PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照

1、Purpose of a pre-Approval Inspection (DMF or ANDA)认证前检查的目的（DMF或ANDA） Ensure 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Ensure that the quality system is functioning correctly 确保质量体系运行正常 Ensure that product is manufactured under cG

2、MPs 确保在cGMPs指导下进行产品生产1PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Purpose of a pre-Approval Inspection认证前检验的目的 Ensure that data submitted in the ANDA or DMF submission is supported by raw data at the facility 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 Data and original records must be documented accord

3、ing to cGMP standards 原始数据和记录必须根据cGMP标准进行Ensure 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 2PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照The Pre-Approval Inspection (PAI) 认证前检查（PAI） When is the DMF reviewed by

4、FDA? DMF什么时候被FDA审查？ Only 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If 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。 However, the DMF holder should still update the DMF through annual reports and DMF amendments to the

5、 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FDAThis way, the DMF will be up-to-date when reviewed这样， DMF被审查时将是最新的 3PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照The Pre-Approval Inspection (PAI)认证前检查（PAI）When is the ANDA reviewed by FDA? FDA什么时候审查ANDAAfter the ANDA holder files the ANDA ANDA持有人将ANDA归档后

6、Because 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 When is the Inspection scheduled? 什么时候进行预先审查 After the ANDA is satisfactorily reviewed ANDA审查圆满后 Deficiency letter may be issued 信件缺乏可能成为问题More information may be requested 可能会要求更多的信息 4PreparingforFDAPreapprovalI

7、nspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查流程FDA Personnel Involved FDA涉及人员 Two people are usually involved: 通常涉及两个人 FDA Investigator (Production issues) FDA调查人员（生产问题）FDA Chemist (Laboratory Issues) FDA化验师（实验室问题） Generally, they will work separately 一般来说，他们将分开工作 Therefore, pre

8、paration for two people is needed因此，需要配备两个人 5PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查流程Preparation for two people generally means:配备两个人通常是指 Two Interpreters (provided by the firm, at present) 两名翻译员（目前由公司提供的） The interpreters are extremely importan

9、t to the smooth running of the inspection 翻译员对于检查顺利进行是非常重要的 Two adjacent conference rooms 两个相邻的会议室 Investigator 调查人员 Chemist化验师 6PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查Inspection will usually take 4 full days 检查通常需要 4天Initial Meeting (1- 1 hours)

10、 首次会议（1 - 1个半小时） Walkthrough of Warehouses, Production, QC Laboratory (5-6 hours) 仓库，生产，QC实验室巡检（5-6小时） Document Review (2-2 days) 文件审查（2-2天半） Closeout (1-2 hours)总结（1-2小时） However, the FDA Inspectors may change this schedule 然而，FDA检查员可能会改变这个时间表 Be prepared for the unexpected 做好出现意外的准备 7PreparingforF

11、DAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查流程Initial Meeting (1-1 1/2 hours) 首次会议（1 - 1个半小时） Introductions and exchange of business cards 介绍并交换名片 The most responsible person at the firm should be present 该公司负责人应该在场QA, Production, QC Representatives should be pres

12、ent QA，生产，QC代表应该在场 8PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查流程Initial Meeting (1-1 hours) 首次会议（1 - 1个半小时） Make sure that every person is identified by n101ame 确保每个人标注姓名 Name and title displayed at initial meeting 姓名和标题呈现在首次会议上 Name tags on uniform

13、 during inspection 检查期间所有姓名标签格式应统一 Consider also a handout with the following information 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 9PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approva

14、l Inspection认证前检查Initial Meeting (1-1 hours) 首次会议（1 - 1个半小时） Company Presentation 公司介绍PowerPoint with hard copies provided 提供可以拷贝的PPTFDA 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10PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Ap

15、proval Inspection/Initial Meeting认证前检查流程/首次会议The Company Presentation (30-45 minutes)公司介绍（30-45分钟） Importance of the Initial Presentation 初始表现很重要It is FDAs first impression of your company 这是FDA对该公司的第一印象 It should be very professional (graphics and presentation) 应该很专业 （图形和文稿） It should be in English

16、 应当是英文的 It should not be too long (1 hour is too long) 不应该过长（不超过1小时） You should rehearse giving the presentation to make sure it is perfec 您应该提前演练您的演讲，保证他的完美11PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection/Initial Meeting认证前检查流程/首次会议The Company Presentation

17、(30-45 minutes)公司介绍（30-45分钟） History of Business企业历史When was it founded? By whom? 什么时候成立？由谁创建？ Important milestones during company development 公司发展中的重要里程碑 Site changes 网站的变化 Addition of buildings, purchase of major equipment 此外还有建筑物，主要设备的采购 Product introductions 产品介绍 Total Number of employees at the

18、 inspection site, and in the following departments:视察现场，以及以下部门的员工总数： Top Management 高层管理人员 Quality Assurance QA Quality Control QCProduction 生产 Research and Development 研发(Administrative) （行政） (Financial and Sales) （财务和销售） 12PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approv

19、al Inspection认证前检查The Company Presentation (30-45 minutes)公司介绍（30-45分钟） Annual Sales (converted to US Dollars)年销售额（换算成美元） Certifications/Achievements relating to Quality (ISO, etc.) 认证/质量成果（ISO，等 ）Introduction to products产品简介 All APIs and all dosage forms produce on-site 所有API和所有剂型的生产现场 US and non-U

20、S markets 美国和非美国市场销路 Inspectional Historyl查阅历史 US FDA US FDA SFDA 食品药品监督管理局 Other Regulatory Agencies 其他管理机构 (Customer Audits) （消费者协会） Other 其他 13PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查流程The Company Presentation (30-45 minutes) 公司介绍（30-45分钟） Plan

21、t Layout (Plan and Photographs) 工厂布局（平面图和照片） Indicate the production areas that FDA will audit 说明FDA将审查的生产区域 Indicate warehouse areas 请注明仓库区 Indicate QC Laboratory location 标明QC实验室位置Give area (square meters) of each workshop, warehouse, QC laboratory 注明各车间，仓库，QC实验室面积（平方米） 14PreparingforFDAPreapprova

22、lInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查The Company Presentation (30-45 minutes)公司介绍（30-45分钟） Organizational Chart 组织机构图 Company as a whole 公司是一个整体 Quality Unit (QA and QC) Organizational Chart 质量部门（QA和QC）的组织机构图 Introduction to Quality System 质量体系简介 Overview of Manufactur

23、ing Process 制造工艺概述 15PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查 Walkthrough of Production and QC Laboratory (5-6 hours) 生产和QC实验室巡检（5-6小时） Warehouses 仓库Production Areas 生产区Clean Finishing Area 洁净完成区 Packaging and Labeling 包装和标签QC Laboratory QC 实验室Wat

24、er, Air, Vacuum, Pressure Systems 水，通风，真空，压力系统 16PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查流程Documents and Records Review (2-2 1/2 days)文件和记录的审查（2-2 1 / 2天） In the conference rooms 在会议室 It is essential to retrieve requested documents quickly迅速检索到要求的

25、文件是至关重要的It 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Do not overcrowd the conference rooms 会议室不要容纳太多人Do not carry out unnecessary side conversations in Chinese不要用中文进行不必要的交谈Do have the person best qualified to explain each document让最有资格的人来解释每个文

26、档 Do maintain a sense of order and professionalism保持条理性和专业性 17PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查FDA Will usually give a daily wrap-upFDA通常会做每日总结 Be proactive and ask for one during the initial meeting在首次会议上采取积极主动End of the day, 15-30 minutes

27、 总结一天的工作，15-30分钟 Issues and concerns found during the day are discussed 讨论白天发现的问题和担忧 This allows the company to assess how the inspection is going 这允许该公司评价检查进度 This 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 18PreparingforFDAPreapprovalInspectio

28、ns准备FDA认证前检查和中英文对照Flow of the pre-Approval Inspection认证前检查流程Closeout (1-1 hours) 总结（1-1个半小时）Presentation of 483 by the FDA team 美国FDA团队提出483Firms verbal response to the 483 is presented to the 483 is presented 公司应口头答复提出的483 A written 483 response should be given to FDA within 15 days of closeout 483

29、书面答复应在工作结束后15天内上交给FDA Set 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Object, 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 19PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照What is the 483 (FDA 483)? 什么是483（FDA的

30、483）？ A form on which inspectional observations are written检查意见的一种书面形式 They are observations, not necessarily deficiencies 他们提出的只是意见并不是缺陷 They are grouped under the sixystems headings: 它们归入sixystems体系： Quality System 质量体系 Facilities and Equipment System 设施和设备系统 Materials System 原料系统 Production Syste

31、m 生产系统 Packaging and Labeling System 包装和标签制度 Laboratory Control System 实验室控制系统 20PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照The FDA Form 483FDA的483表格The 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 The company should respond in writing within 15 days of issua

32、nce 该公司要在15日内发布书面答复 The 483, Establishment 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 A decision is made whether the inspection is: 作出决定检查是否是 NAI (No Action Indicated) NAI（无行动可能性）VAI (Voluntary Action Indicated)

33、VAI（无随意行动的可能性）OAI (Official Action Indicated) OAI（无官方行动的可能性）21PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照General Considerations 总则Establish 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 Lunch times generally one hour at most 午餐时间一般最多一小时 Do not have long, elaborate lu

34、nches 午餐不要太长，太复杂Be prepared to work during evenings if needed 如果有需要要在晚上做准备工作 Deliver Requested Documents Promptly and Efficiently! 迅速而高效地提供要求的文件！ 22PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照General Considerations 总则Do not use a recorder to tape the inspection 不要使用磁带录音机在检查中录音 Do not take p

35、hotos 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中拍照 Do 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 During the walkthrough在巡检过程中During document review在文件审查过程中23PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照General Considerations 一般考虑Lou

36、d side-discussions 大声私下讨论Are distracting to the FDA 会分散FDA注意力 Appear extremely unprofessional 出现极不专业情况 Give the appearance that the company is not prepared 给予公司没有事先准备的期望24PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照General Considerations 一般考虑Always keep in Mind: 始终牢记The company should alway

37、s appear to be professional 该公司应始终表现出专业性 The company should always appear to be prepared 该公司应始终表现出有所准备 The company 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The 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25Prepa

38、ringforFDAPreapprovalInspections准备FDA认证前检查和中英文对照General Considerations 一般考虑Decide your companys policy on FDA taking photos before the PAI 在PAI之前在FDA发出的照片上决定公司的方针政策 You 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However, you may decide to do this 但是，您也可以决定这样做 Do not b

39、ring 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 26PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照General Considerations 一般考虑Decide 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 In general, you should (must

40、) 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” You do not have to provide internal audit and self inspection 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To show that the company is committed to quality, an

41、d the continuous improvement of quality 表明公司致力于质量，质量不断提高 27PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照General Considerations 一般考虑Understand FDAs Policy on Meals, Hotel Accommodations, and Gifts 了解FDA关于餐饮，酒店住宿，及礼品的政策 At Present, FDA pays for meals, hotel accommodations 目前，FDA支付餐饮，酒店住宿费用Ask

42、inspectors about their preferences for evening meals: 询问检查员对晚餐的需求；They may wish to dine with the company 他们可能希望与该公司吃饭 They may wish to dine alone 他们可能想单独用餐 Ask inspectors about their preferences on entertainment after hours 询问他们业余时间的娱乐项目 Do not offer elaborate gifts 不赠予贵重的礼物28PreparingforFDAPreappro

43、valInspections准备FDA认证前检查和中英文对照The Importance of the Interpreter翻译员的重要性Interpreter should be very professional 翻译员应该非常专业 Interpreter should represent FDA and be neutral 口译员应代表FDA并保持中立Interpreter should not 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 Chinese to English汉语译成英语 English to

44、 Chinese 英语译成中文 29PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照The Importance of the Interpreter翻译员的重要性Interpreter must be familiar with: 翻译员必须熟悉GMP terminology GMP的术语 Pharmaceutical Manufacturing terminology 制药业术语 Chemical names (raw materials, intermediates, API, dosage forms) 化学名称（原材料，中间体

45、，空气污染指数，剂型） Laboratory Instrument names 实验室仪器名称 30PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Planning and Logistics: Document Staging Area规划和物流：文件临时存储区域 Establish a Document Staging Area建立一个文件临时存储区域Document Staging Area is where all planned and anticipated documents are stored 文件临时存储区域存储所有

46、计划和预期的文件Document Staging Area is near the Conference Rooms 文件临时存储区域靠近会议室Document Staging Area is stocked with documents before the inspection文件临时存储区域保存备份文件31PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Planning and Logistics: Document Staging Area规划和物流：文件临时存储区域 Separate Room, Near Investigat

47、ors 单独的房间，靠近调查员Documents Arranged and Available 文件有规划并且容易找到People Assigned to Retrieve Documents 专人负责文件检索Have documents filed so they can be retrieved instantly 将文件归档，需要时就可以立刻被找到Have a photocopier easily available (and a backup machine) 有一台可用的复印机(和备份机)32PreparingforFDAPreapprovalInspections准备FDA认证前检

48、查和中英文对照Planning and Logistics: Document Staging Area规划和物流：文件临时存储区域All 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Keep a log of each document requested by FDA FDA要求的每一份文件形成一个记录 Document name文件名称 Request date/time要求日期/时间 Delivery date/time送交日期/时间 If FDA req

49、uests 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FDABrief review (by QA) before releasing it 在放出前由QA简要回顾一下Stamp 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33PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Planning and

50、Logistics: Company Inspectional File规划和物流：文件临时存储区域 Contains a Record of notes taken by the scribe 包含手抄记录Contains 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 Contains Copies of all documents given to FDA Inspectors包含给FDA检查的所有文件副本Contains a Record of

51、 any discussions with FDA Inspectors包含FDA检察员的学术报告记录During inspection在检查过程中Daily closeouts 日常总结483 closeout 483总结Contains a Record of any corrections made during the inspection 包含视察期间作出的更正的记录 34PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Planning and Logistics: The Scribe(s)规划和物流：记录员Scribe(s

52、): Takes Notes during the walkthrough (and in the conference room) 记录员：在巡检过程中做记录（在会议室）The Scribe(s) should take notes of the inspection 记录员应在检查过程中做笔记The Scribe records all FDA requests for documents 记录员记录FDA对文件的要求35PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照The RunnersBeijing 200836Prepari

53、ngforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Planning and Logistics: The Runners规划和物流：联络员Runners: Retrieve documents requested during the walkthrough (and during document review) 联络员：检索在巡检过程中要求的文件（文件审查期间）The Runners retrieve the Documents requested during Plant Tour, and deliver them to the Confere

54、nce Room 联络员检索在车间检查时要求的文件，并送到指定的会议室Documents requested should be available in conference room when plant tour is completed 在车间检查结束后在会议室应该可以找到要求的文件 QA should present the documents requested as soon as FDA returns to the conference room QA应在FDA回到会议室前尽快提供要求的文件Show FDA the documents that were requested

55、出示FDA要求的文件This gives an excellent impression of efficiency and professionalism 这将给人一种高效专业的印象37PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Factory Tour 工厂检查Warehouses 仓库Raw Material 原料Solvents 溶剂Intermediates 中间体Final Product 最终产品Packaging and Labeling 包装和标签Sampling rooms or areas 采样室或采样区Rej

56、ected product areas 不合格产品区38PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Factory Tour 工厂检查Production Areas 生产区From beginning to end 从开始到结束Following the manufacturing process 按照制造流程Describe the material flow and the people flow 标示出人流和物流If intermediates are transferred, explain how (open or cl

57、osed): 如果中间体转移，描画出具体的程序（打开或关闭）Discharge through reactor outlet (liquids) 出口释放（液体）Transferred to bins (wet cake, powders) 转至储藏箱（湿滤饼，粉末）Pumped through piping (liquids) 泵压管道（液体）39PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Factory Tour/Production Areas工厂检查/生产区FDA may, during the Warehouse and

58、Factory Tour FDA可能在仓库和工厂参观 Ask workers questions (job knowledge and GMP awareness)询问工人问题（工作知识和GMP的认识） Request QC Test records for selected lots of materials要求QC考察记录大量的材料挑选 The runner should retrieve these from the staging area and have them ready after the tour流动人员应从文件临时存储区域找到这些文件并在参观结束时准备好 Examine

59、batch records for in-process production审查生产进程的一组记录 Make sure steps are signed and witnessed at the time they are performed确保在执行过程中每个步骤都有签署有依据Request Cleaning Records for equipment (for example last 6 months) (Runner)要求清空设备记录（例如 ， 过去6个月 ）（流动人员） Request copies of Master Labels (Runner)要求复制主要的标记（ 流动人员

60、） Make sure that SOPs are present确保当前按标准操作程序进行 40PreparingforFDAPreapprovalInspections准备FDA认证前检查和中英文对照Factory Tour/QC Laboratory工厂检查/QC实验室QC Laboratory: Prepare to QC实验室：准备Explain paperwork flow and records 解释文书记录工作流程Requests for sampling 请求抽样Sampling and receiving logbook 采样和接收日志How samples are ass