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1、Conducting an FDA Inspection执行FDA检查,Douglas A.Campbell Compliance Officer Senior Policy AdvisorCDER/Office of Compliance药品审批研究中心/执法办公室Division of Manufacturing and Product QualityInternational Compliance Branch China-June 2011,Inspections检查,Are FACT finding in nature 是事实性的调查结果Require EVIDENCE 需要证据Ar
2、e REGUALTORY in nature 实质上是一种监管What is said could end up in court 所说的内容可能最终会在法庭上裁决Require ORGANIZATION and TIME MANAGEMENT 需要组织和时间管理,Objectives of Inspection检查的目标,Conduct the inspection in accordance with FD&C Act and Current Good Manufacturing Practice(CGMP)Regulations 检查的执行依据联邦食品，药品和化妆品法(FD&C Act)
3、及现行药品生产管理规范(CGMP)条例Accomplish what is necessary per the established,supporting Compliance Policy Guidance Manual 检查执行的程度依据 符合性方针指导手册 7356.002“Drug Manufacturing Inspections”7356.002“药品生产检查”“Systems Approach”“系统化方法”Accomplish necessary,additional questions/concerns listed in the inspection assignment
4、(“For Cause”Inspection)要完成必要的检查、其它问题/额外关注点见“追因”检查的检查任务分配,The Law says.法律规定.,“A drug shall be deemed adulterated if:“一种药品应当被视为掺假药品，如果：.the methods used in,or the facilities or controls used for,its manufacture,processing,packing,or holding do not conform to or are not operated or administered in conf
5、ormity with current good manufacturing practice.”使用于制造、加工、包装或置放的方法或设施、控制装置不符合或没有遵照在安全性上保证药品符合现行GMP的规定”,The Law says法律规定.,“to assure that such drug meets the requirements of this Act as to safety and has the identity and strength,and meets the quality and purity characteristics,which it purports or i
6、s represented to possess.”“并保证符合其声称或据称的鉴别和含量、质量和纯度特征的现行药品生产质量管理规范操作和管理。”,The CGMP Regulation CGMP法规,Current Good Manufacturing Practice for Finished Pharmaceuticals 对于成品药的现行药品生产管理规范（CGMP）21 CFR Parts 210 and 211Substantive实质性 Force and effect of law 法律效力,The CGMP Regulation CGMP 法规,CGMP for Finished
7、 Pharmaceuticals 对于成品药的现行药品生产管理规范（CGMP）21 CFR Parts 210 and 211Establish“what to”do,not“how to”确定“要做什么,而不是“如何做”Minimal standards 最低标准Maximum flexibility 最大的灵活性Specific enough to address problems 具体到足以解决问题e.g.,Penicillin contamination control 例如，青霉素污染控制Technology neutral 技术中立Scalable 可扩展性,Conducting
8、an FDA Inspection:Objectives进行FDA检查的目标,“Systems Approach”“系统化方法”6 systems overview 6大系统概述Type of coverage:覆盖类型:Records we audit/review 记录审计/审评的内容Operations/practices 操作/规范Explain how to identify and document inspection observations 讲解如何确定和记录检查到的内容,Compliance Program Guidance Manual 符合性项目指南手册7356.002
9、“Drug Manufacturing Inspections”“药品生产检查”,“Systems Approach”“系统化方法”Quality System 质量体系Facilities and Equipment System 设施和设备系统Materials System 物料体系Production System 生产体系Packaging and Labeling System 包装和标签体系Laboratory Control System 实验室控制体系http:/www.fda.gov/AboutFDA/CentersOffices/CDER/ucm095598.htm,Wh
10、at type of inspection can be done?可以进行什么类型的检查？,Full Inspection Option 全面检查方案Quality System plus(at least)three other systems 质量体系加（至少）三个其他系统Abbreviated Inspection Option 简化检查方案Quality System plus one other system 质量体系加一个其他系统,Quality质量,Packaging&Labeling包装和标签,Laboratory实验室,Facilities&Equipment设施及设备,P
11、roduction生产,Materials物料,Records记录,Tools for control of highly-variable parts of the manufacturing processHUMANS 用以控制生产过程中具有高变化性的那一部分.人类“If you didnt document it,then it didnt happen”“没有记录，就没有发生”Requirements in 21 CFR 211 21 CFR 211要求,Records记录,As part of the inspection process 作为检验工作的一部分 Records are
12、 a cornerstone for evaluation of compliance with CGMP 记录是检查CGMP符合性的基础,Records记录,Standard Operating Procedures(SOPs)标准操作规程（SOP）Provide instructions for 为提供指示Completing the task 完成任务Completing the associated documentation 完成相关的文档(the bulk of record review)(大量的记录审查),More Records更多的记录,Process Validation
13、 工艺验证Equipment Qualification 设备确认Computer System Validation 计算机系统验证(Protocol and Executed Protocol)(方案和已执行方案),Quality System质量体系,Annual Product Reviews(APRs)年度产品回顾（APR）Summary综述Specific information required by 21 CFR 211 21 CFR 211要求的具体信息Trends“Snapshot 趋势“快照”Complaints 投诉Procedures define responsib
14、ilities 建立规程明确责任Investigation Reports 调查报告,Quality System cont.质量体系 续,Deviations(Non-Conformances)/OOS 偏差（不合格项）/超规SOPs define responsibilities 建立SOP明确责任Investigation Reports 调查报告Conclusions Final Disposition 结论-最后处置Change Control 变更控制Associated documentation referenced throughout the inspection(reco
15、rd review)在整个检查引用的相关文件(记录评审),Facilities and Equipment System设施和设备系统,Facilities设施 Major considerations when evaluating aseptic processing operations 对无菌工艺操作评估需要重要考虑的因素Building Management System(BMS)建筑管理系统（BMS）Environmental Controls(Temp,RH,DP)环境控制（温度、湿度、压差）Qualification of System 系统确认Maintenance/Cali
16、bration of system and sensors 系统和传感器的维护/校准,Facilities and Equipment System设施和设备系统,Equipment设备Qualification 确认Initial 初始确认Re-evaluation-after changes 再确认-变更发生后*(Change Control Documentation)*(变更控制文件)Preventive Maintenance/Calibration 预防性维护/校准SOP dictates schedule or software program SOP规程或软件程序Outside
17、 Contract?合同外?,Facilities and Equipment System设施和设备系统,Equipment设备Cleaning Validation 清洁验证Establishing Limits 建立限度Recovery Studies 回收率研究Executed Protocol 执行方案,Materials System物料体系,Manual System 人工系统Inventory Cards 货位卡Follow trail from receipt,sampling,testing,approval,storage,and use 跟踪接收、取样、抽检、批准、保存
18、和领用,Computer System 计算机系统Validation 验证Determine the extent of the functions 确定职能范围,Materials System材料系统,Storage Conditions 储存条件Connected to BMS?是否与BMS链接?Temperature Mapping Studies 温度测绘研究Preventive Maintenance/Calibration of sensors 传感器的预防性维护/校准,Materials System材料系统,Water System 水系统 Qualification 确认
19、Monitoring 监测 Sampling SOP 取样SOPTrend Reports 趋势报告,Production System生产体系,Process Validation 工艺验证May not be complete evaluate protocol 可能不完整-评估方案New“Guidance for Industry”from FDA FDA新的“行业指南”Batch Production and Control Records 批生产和检定记录 In-process samples 过程样品Batch Approval and Release 批次审批和放行,Packag
20、ing and Labeling System包装和标签体系,Packaging包装SOPs Line Clearance 清场Includes instructions for start up 包括启动指令Packaging Record 包装记录Initial challenges and periodic monitoring 初步挑战和定期监测,Packaging and Labeling System包装和标签体系,Labeling 标签SOPsReceipt,Issue,Return 标签的接收、签发和回收Packaging Record 包装记录Vendor qualifica
21、tion 供应商确认,Laboratory Control System实验室控制体系,Adequate procedures 充分的规程Standard operating procedures(SOPs)for day-to-day laboratory activities,i.e.实验室日常检测活动的标准操作规程（SOP），如investigation of out-of-specification(OOS)results 超规结果调查standard stock solution preparation 标准浓缩液配制Validated analytical methods 经过验证
22、的分析方法finished product and in-process 成品、过程控制品cleaning validation 清洁验证Audit to ensure:进行审核，以确保:written and/or approved by QC Unit 由QC进行编写和审批current version in use 目前使用的版本easily accessible to laboratory staff 便于实验室工作人员取用,Laboratory Control System实验室控制体系,Sample Tracking 样本追踪Track sample(s)of product(s)
23、including the procedures,equipment and lab personnel involved,e.g.:跟踪产品的样品，包括规程、设备和实验室人员，如：Validated Method 经过验证的方法Properly trained personnel 经过培训的人员Equipment properly maintained and calibrated 经过妥善维护和校准的设备Current/unexpired standards and reagents used 使用的现行/未过期的标准品和试剂Raw material receipt,sampling,qu
24、arantine,testing and release by QC laboratory QC实验室对原辅料的接收、取样、待检、检测和放行In-process&finished product testing 对过程控制品和成品的检测,Laboratory Control System实验室控制体系,Standards 标准Written procedures for:用于的书面规程：receipt,handling,storage,preparation,etc.接收、处理、储存、配制等.Appropriate storage conditions,i.e.适当的贮存条件，如under v
25、acuum,refrigerated,frozen,etc.真空条件、冷藏、冷冻等Appropriately labeled,i.e.适当标记，如reagents,standard stock,volumetric and test solutions clearly identified with preparation and expiry dates试剂、标准储存缩液、试验溶液应清楚标明配制和失效日期Current or unexpired,i.e.current USP lot 现行使用或未过期的，如现行USP批Well characterized primary standard 良
26、好的一级标准Secondary standards traceable to primary standard,i.e.USP,BP,JP 二级标准，可追溯至一级标准，如 USP,BP,JP,Laboratory Control System实验室控制体系,Stability 稳定性Written protocol including:书面方案包括:Duration 持续时间frequency of testing 测试频率storage conditions 储存条件stability indicating test methods 显示稳定性试验方法Adequate stability c
27、hamber 足够稳定性试验箱Data trends 数据趋势,How to identify and document Inspectional Observations如何确定和记录检查到的内容,Evaluation of Compliance 合规性评价Do the firms SOPs,documentation practices,etc.provide a foundation for an assurance of control and compliance with CGMPs?企业的SOP、文件规范等是否足以保证CGMP的控制和符合性？(remember CGMPs are
28、 the minimum standard)(注：CGMPs是最低标准)Does the work product meet the expectations and requirements of the firms SOPs,etc.?产品是否符合该企业SOP等的预期和要求？,How to identify and document Inspectional Observations如何确定和记录检查到的内容,Gotcha!Isolated Incident 抓把柄！-孤立事件Pattern or Practice 模式还是实践Significance!重要性！,Daily Closeou
29、t Meeting每日总结会议,Present and discuss any deficiencies observed 展示并讨论观察到的任何不足之处Make requests for documents,interviews,etc.in preparation for the upcoming day 为以后的完善，提出文件、访谈等要求,Closeout Meeting总结会议,Issue the“List of Observations”列出“观察到的内容清单”Items for discussion only 只讨论事项Managements response 管理层的回应Prop
30、osed corrective actions 建议的纠正措施,Conducting the Inspection进行检查,In summary 总之“Systems Approach”“系统化方法”Identify and document significant observations 确定并记录重要的观察内容,Questions?问题?,Douglas A CampbellCompliance Officer Senior Policy AdvisorCDER/OC/DMPQ/International Compliance Branchdouglas.campbellfda.hhs.
31、gov,Pre-Approval Inspection(PAI)美国FDA药品申报注册批准前检查（PAI）,Objectives目标,Describe the PAI Compliance Program 描述 PAI 合规计划-7346.832(CDER NDA/ANDA/BLA)7346.832（药品、评价和研究中心 新药申请/简化新药申请/生物制品许可证申请）Describe the PAI 描述 PAI The PAI Process PAI 过程Inspectional and Audit Coverage 检查和审计范围,PAI Program PAI 计划,This progra
32、m is designed to provide close inspectional and analytical attention to the authenticity and accuracy of data in applications and to provide information regarding facilities.该方案旨在提供近距离的检索和分析注意的真实性和准确性，应用程序和数据，提供有关设施的资料.PAI Compliance Program-7346.832,“Pre-Approval Inspections/Investigations”for Huma
33、n Drugs,dated 05/12/10 PAI 合规计划-7346.832,人用药“批准前检查/调查”,日期 05/12/10,Compliance Program Objectives合规计划目标-Assure that establishments involved in the manufacturing,testing,or other manipulation of new drug dosage forms and new drug substances are audited:确保新药剂型和新药的生产、测试或其它处理过程中涉及的设施经过审核：*through on-site
34、 inspections for compliance with CGMPs 通过现场检查看CGMPs合规性*for conformance with application commitments 是否与申请资料保持一致*to assure data is authentic and accurate 以确保数据的真实、准确*through laboratory testing of products,including evaluation of the adequacy of analytical methodology.通过对产品的检测，包括评估分析方法的充分性,Compliance
35、Program合规计划,Compliance Program provides guidance for:合规计划为提供指导：-establishment inspections and related investigations 确定检查和相关调查-laboratory evaluations of methods of analysis proposed by applicants in NDA and ANDA submissions(NADA and ANADA for animals)对申请人在NDA和ANDA申报资料（兽药则为NADA和ANADA）中提出的分析方法进行实验室评估-
36、headquarters and field-initiated PAI 总部和实地发起的 PAI,The Pre-Approval Inspection(PAI)批准前检查,How to conduct a Pre-approval Inspection 如何进行批准前检查Specific areas for consideration 需考虑的具体领域Inspection coverage directed to the product referenced in an application to the FDA 检查范围取决于向FDA申报的产品,Three Primary Inspec
37、tional Objectives三个主要的检查目标,-Readiness for Commercial Manufacturing 为商业化生产做准备-Conformance to Application 与申报资料的一致性-Data Integrity Audit 数据完整性审计,Objective 1:Readiness for Commercial Manufacturing 目标1：为商业化生产做准备Does the firm have a quality system that is designed to achieve sufficient control over the f
38、acility and commercial manufacturing operations through the product life cycle?企业是否建立了质量体系，以便在产品生命周期内对厂房和生产进行充分的控制？,a.Manufacturing and laboratory changes,deviations and trends not adequately evaluated.生产和实验室变更、偏差和趋势没有充分的评估b.Scientifically statistical and appropriate sampling,testing,evaluation of c
39、omponents,in-process materials,finished products,containers and closures for release of products including a robust supplier qualification program.科学的成分、过程物料、成品及放行产品的容器的取样、测试和评估，包括对供应商的确认计划c.Sufficient facility and equipment controls in place to prevent contamination of the application product or AP
40、I.对厂房设备的足够控制，以防止对产品的污染d.Adequate SOPs covering batch release,change control,failure investigations,deviations/non-conformances,complaints,ADEs and for reporting information to the Agency(e.g.FARs).足够的SOP，包括批放行、变更控制、失败调查、偏差/不符合项、投诉、不良反应，及向有关当局报告e.Scientific and objective justification of proposed com
41、mercial process and manufacturing batch record,including instructions,processing parameters and process control measures.For example,PV program for evaluation and knowledge/understanding of the process throughout the product life cycle.对商业化生产过程和生产批记录科学客观的证明，包括生产指令、工艺参数和工艺控制措施。如，工艺验证，以便对贯穿整个产品生命周期的工艺
42、进行评估和了解,Objective 1a:Manufacturing and laboratory changes Are deviations and trends adequately evaluated?目标1a：生产和实验室变更是否对偏差和趋势进行有效评估？,The firm should appropriately document,record and objectively assess all development data and information including data submitted and/or generated after the filing o
43、f an application.For examples:企业应适当记录并客户评价所欲开发数据和信息，包括递交申请文件后产生的数据。如：Laboratory issues after MV:unexpected events,including OOS results for stability,in-process and finished product testing for Biobatch(es)or PV batches.方法验证后的实验室问题：意外事件，包括稳定性试验、生物批次或工艺验证批次中间品和成品检测的超规结果Equipment maintenance and perfo
44、rmance that could affect the proposed commercial batch manufacture.对设备的维护以及设备的性能也将影响到商业生产活动Can the firm manufacture the proposed commercial scale batch?企业有能力进行计划的商业比例批量吗？Does the firm have controls in place to detect and/or mitigate significant problems?企业是否具有能检测和/或减少问题发生的控制措施？,Objective 1b:Sound an
45、d appropriate sampling,testing,and evaluation of components(including APIs),in-process materials,finished products,containers and closures for release of products including a robust supplier qualification program.目标1b：科学的成分、过程物料、成品、及放行产品的容器的取样、测试和评估，包括对供应商的确认计划,The firm should review sampling plans
46、for components,in-process,and finished products and assure that representative samples are collected and tested/examined as verification of product quality.企业应审核成分、中间品和成品的取样计划，确保对具有代表性的样品进行采集和检测，以检验成品质量。Method of selecting sample,the statistical criteria for sample size,and the acceptable and unacce
47、ptable quality limits should be scientifically based.应建立有取样方法、取样量标准、可接受质量限度和不可接受质量限度The commercial process should be considered when determining the adequacy of sampling plans 在确立取样计划的适当性时，要把整个生产过程考虑在内Areas of critical or process vulnerability should be considered,as this may require more extensive
48、sampling.关键区域或工艺区域也要考虑，可能需要重点取样,Objective 1c:Sufficient facility and equipment controls in place to prevent contamination of the application product or API.目标1c：足够的厂房和设备控制，以防止对申请产品或API的污染,Coverage is warranted for new construction or facility design,new uses of existing equipment that post potential
49、 risks(e.g.,new highly potent product),or unique application equipment operations.要保证可能造成潜在风险的新建工程或厂房设计、现有设备的重新启用（如，新的高效价产品），或专用设备操作Observe the firms operations and review blueprints,floor plans,or as-built diagrams of utility systems,e.g.Purified water system piping and Air Handling Units(AHUs).查看企
50、业的运作，审核公用设施系统的蓝图、平面布局图或竣工图，如纯水系统管路、AHUVerify that the firm as equipment and containment controls in place designed to prevent contamination and cross-contamination.检查企业是否有防止污染和交叉污染的设备和密封控制设施Inspect new construction and installation of new equipment and any other significant changes to the existing f
