriting methods,please pay attention!FDA（美国食品药品监督管理局）对临床试验的现场审计是为了确保临床试验的质量和合规性。
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.。
FDA清洁验证审计指南
Validation of Cleaning Processes(7/93)SHARETWEETLINKEDINPIN ITMORE SHARING OPTIONSLINKEDINPIN ITEMAILPRINTGUIDE TO INSPECTIONS VALIDATION OF CLEANINGPROCESSESNote: This document is reference material for investigators and other FDApersonnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).I. INTRODUCTIONValidation of cleaning procedures has generated considerable discussionsince agency documents, including the Inspection Guide for BulkPharmaceutical Chemicals and the Biotechnology Inspection Guide, havebriefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable).Simultaneously, one must recognize that for cleaning validation, as withvalidation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientificdata shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.This guide is intended to cover equipment cleaning for chemical residuesonly.II. BACKGROUNDFor FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shallbe maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to preventcontamination or adulteration of drug products. Historically, FDAinvestigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipme nt an d/or poor dust con trol systems. Also,historically speak ing, FDA was more concerned about the con tam in ati onof nonpenicillin drug products with penicillins or the cross-contamination ofdrug products with pote nt steroids or horm on es. A nu mber of productshave bee n recalled over the past decade due to actual or pote ntial peni cilli n cross-c on tam in ati on.One eve nt which in creased FDA aware ness of the pote ntial for cross con tam in ati on due to in adequate procedures was the 1988 recall of afinished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become con tam in ated with low levels of in termediates and degrada nts from the producti on of agricultural pesticides. The cross-c on tam in ati on in that case is believed to have bee n due to the reuse of recovered solve nts. The recovered solve nts had bee n con tam in ated because of a lack of con trol over the reuse of solve ntdrums. Drums that had bee n used to store recovered solve nts from apesticide producti on process were later used to store recovered solve ntsused for the res in manu facturi ng process. The firm did not have adequate con trols over these solve nt drums, did not do adequate testi ng ofdrummed solve nts, and did not have validated clea ning procedures for the drums.Some shipme nts of this pesticide con tam in ated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers withpesticide contamination. This in turn led to cross contamination of lotsproduced at that site, a site where no pesticides were no rmally produced.FDA instituted an import alert in 1992 on a foreign bulk pharmaceuticalmanu facturer which manu factured pote nt steroid products as well as non-steroidal products using com mon equipme nt. This firm was a multi-usebulk pharmaceutical facility. FDA con sidered the pote ntial for cross-contamination to be significant and to pose a serious health risk to thepublic. The firm had only recently started a cleaning validation program atthe time of the in spect ion and it was con sidered in adequate by FDA. One of the reas ons it was con sidered in adequate was that the firm was onlylook ing for evide nee of the abse nee of the previous compo und. The firm had evidenee, from TLC tests on the rinse water, of the presence ofresidues of react ion byproducts and degrada nts from the previous process. III. GENERAL REQUIREMENTSFDA expects firms to have writte n procedures (SOP's) detaili ng the cleaning processes used for various pieces of equipme nt. If firms have one clea ning process for clea ning betwee n differe nt batches of the same productand use a differe nt process for clea ning betwee n product cha nges, weexpect the written procedures to address these different scenario. Similarly, if firms have one process for rem oving water soluble residues and ano ther process for non-water soluble residues, the writte n procedure shouldaddress both sce narios and make it clear whe n a give n procedure is to be followed. Bulkpharmaceutical firms may decide to dedicate certa in equipme nt for certa in chemical manu facturi ng process steps that produce tarry or gummyresidues that are difficult to remove from the equipment. Fluid bed dryerbags are ano ther example of equipme nt that is difficult to clea n and is ofte n dedicated to a specific product. Any residues from the clea ning processitself (detergents, solvents, etc.) also have to be removed from the equipme nt.FDA expects firms to have writte n gen eral procedures on how clea ningprocesses will be validated.FDA expects the gen eral validati on procedures to address who is resp onsible for perform ing and appro ving the validati on study, the acceptancecriteria, and when revalidation will be required.FDA expects firms to prepare specific writte n validati on protocols in advance for the studies to be performed on each manu facturi ng system or piece of equipme nt which should address such issues as sampli ng procedures,and an alytical methods to be used in clud ing the sen sitivity of thosemethods. FDA expects firms to con duct the validati on studies in accordance with the protocols and to docume nt the results of studies.FDA expects a final validati on report which is approved by man ageme ntand which states whether or not the clea ning process is valid. The datashould support a con clusi on that residues have bee n reduced to an"acceptable level."IV.EVALUATION OF CLEANING VALIDATIONThe first step is to focus on the objective of the validation process, and wehave see n that some compa nies have failed to develop such objectives. It is not unu sual to see manu facturers use exte nsive sampli ng and testi ngprograms follow ing the clea ning process without ever really evaluati ng the effective ness of the steps used to clea n the equipme nt. Several questi ons n eed to be addressed whe n evaluat ing the clea ning process. Forexample, at what point does a piece of equipme nt or system become clean? Does it have to be scrubbed by hand? What is accomplished by handscrubb ing rather tha n just a solve nt wash? How variable are manual cleaning processes from batch to batch and product to product? The an swers to these questions are obviously important to the inspection and evaluation ofthe clea ning process since one must determ ine the overall effective ness of the process. An swers to these questi ons may also ide ntify steps that canbe elimi nated for more effective measures and result in resource sav ingsfor the compa ny.Determ ine the nu mber of clea ning processes for each piece of equipme nt.Ideally, a piece of equipment or system will have one process for cleaning,however this will depe nd on the products being produced and whether theclea nup occurs betwee n batches of the same product (as in a largecampaig n) or betwee n batches of differe nt products. Whe n the clea ningprocess is used only betwee n batches of the same product (or differe nt lotsof the same in termediate in a bulk process) the firm n eed only meet a criteria of, "visibly clea n" for the equipme nt. Such betwee n batch clea ning processes do not require validati on.1. Equipme nt Desig nExam ine the desig n of equipme nt, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represe nt sig nifica nt concern. For example, sanitary type pip ing without ball valves should be used. Whe n suchnonsan itary ball valves are used, as is com mon in the bulk drug industry, the clea ning process is more difficult.When such systems are ide ntified, it is importa nt that operatorsperform ing clea ning operatio ns be aware of problems and havespecial trai ning in clea ning these systems and valves. Determ inewhether the clea ning operators have kno wledge of these systems and the level of training and experie nee in clea ning these systems. Alsocheck the writte n and validated clea ning process to determ ine if these systems have been properly identified and validated.In larger systems, such as those employi ng long tran sfer lines or pipi ng, check the flow charts and pip ing diagrams for the ide ntificati on of valves and writte n clea ning procedures. Pip ing and valves should be tagged and easily identifiable by the operator performing the cleaningfunction. Sometimes, in adequately ide ntified valves, both on prints and physically, have led to in correct clea ning practices.Always check for the prese nee of an ofte n critical eleme nt in thedocume ntati on of the clea ning processes; ide ntify ing and con troll ing the len gth of time betwee n the end of process ing and each clea ning step. This is especially importa nt for topicals, suspe nsions, and bulkdrug operations. In such operations, the drying of residues will directly affect the efficie ncy of a clea ning process.Whether or not CIP systems are used for clea ning of process ingequipme nt, microbiological aspects of equipme nt clea ning should be con sidered. This con sists largely of preve ntive measures rather tha n removal of con tam in ati on once it has occurred. There should besome evide nee that rout ine clea ning and storage of equipme nt does not allow microbial proliferation. For example, equipment should bedried before storage, and un der no circumsta nces should stag nantwater be allowed to rema in in equipme nt subseque nt to clea ningoperati ons.Subseque nt to the clea ning process, equipme nt may be subjected to sterilizati on or san itizati on procedures where such equipme nt is used for sterile process ing, or for non sterile process ing where the products may support microbial growth. While such sterilizatio n or san itizati on procedures are bey ond the scope of this guide, it is importa nt to note that con trol of the bioburde n through adequate clea ning and storageof equipme nt is importa nt to en sure that subseque nt sterilizati on orsanitization procedures achieve the necessary assuranee of sterility.This is also particularly important from the standpoint of the control ofpyroge ns in sterile process ing since equipme nt sterilizati on processes may not be adequate to achieve sig nifica nt in activati on or removal of pyroge ns.2. Clea ning Process Writte nProcedure and Docume ntati onExam ine the detail and specificity of the procedure for the (clea ning)process being validated, and the amount of docume ntati on required.We have see n gen eral SOPs, while others use a batch record or logsheet system that requires some type of specific docume ntati on forperform ing each step. Depe nding upon the complexity of the systemand cleaning process and the ability and training of operators, theamount of docume ntati on n ecessary for executi ng various clea ningsteps or procedures will vary.When more complex clea ning procedures are required, it is importa nt to docume nt the critical clea ning steps (for example certa in bulk drug syn thesis processes). I n this regard, specific docume ntati on on theequipme nt itself which in cludes in formati on about who clea ned it and when is valuable. However, for relatively simple cleaning operations, the mere docume ntati on that the overall clea ning process was performed might be sufficie nt.Other factors such as history of clea nin g, residue levels found aftercleaning, and variability of test results may also dictate the amount ofdocume ntati on required. For example, whe n variable residue levelsare detected follow ing clea ning, particularly for a process that isbelieved to be acceptable, one must establish the effective ness of the process and operator performa nee. Appropriate evaluati ons must bemade and whe n operator performa nee is deemed a problem, moreexte nsive docume ntati on (guida nee) and training may be required. 3. Analytical MethodsDetermine the specificity and sensitivity of the analytical method used to detect residuals or con tam inan ts. With adva nces in an alytical tech no logy, residues from the manu facturi ng and clea ning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual con tam inant prese nt after clea nin g. It only means that levels of con tam inant greaterthan the sensitivity or detection limit of the analytical method are notpresent in the sample. The firm should challenge the analytical method in comb in ati on with the sampli ng method(s) used to show that contam inants can be recovered from the equipme nt surface and at whatlevel, i.e. 50% recovery, 90%, etc. This is n ecessary before any conclusi ons can be made based on the sample results. A n egative testmay also be the result of poor sampli ng tech nique (see below).4. Sampli ngThere are two gen eral types of sampli ng that have bee n foundacceptable. The most desirable is the direct method of sampling thesurface of the equipme nt. Ano ther method is the use of rinse soluti ons.a. Direct Surface Sampli ng - Determi ne the type of samplingmaterial used and its impact on the test data since the sampli ngmaterial may in terfere with the test. For example, the adhesiveused in swabs has been found to interfere with the analysis ofsamples. Therefore, early in the validation program, it is importantto assure that the sampli ng medium and solve nt (used for extraction from the medium) are satisfactory and can be readily used.Advantages of direct sampling are that areas hardest to clean andwhich are reas on ably accessible can be evaluated, lead ing toestablish ing a level of con tam in ati on or residue per give nsurface area. Additi on ally, residues that are "dried out" or are insoluble can be sampled by physical removal.b.systems or ones that cannot be routi nely disassembled can besampled and evaluated.A disadva ntage of rinse samples is that the residue or con tam inantmay not be soluble or may be physically occluded in the equipme nt. An an alogy that can be used is the "dirty pot." In the evaluatio n of cleaning of a dirty pot, particularly with dried out residue, one does no t look at the rinse water to see that it is clea n; one looks at the pot.Check to see that a direct measureme nt of the residue or con tam inant has bee n made for the rinse water whe n it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.c. Rout ine Producti on In-Process Con trolMon itori ng - In direct test ing, such as con ductivity testi ng, may be of some value for rout ine mon itori ng once a clea ning process has bee n validated. This would be particularly true for the bulk drug substa neemanu facturer where reactors and cen trifuges and pip ing betwee nsuch large equipme nt can be sampled only using rinse soluti onsamples. Any in direct test method must have bee n show n to correlate with the condition of the equipment. During validation,the firm should docume nt that test ing the un clea ned equipme nt givesa not acceptable result for the in direct test.ESTABLISHMENT OF LIMITSFDA does not intend to set accepta nee specificati ons or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variati on in equipme nt and products used throughout the bulk and fini shed dosage form in dustries. The firm's rati on ale for the residue limitsestablished should be logical based on the manu facturer's kno wledge of the materials invo Ived and be practical, achievable, and verifiable. It is important to define the sensitivity of the an alytical methods in order to set reas on able limits. Some limits that have bee n men tio ned by in dustry represe ntatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and orga no leptic levels such as no visible residue.Check the manner in which limits are established. Uni ike fini shedpharmaceuticals where the chemical ide ntity of residuals are known (i.e., from actives, in actives, deterge nts) bulk processes may have partial reacta nts and unwan ted by-products which may n ever have bee n chemically identified. In establishing residual limits, it may not be adequate to focus only on the prin cipal reacta nt since other chemical variati ons may be more difficult to remove. There are circumsta nces where TLC scree ning, in additi on to chemical an alyses, may be n eeded. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products n eeds to be con sidered if equipme nt is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scie ntifically justifiable.OTHER ISSUESa. Placebo ProductIn order to evaluate and validate clea ning processes some manu facturers have processed a placebo batch in the equipme nt un der esse ntially the same operat ing parameters used for process ing product. A sample of the placebo batch is then tested for residual contamination. However, we have docume nted several sig nifica nt issues that n eed to be addressed whe n using placebo product to validate clea ning processes.One cannot assure that the con tam in ate will be uniformly distributedthroughout the system. For example, if the discharge valve or chute of a ble nder are con tam in ated, the con tam inant would probably not be uni formly dispersed in the placebo; it would most likely be concen trated in the in itial discharge portion of the batch. Additi on ally, if the con tam inant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo. V. VI.Some firms have made the assumpti on that a residual con tam inant would be worn off the equipme nt surface uniformly; this is also an inv alid con clusi on.Fin ally, the an alytical power may be greatly reduced by diluti on of the contam in ate. Because of such problems, rinse an d/or swab samples should beused in conj un cti on with the placebo method.b. Deterge ntIf a deterge nt or soap is used for clea ning, determ ine and con sider thedifficulty that may arise whe n attempti ng to test for residues. A com monproblem associated with deterge nt use is its compositi on. Many deterge ntsuppliers will not provide specific compositi on, which makes it difficult for theuser to evaluate residues. As with product residues, it is importa nt and it isexpected that the manu facturer evaluate the efficie ncy of the clea ningprocess for the removal of residues. However, un like product residues, it isexpected that no (or for ultra sen sitive an alytical test methods - very low)deterge nt levels remai n after clea ning. Deterge nts are not part of the manufacturi ng process and are only added to facilitate clea ning duri ng the cleaning process. Thus, they should be easily removable. Otherwise, a differe ntdeterge nt should be selected.c. Test Until CleanExamine and evaluate the level of testing and the retest results since testinguntil clean is a concept utilized by some manufacturers. They test, resample,and retest equipme nt or systems un til an "acceptable" residue level isattained. For the system or equipment with a validated clea ning process, thispractice of resampli ng should not be utilized and is acceptable only in rarecases. Constant retesting and resampling can show that the clea ning processis not validated since these retests actually docume nt the prese nee of unacceptable residue and con tam inants from an in effective clea ning process.REFERENCES0. J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of Wisc VII.onsin's Con trol Procedures in Drug Productio n Sem inar, July 17-22, 1966,William Blockstein, Editor, Published by the University of Wisco nsi n,L.O.C.#66-64234.1. J.A. Constanee, "Why Some Dust Control Exhaust Systems Don't Work,"Pharm. Eng., January-February, 24-26 (1983).2. S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8 (5),29-34 (1984)3. W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng.7(3), 29-33 (1987).4. J.A. Smith, "A Modified Swabb ing Tech ni que for Validati on of Deterge ntResidues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).5. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptanee Limits for Pharmaceutical Manu facturi ng Operati on s," Pharm. Tech nol.17(4), 54-60 (1993).6. McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2ndEd., edited by I.R. Berry and R.A. Nash, 319-349 (1993)。
FDA审计详细(含接待)工作计划
培训体系的介绍 （特别是、的培训是否齐全）
谁放行？放行的条件？如何放行？
文件管理体系介绍，文件分类，文件如何编码？文件发放和回收的控制？公司及质量部门的组织机 构和岗位职责。
公司总的验证分类和管理 （设备确认、工艺验证、清洁验证）；要保证SOP和验证报告及上报的数 据保持一致；要将验证报告对应的成品、中间体、原辅料检验记录全套保存在备战室；清洁验证要 准确回答化学残留计算依据和依据；设备确认要注意拿到的要和工艺验证前确认的编号一致 （VR\IQ\OQ\PQ) 对外部供应商的审计计划和管理，审计情况的追踪
文件 14.使用后的包装材料存放位置正确 15.防虫灭鼠器具配置齐全 16.停运设备或设施标示明确 17.原料摆放、防虫防鼠、紫外灯、门帘、空气帘、粘鼠板、出入库卡、称重
、阴凉库 计量器具（称）的校验、标准法码、定期校验、记录。 18.周转桶的清洗记录 19包装材料的明细账
负责人
各区域 负责人 自查
21.仪器确认及维修、数据备份（SOP及 记录）
23.稳定性管理、留样管理(我们按单装配， 不适用 无样品)
25.过去3年产品的批记录审核
27.质量标准（原料、包材、中间体、成 品）
29.不合格品管理的SOP及清单
18.投诉/退货/CAPA的SOP及例子
20.培训SOP/培训计划/记录/档案 22.方法验证、标准品及标准溶液使用管理规定 不适用
4.带有关键工艺参数和中控点 的工艺流程图
6.SOP清单和产品清单
7、彩色PPபைடு நூலகம்五套
8、参加首次会议的人名单（姓名、职务、联系方式）
负责人 见前面几张PPT安排
首次会议审计官指定要看的文件准备：如果是马上要看的文件，要在10~15分 钟内拿到现场；如果不是马上看，相关人员准备好，等现场看完后提供。
美国FDA药品质量控制实验室检查指南1 9 9 3年
评价公司复检的标准操作规程是否依照了科学上正确、适宜的程序。最近的一次法庭判决所做出的重要裁决提供了一套程序用来指导复检工程。这项地方法院的裁决为评价药品实验室的某些方面提供了出色的指导，但该裁决尚不能被视为法律、法规或有约束力的法律判例。法庭认为公司应具备一套预先确定的检验程序，应确定检验终止和产品评估的时间，如果结果不令人满意，产品将被拒收。
企业总部与生产现场的协调一致对完成药物申请和药厂的全面审查是必不可少的。当发现有关规格和标准的问题时，有经验的凋查人员和分析人员可以同参加审查的化学家联系(由适宜的主管人员协助)。
检查时应将提交的分析结果与所生产的其他批次的分析结果比拟。评价这些方法并且注意实际使用的程序或设备与申请中所列的程序和设备有无例外，要进—步证实申请中所列的方法与实际用的方法是相同的。希望分析人员评价对参检批次(小试与临床试验样品)所检验
4
A.总那么
除了采用对药品进行现行药品生产质量管理标准的—般检查方法之外，对实验室的检查还要采用观察实验操作和检查原始数据的方法，以评价其符合现行药品生产质量管理标准的情况，以及实现申请书中或者药品工艺档案中约定的义务。对实验室进行综合检查时，应评价实验室操作的各个方面。
实验室记录和实验记录本是不可缺少的资料来源，从这些资料中可以全面了解从业人员的技术能力和全部质量控制程序。标准操作程序应当是全面而恰当的，实验室的操作应当与书面的规程相—致。规格标准和分析程序应当适宜，而且也符合申请中记载的内容及法定方法的要求。
当实验室调查不能得出结论(误差原因不明)时，该药厂：
(1)不得进行两次复检和根据三次化验的平均值对产品进行发放；
(2)不能用。outlinertest做化学检验；
fda远程审计指导原则
FDA远程审计指导原则远程审计是指在不需要亲自到现场进行的情况下，通过技术手段进行远程审核和检查的过程。
在食品和药物管理局（FDA）的监管中，远程审计也开始得到广泛应用。
下面将详细介绍FDA远程审计的指导原则，包括其定义、适用范围、流程和关键要点。
1. 定义远程审计是指FDA通过远程技术手段（如视频会议、远程桌面共享等）对企业进行审核和检查的过程。
与传统的现场审计相比，远程审计可以节省时间、成本和人力资源，并且可以实时获取企业的数据和信息。
2. 适用范围FDA远程审计适用于各类食品、药物和医疗器械生产企业以及相关监管机构。
无论企业规模大小，只要具备远程技术条件，都可以申请进行远程审计。
3. 远程审计流程远程审计流程一般包括以下几个步骤：步骤一：申请和准备企业需要向FDA提出远程审计申请，并提供相关企业信息和技术设备的准备。
FDA将根据申请情况进行评估，决定是否接受远程审计。
步骤二：技术测试和准备企业和FDA之间将进行技术测试和准备，以确保远程通信设备和软件的正常运行。
双方需要测试视频会议、文件共享、数据传输等功能，确保信息的安全性和准确性。
步骤三：远程审核和检查在约定的时间内，FDA的审计员将通过远程技术与企业进行实时的审核和检查。
企业需要提供相关的文件和数据，并回答审计员的问题。
审计员将根据文件、数据和现场讨论的内容来评估企业的合规性和符合性。
步骤四：报告和总结FDA审计员将根据远程审计的结果编写审计报告，并向企业提供反馈和建议。
企业可以根据报告进行改进和调整，以提高合规性和符合性水平。
4. 关键要点在进行FDA远程审计时，以下是一些关键要点需要注意：•技术准备：企业需要准备好适当的远程通信设备和软件，保证正常的视频会议和文件共享功能。
•数据安全：企业在远程审计中需要保护好敏感数据的安全性，防止泄露和被未授权的人员访问。
•合作沟通：双方需要保持良好的沟通和合作，及时解决技术问题和提供所需的文件和数据。
中国原料药通过FDA审计步骤
中国原料药通过FDA审计,主要是文件的编制和现场检查，可以参照如下步骤：
（1）根据市场调研，摸清美国市场目前的销售情况，对市场发展趋势与走向做出正确的预测、分析，在此基础上，选好申请FDA认证品种。
（2）选择好申请代理人（代理人）和代理经销商（经销商）并向FDA递交代理经销商（经销商）并向FDA递交委托代理的证明书即委托书。
（3）编写申请文件，化学原料药为DMF，交代理人修改定稿后，由代理人向FDA递交，取得DMF分配号和NDC登记号。
（4）FDA收到材料后将发函通知表示何时收到何产品的DMF材料，DMF 分配号是多少，该产品由谁供货，由谁代理、谁经营，其次说明根据NDA（新药申请）程序，FDA将来检查。
（5）工厂按GMP要求进行厂房、设备和各项管理方面的准备工作。
其间，代理人和代理商可合作几次预检。
（6）FDA派员检查。
按他们的检查指南并对照DMF文件逐项对照，查后当场写出书面意见并由检查人员向FDA报告检查结果。
（7）FDA审核批准后通知代理商，由代理商通知外贸部签约，通知该药品已获准，可直接进入美国市场。
（8）每年通过代理人向FDA递交一份DMF修改材料，2--3年接受一次复查。
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审计
FDA审计某公司顾问审查过程纪要审查依据：Q7A内容：简要的概述：1、Q7A已成为欧洲法定的GMP法规；Q7A可以促进专业技术的完善，企业应有完善的QA 体制，能体现出QA在整个控制过程中的重要作用；2、QA和QC的关系：QA相当于药政部门，QC相当于药检所，QC的职责很明确，即保证取样、检验、报告的准确性；3、质量体系的组成应涉及四个方面的问题：机构（包括职责、权限）、工艺（写入DMF的工艺，保证按写入的工艺进行生产）、文件体系（划分单元组织编写，根据职责写文件）、资源。
仓库的检查：1、物料入库的程序：根据入库单检查数量、品名，检查物料供应商的正确性（库管员根据QA部盖章批准供应商的清单），检查外观，办理入库手续。
2、仓库的温湿度可进行验证，根据春夏秋冬的温度进行回顾性的统计，有全年温湿度分布的曲线，标明最高温湿度和最低温湿度的天数。
3、不合格物料的管理程序，QA部要有批准不合格物料使用的程序。
4、货位架上物料不是同一种物料总是放在一个地方，要进行物料垫板的清洁（规定多长时间进行清理），对于木制垫板应该作防虫处理，最好用塑料垫板，物料表面的清洁应在入库的程序中加以规定。
5、物料的储存周期应有规定。
6、固体物料的取样应有取样间，取样间应有排风的设施，库管员在办理入库时应规定搬运工随机取样，置于取样间，便于QC取样人员取样，建立取样间取样SOP，规定如何清场；取样工具应该放在现场。
7、灭蝇灯的开启时间应确定，包括夜间的规定。
8、标签：标签检验后，在货位卡应该剔除这几张；QA对每批标签应进行留样。
9、包材的内塑料袋的取样件数可用一个包装替代，取样要在超净工作台上进行，内包材少一个药用包材生产厂的资质证明。
10、货位卡和状态标示最好不要分开，应为一个为好。
11、液体物料的批号编制及测试：对进厂槽车进行取样测试并进行批号编制，打至罐后，整个混合样品的批号可按照最新的槽车批号进行编制；混合样品打至车间后，由车间根据需要测试部分或全部项目。
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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)。