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1、Richard Needham,RFL Associates1Preparing for FDA Preapproval Inspections准备FDA认证前检查Richard Needham,RFL Associates2Purpose of a pre-Approval Inspection(DMF or ANDA)认证前检查的目的（DMF或ANDA）oEnsure that the facilities,equipment,and instruments are suitable for producing a quality product 确保设施，设备和仪器适合高质量产品的生产o
2、Ensure that the quality system is functioning correctly 确保质量体系运行正常 oEnsure that product is manufactured under cGMPs 确保在cGMPs指导下进行产品生产Richard Needham,RFL Associates3Purpose of a pre-Approval Inspection认证前检验的目的 oEnsure that data submitted in the ANDA or DMF submission is supported by raw data at the f
3、acility 确保在ANDA或DMF文件中提交的数据以设施的原始数据为依据 nData and original records must be documented according to cGMP standards 原始数据和记录必须根据cGMP标准进行oEnsure that the ANDA or DMF submission is an accurate reflection of what is being done at the facility确保ANDA或DMF中提交的是设施正在进行的情况的准确反应 Richard Needham,RFL Associates4The
4、Pre-Approval Inspection(PAI)认证前检查（PAI）oWhen is the DMF reviewed by FDA?DMF什么时候被FDA审查？nOnly after the ANDA holder files the ANDA and refers to the DMF 只有在ANDA持有人将ANDA归档并提交到DMF后nIf no ANDA is filed,the DMF is filed away without review.如果ANDA没有归档，那么DMFjiang将其移开不进行审查。oHowever,the DMF holder should still
5、 update the DMF through annual reports and DMF amendments to the FDA 然而，DMF持有人仍应通过年度报告和DMF修订将更新提交给FDAoThis way,the DMF will be up-to-date when reviewed这样，DMF被审查时将是最新的 Richard Needham,RFL Associates5The Pre-Approval Inspection(PAI)认证前检查（PAI）oWhen is the ANDA reviewed by FDA?FDA什么时候审查ANDAnAfter the AN
6、DA holder files the ANDA ANDA持有人将ANDA归档后nBecause of backlogs,expect at least 6 month delay before reviewing 由于积压，预计至少延迟6个月才能被审查 oWhen is the Inspection scheduled?什么时候进行预先审查 nAfter the ANDA is satisfactorily reviewed ANDA审查圆满后 oDeficiency letter may be issued 信件缺乏可能成为问题oMore information may be reques
7、ted 可能会要求更多的信息 Richard Needham,RFL Associates6Flow of the pre-Approval Inspection认证前检查流程oFDA Personnel Involved FDA涉及人员 nTwo people are usually involved:通常涉及两个人 oFDA Investigator(Production issues)FDA调查人员（生产问题）oFDA Chemist(Laboratory Issues)FDA化验师（实验室问题）nGenerally,they will work separately 一般来说，他们将分
8、开工作 oTherefore,preparation for two people is needed因此，需要配备两个人 Richard Needham,RFL Associates7Flow of the pre-Approval Inspection认证前检查流程oPreparation for two people generally means:配备两个人通常是指 nTwo Interpreters(provided by the firm,at present)两名翻译员（目前由公司提供的）oThe interpreters are extremely important to t
9、he smooth running of the inspection 翻译员对于检查顺利进行是非常重要的 nTwo adjacent conference rooms 两个相邻的会议室 oInvestigator 调查人员 oChemist化验师 Richard Needham,RFL Associates8Flow of the pre-Approval Inspection认证前检查oInspection will usually take 4 full days 检查通常需要 4天nInitial Meeting(1-1 hours)首次会议（1-1个半小时）nWalkthrough
10、of Warehouses,Production,QC Laboratory(5-6 hours)仓库，生产，QC实验室巡检（5-6小时）nDocument Review(2-2 days)文件审查（2-2天半）nCloseout(1-2 hours)总结（1-2小时）oHowever,the FDA Inspectors may change this schedule 然而，FDA检查员可能会改变这个时间表 nBe prepared for the unexpected 做好出现意外的准备 Richard Needham,RFL Associates9Flow of the pre-App
11、roval Inspection认证前检查流程oInitial Meeting(1-1 1/2 hours)首次会议（1-1个半小时）nIntroductions and exchange of business cards 介绍并交换名片 oThe most responsible person at the firm should be present 该公司负责人应该在场oQA,Production,QC Representatives should be present QA，生产，QC代表应该在场 Richard Needham,RFL Associates10Flow of the
12、 pre-Approval Inspection认证前检查流程oInitial Meeting(1-1 hours)首次会议（1-1个半小时）oMake sure that every person is identified by n10o1ame 确保每个人标注姓名 nName and title displayed at initial meeting 姓名和标题呈现在首次会议上 nName tags on uniform during inspection 检查期间所有姓名标签格式应统一 nConsider also a handout with the following infor
13、mation for key people:还考虑分发含有以下信息的资料给关键人员：Full name(and English surname if applicable)全名（如果适用加上英文姓氏）Title 标题 Thumbnail photograph 照片缩图 Richard Needham,RFL Associates11Flow of the pre-Approval Inspection认证前检查oInitial Meeting(1-1 hours)首次会议（1-1个半小时）nCompany Presentation 公司介绍oPowerPoint with hard copie
14、s provided 提供可以拷贝的PPTnFDA will have initial questions and will request essential documents FDA会提出一些初始问题，并要求提供一些精炼的文档Richard Needham,RFL Associates12Flow of the pre-Approval Inspection/Initial Meeting认证前检查流程/首次会议oThe Company Presentation(30-45 minutes)o公司介绍（30-45分钟）nImportance of the Initial Presenta
15、tion 初始表现很重要oIt is FDAs first impression of your company 这是FDA对该公司的第一印象 oIt should be very professional(graphics and presentation)应该很专业（图形和文稿）oIt should be in English 应当是英文的 oIt should not be too long(1 hour is too long)不应该过长（不超过1小时）oYou should rehearse giving the presentation to make sure it is per
16、fec 您应该提前演练您的演讲，保证他的完美Richard Needham,RFL Associates13Flow of the pre-Approval Inspection/Initial Meeting认证前检查流程/首次会议oThe Company Presentation(30-45 minutes)o公司介绍（30-45分钟）nHistory of Business企业历史oWhen was it founded?By whom?什么时候成立？由谁创建？oImportant milestones during company development 公司发展中的重要里程碑 nSi
17、te changes 网站的变化 nAddition of buildings,purchase of major equipment 此外还有建筑物，主要设备的采购 nProduct introductions 产品介绍 nTotal Number of employees at the inspection site,and in the following departments:n视察现场，以及以下部门的员工总数：oTop Management 高层管理人员 oQuality Assurance QA oQuality Control QCoProduction 生产 oResearc
18、h and Development 研发o(Administrative)（行政）o(Financial and Sales)（财务和销售）Richard Needham,RFL Associates14Flow of the pre-Approval Inspection认证前检查oThe Company Presentation(30-45 minutes)公司介绍（30-45分钟）nAnnual Sales(converted to US Dollars)n年销售额（换算成美元）nCertifications/Achievements relating to Quality(ISO,et
19、c.)认证/质量成果（ISO，等）nIntroduction to products产品简介 oAll APIs and all dosage forms produce on-site 所有API和所有剂型的生产现场 nUS and non-US markets 美国和非美国市场销路 nInspectional Historyl查阅历史 oUS FDA US FDA oSFDA 食品药品监督管理局 oOther Regulatory Agencies 其他管理机构 o(Customer Audits)（消费者协会）oOther 其他 Richard Needham,RFL Associate
20、s15Flow of the pre-Approval Inspection认证前检查流程oThe Company Presentation(30-45 minutes)公司介绍（30-45分钟）nPlant Layout(Plan and Photographs)工厂布局（平面图和照片）oIndicate the production areas that FDA will audit 说明FDA将审查的生产区域 oIndicate warehouse areas 请注明仓库区 oIndicate QC Laboratory location 标明QC实验室位置oGive area(squa
21、re meters)of each workshop,warehouse,QC laboratory 注明各车间，仓库，QC实验室面积（平方米）Richard Needham,RFL Associates16Flow of the pre-Approval Inspection认证前检查oThe Company Presentation(30-45 minutes)公司介绍（30-45分钟）nOrganizational Chart 组织机构图 oCompany as a whole 公司是一个整体 oQuality Unit(QA and QC)Organizational Chart 质量
22、部门（QA和QC）的组织机构图 nIntroduction to Quality System 质量体系简介 nOverview of Manufacturing Process 制造工艺概述 Richard Needham,RFL Associates17Flow of the pre-Approval Inspection认证前检查o Walkthrough of Production and QC Laboratory(5-6 hours)生产和QC实验室巡检（5-6小时）nWarehouses 仓库nProduction Areas 生产区nClean Finishing Area 洁
23、净完成区 nPackaging and Labeling 包装和标签nQC Laboratory QC 实验室nWater,Air,Vacuum,Pressure Systems 水，通风，真空，压力系统 Richard Needham,RFL Associates18Flow of the pre-Approval Inspection认证前检查流程oDocuments and Records Review(2-2 1/2 days)o文件和记录的审查（2-2 1/2天）nIn the conference rooms 在会议室 nIt is essential to retrieve re
24、quested documents quickly迅速检索到要求的文件是至关重要的nIt is essential to have the right people in the conference rooms at the right time 在适当的时间适当的人留在会议室是必要的oDo not overcrowd the conference rooms 会议室不要容纳太多人oDo not carry out unnecessary side conversations in Chineseo不要用中文进行不必要的交谈oDo have the person best qualified
25、 to explain each documento让最有资格的人来解释每个文档 oDo maintain a sense of order and professionalismo保持条理性和专业性 Richard Needham,RFL Associates19Flow of the pre-Approval Inspection认证前检查oFDA Will usually give a daily wrap-upoFDA通常会做每日总结 nBe proactive and ask for one during the initial meeting在首次会议上采取积极主动nEnd of
26、the day,15-30 minutes 总结一天的工作，15-30分钟 nIssues and concerns found during the day are discussed 讨论白天发现的问题和担忧 nThis allows the company to assess how the inspection is going 这允许该公司评价检查进度 nThis allows the company to begin preparing corrections or clear up misunderstandings 这允许该公司开始准备更正或澄清误解 Richard Needh
27、am,RFL Associates20Flow of the pre-Approval Inspection认证前检查流程oCloseout(1-1 hours)总结（1-1个半小时）nPresentation of 483 by the FDA team 美国FDA团队提出483nFirms verbal response to the 483 is presented to the 483 is presented 公司应口头答复提出的483 oA written 483 response should be given to FDA within 15 days of closeout
28、483书面答复应在工作结束后15天内上交给FDA nSet out,with documentation,corrective action plan to 483 observations 列出更改483行动计划的意见，并列出依据nObject,with documentation,to observations that you feel are incorrect 将你认为不正确的提出反对意见，并列出依据 Richard Needham,RFL Associates21What is the 483(FDA 483)?什么是483（FDA的483）？oA form on which in
29、spectional observations are written检查意见的一种书面形式 oThey are observations,not necessarily deficiencies 他们提出的只是意见并不是缺陷 oThey are grouped under the sixystems headings:它们归入sixystems体系：nQuality System 质量体系 nFacilities and Equipment System 设施和设备系统 nMaterials System 原料系统 nProduction System 生产系统 nPackaging and
30、 Labeling System 包装和标签制度 nLaboratory Control System 实验室控制系统 Richard Needham,RFL Associates22The FDA Form 483FDA的483表格oThe company can discuss the observations verbally at closeout 在检查总结时该公司可以口头讨论检查 oThe company should respond in writing within 15 days of issuance 该公司要在15日内发布书面答复 oThe 483,Establishme
31、nt Inspection report(EIR),and firms documented response are reviewed by FDA Compliance Branch FDA下属分支将检查设立检查报告（EIR），和公司有证据的回复的483材料 oA decision is made whether the inspection is:作出决定检查是否是 nNAI(No Action Indicated)NAI（无行动可能性）nVAI(Voluntary Action Indicated)VAI（无随意行动的可能性）nOAI(Official Action Indicated
32、)OAI（无官方行动的可能性）Richard Needham,RFL Associates23General Considerations 总则oEstablish Work Hours and Lunch Times at beginning of audit 在审计工作开始时确定工作时间和午餐时间 nLunch times generally one hour at most 午餐时间一般最多一小时 oDo not have long,elaborate lunches 午餐不要太长，太复杂nBe prepared to work during evenings if needed 如果有
33、需要要在晚上做准备工作 oDeliver Requested Documents Promptly and Efficiently!迅速而高效地提供要求的文件！迅速而高效地提供要求的文件！Richard Needham,RFL Associates24General Considerations 总则oDo not use a recorder to tape the inspection 不要使用磁带录音机在检查中录音 oDo not take photos during the inspection without FDAs permission 亦不得在未经FDA的许可的情况下在检查过程
34、中拍照 oDo not carry out loud side-discussions during the inspection!不要在检查过程中大声进行多余的讨论 nDuring the walkthrough在巡检过程中nDuring document review在文件审查过程中Richard Needham,RFL Associates25General Considerations 一般考虑oLoud side-discussions 大声私下讨论nAre distracting to the FDA 会分散FDA注意力 nAppear extremely unprofession
35、al 出现极不专业情况 nGive the appearance that the company is not prepared 给予公司没有事先准备的期望Richard Needham,RFL Associates26General Considerations 一般考虑oAlways keep in Mind:始终牢记nThe company should always appear to be professional 该公司应始终表现出专业性 nThe company should always appear to be prepared 该公司应始终表现出有所准备 nThe com
36、pany should always work to make the inspection run smoothly and efficiently 公司应该尽可能保证检查工作顺利高效的进行nThe investigators will be happiest if you can make their jobs easy 如果你们能让检查员工作顺利他们将非常高兴Richard Needham,RFL Associates27General Considerations 一般考虑oDecide your companys policy on FDA taking photos before
37、the PAI 在PAI之前在FDA发出的照片上决定公司的方针政策 nYou are not required to permit them to photograph your facility 你不需要允许他们为设施设备拍照nHowever,you may decide to do this 但是，您也可以决定这样做 nDo not bring it up,but if it comes up,make sure that you have a clear policy 不要提出，但是一旦提出，请确保你有一个明确的方针 Richard Needham,RFL Associates28Gen
38、eral Considerations 一般考虑oDecide before the inspection your companys policy on providing documents 在检查之前倘若有依据确定你的公司方针政策 nIn general,you should(must)provide all documents requested,but mark them as“Confidential”一般情况下，你应该（必须）提供所有要求的文件，但标记为“机密”nYou do not have to provide internal audit and self inspecti
39、on results to FDA,but you may wish to do so in some cases 您没有必要FDA审计和自查结果，但是你可能在某些个案里样做oTo show that the company is committed to quality,and the continuous improvement of quality 表明公司致力于质量，质量不断提高 Richard Needham,RFL Associates29General Considerations 一般考虑oUnderstand FDAs Policy on Meals,Hotel Accomm
40、odations,and Gifts 了解FDA关于餐饮，酒店住宿，及礼品的政策 nAt Present,FDA pays for meals,hotel accommodations 目前，FDA支付餐饮，酒店住宿费用oAsk inspectors about their preferences for evening meals:询问检查员对晚餐的需求；nThey may wish to dine with the company 他们可能希望与该公司吃饭 nThey may wish to dine alone 他们可能想单独用餐 oAsk inspectors about their
41、preferences on entertainment after hours 询问他们业余时间的娱乐项目 oDo not offer elaborate gifts 不赠予贵重的礼物Richard Needham,RFL Associates30The Importance of the Interpreter翻译员的重要性oInterpreter should be very professional 翻译员应该非常专业 oInterpreter should represent FDA and be neutral 口译员应代表FDA并保持中立oInterpreter should n
42、ot add words or change the meaning of words 口译员不应该增加词语或改变词语的意思 nChinese to English汉语译成英语 nEnglish to Chinese 英语译成中文 Richard Needham,RFL Associates31The Importance of the Interpreter翻译员的重要性oInterpreter must be familiar with:翻译员必须熟悉nGMP terminology GMP的术语 nPharmaceutical Manufacturing terminology 制药业术
43、语 nChemical names(raw materials,intermediates,API,dosage forms)化学名称（原材料，中间体，空气污染指数，剂型）nLaboratory Instrument names 实验室仪器名称 Richard Needham,RFL Associates32Planning and Logistics:Document Staging Area规划和物流：文件临时存储区域 oEstablish a Document Staging Areao建立一个文件临时存储区域nDocument Staging Area is where all pla
44、nned and anticipated documents are stored 文件临时存储区域存储所有计划和预期的文件nDocument Staging Area is near the Conference Rooms 文件临时存储区域靠近会议室nDocument Staging Area is stocked with documents before the inspectionn文件临时存储区域保存备份文件Richard Needham,RFL Associates33Planning and Logistics:Document Staging Area规划和物流：文件临时存储
45、区域 oSeparate Room,Near Investigators 单独的房间，靠近调查员nDocuments Arranged and Available 文件有规划并且容易找到nPeople Assigned to Retrieve Documents 专人负责文件检索oHave documents filed so they can be retrieved instantly 将文件归档，需要时就可以立刻被找到oHave a photocopier easily available(and a backup machine)有一台可用的复印机(和备份机)Richard Needh
46、am,RFL Associates34Planning and Logistics:Document Staging Area规划和物流：文件临时存储区域oAll Documents requested by FDA are taken from and returned to this area FDA要求的所有文件均取自并返回这一区域nKeep a log of each document requested by FDA FDA要求的每一份文件形成一个记录 oDocument name文件名称 oRequest date/time要求日期/时间 oDelivery date/time送交
47、日期/时间 nIf FDA requests a copy,make 2 copies:如果FDA要求要副本，准备2份：1.For FDA 其中一份交给FDAnBrief review(by QA)before releasing it 在放出前由QA简要回顾一下nStamp it as“Confidential”or“Uncontrolled Copy”标记为“机密”或“可以复制”2.For the Company Inspectional File 另一份由公司检查归档Richard Needham,RFL Associates35Planning and Logistics:Compan
48、y Inspectional File规划和物流：文件临时存储区域o Contains a Record of notes taken by the scribe 包含手抄记录oContains a Record of all employees interviewed by FDA Inspectors and the subject matter 包含了所有员工谈话和常见问题记录 oContains Copies of all documents given to FDA Inspectors包含给FDA检查的所有文件副本oContains a Record of any discussi
49、ons with FDA Inspectors包含FDA检察员的学术报告记录nDuring inspection在检查过程中nDaily closeouts 日常总结n483 closeout 483总结oContains a Record of any corrections made during the inspection 包含视察期间作出的更正的记录 Richard Needham,RFL Associates36Planning and Logistics:The Scribe(s)规划和物流：记录员oScribe(s):Takes Notes during the walkthr
50、ough(and in the conference room)记录员：在巡检过程中做记录（在会议室）nThe Scribe(s)should take notes of the inspection 记录员应在检查过程中做笔记nThe Scribe records all FDA requests for documents 记录员记录FDA对文件的要求Richard Needham,RFL Associates37The RunnersRichard Needham,RFL Associates38Planning and Logistics:The Runners规划和物流：联络员oRu