FDA检查员指导手册

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FDA检查员指导手册

FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求……………………………………………………3 5第一部分背景……………………………………………………………………36第二部分执行…………………………………………………………………362.1.目的……………………………………………………………………362.2.策略……………………………………………………………………362.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等）…362.2.2.系统性检查……………………………………………………………372.2.3.对原料药及制剂生产的系统性检查计划……………………………382.2.3.1.质量系统………………………………………………………………382.2.3.2.厂房设施与设备系统…………………………………………………382.2.3.3.物料系统………………………………………………………………382.2.3.4.生产系统………………………………………………………………382.2.3.5.包装和贴签系统………………………………………………………382.2.3.6.实验室控制系统……………………………………39…………………2.3.程序管理指导…………………………………………………………392.3.1.定义……………………………………………………………………392.3.1.1.监督性检查……………………………………………………………392.3.1.2.达标检查………………………………………………………………42.3.1.3.受控状态………………………………………………………………42.3.1.4.药品工艺………………………………………………………………42.3.1.5.药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………413.1.检查活动………………………………………………………………413.1.1.总则……………………………………………………………………413.1.2.检查方法………………………………………………………………423.1.2.1.全面性检查的选择……………………………………………………433.1.2.2.简略性检查的选择……………………………………………………433.1.2.3.综合性检查范围………………………………………………………433.1.3.系统性检查范围………………………………………………………433.1.3.1.质量系统………………………………………………………………443.1.3.2. 厂房设施与设备系统…………………………………………………443.1.3.3.物料系统………………………………………………………………453.1.3.4.生产系统………………………………………………………………463.1.3.5.包装和贴签系统………………………………………………………473.1.3.6.实验室控制系统………………………………………………………483.1.4.取样……………………………………………………………………493.1.5.检查组组成……………………………………………………………493.1.6.报告……………………………………………………………………49第四部分分析……………………………………………………………………5第五部分法律性/行政性策略…………………………………………………55.1.质量系统………………………………………………………………515.2.厂房设施和设备………………………………………………………515.3.物料系统……………………………………51…………………………5.4.生产系统………………………………………………………………525.5.包装和贴签系统………………………………………………………525.6.实验室控制系统………………………………………………………52对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。

FDA检查员指导手册——药品生产检查程序

FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求……………………………………………………3 5第一部分背景……………………………………………………………………36第二部分执行…………………………………………………………………362.1.目的……………………………………………………………………362.2.策略……………………………………………………………………362.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等）…362.2.2.系统性检查……………………………………………………………372.2.3.对原料药及制剂生产的系统性检查计划……………………………382.2.3.1.质量系统………………………………………………………………382.2.3.2.厂房设施与设备系统…………………………………………………382.2.3.3.物料系统………………………………………………………………382.2.3.4.生产系统………………………………………………………………382.2.3.5.包装和贴签系统………………………………………………………382.2.3.6.实验室控制系统………………………………………………………392.3.程序管理指3………………2.3.1.定义……………………………………………………………………392.3.1.1.监督性检查……………………………………………………………392.3.1.2.达标检查………………………………………………………………42.3.1.3.受控状态………………………………………………………………42.3.1.4.药品工艺………………………………………………………………42.3.1.5.药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………413.1.检查活动………………………………………………………………413.1.1.总则……………………………………………………………………413.1.2.检查方法………………………………………………………………423.1.2.1.全面性检查的选择……………………………………………………433.1.2.2.简略性检查的选择……………………………………………………433.1.2.3.综合性检查范围………………………………………………………433.1.3.系统性检查范围………………………………………………………433.1.3.1.质量系4……………………3.1.3.2. 厂房设施与设备系统…………………………………………………443.1.3.3.物料系统………………………………………………………………453.1.3.4.生产系统………………………………………………………………463.1.3.5.包装和贴签系统………………………………………………………473.1.3.6.实验室控制系统………………………………………………………483.1.4.取样……………………………………………………………………493.1.5.检查组组成……………………………………………………………493.1.6.报告……………………………………………………………………49第四部分分析……………………………………………………………………5第五部分法律性/行政性策略…………………………………………………55.1.质量系统………………………………………………………………515.2.厂房设施和设备………………………………………………………515.3.物料系统………………………………………………………………515.4.生产系统………………………………………………………………525.5.包装和贴签系5……………5.6.实验室控制系统………………………………………………………52对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。

CP7356.002FDA检查员指导手册范本

FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1.目的 (36)2.2.策略 (36)2.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2.系统性检查 (37)2.2.3.对原料药及制剂生产的系统性检查计划 (38)2.2.3.1.质量系统 (38)2.2.3.2.厂房设施与设备系统 (38)2.2.3.3.物料系统 (38)2.2.3.4.生产系统 (38)2.2.3.5.包装和贴签系统 (38)2.2.3.6.实验室控制系统 (39)2.3.程序管理指导 (39)2.3.1.定义 (39)2.3.1.1.监督性检查 (39)2.3.1.2.达标检查 (40)2.3.1.3.受控状态 (40)2.3.1.4.药品工艺 (40)2.3.1.5.药品生产检查 (41)第三部分检查 (41)3.1.检查活动 (41)3.1.1.总则 (41)3.1.2.检查方法 (42)3.1.2.1.全面性检查的选择 (43)3.1.2.2. 简略性检查的选择 (43)3.1.2.3.综合性检查围 (43)3.1.3.系统性检查围 (43)3.1.3.1.质量系统 (44)3.1.3.2. 厂房设施与设备系统 (44)3.1.3.3.物料系统 (45)3.1.3.4.生产系统 (46)3.1.3.5.包装和贴签系统 (47)3.1.3.6.实验室控制系统 (48)3.1.4.取样 (49)3.1.5.检查组组成 (49)3.1.6.报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1.质量系统 (51)5.2.厂房设施和设备 (51)5.3.物料系统 (51)5.4.生产系统 (52)5.5.包装和贴签系统 (52)5.6.实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。

fda检查员指导手册--药品生产检查程序(doc75页)(1)

FDA检查员指导手册CP 7356.002:药品生产检查程序对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1. 目的 (36)22 策略 (36)221. 对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2. 系统性检查 (37)2.2.3. 对原料药及制剂生产的系统性检查计划 (38)2.2.3.1. 质量系统 (38)2.2.32 厂房设施与设备系统 (38)2.2.33 物料系统 (38)2.2.34 生产系统 (38)2.2.3.5. 包装和贴签系统 (38)2.2.3.6. 实验室控制系统 (39)2.3. 程序管理指导 (39)2.3.1. 定义 (39)2.3.1.1. 监督性检查 (39)2.3.1.2. 达标检查 (40)2.3.1.3. 受控状态 (40)2.3.1.4. 药品工艺 (40)2.3.1.5. 药品生产检查 (41)第三部分检查 (41)3.1. 检查活动 (41)3.1.1. 总则 (41)3.1.2. 检查方法 (42)3.1.2.1. 全面性检查的选择 (43)3.1.2.2. 简略性检查的选择 (43)3.1.2.3. 综合性检查范围 (43)3.1.3. 系统性检查范围 (43)3.131. 质量系统 (44)3.1.32厂房设施与设备系统 (44)3.1.3.3. 物料系统 (45)3.1.3.4. 生产系统 (46)3.1.3.5. 包装和贴签系统 (47)3.1.3.6. 实验室控制系统 (48)3.1.4. 取样 (49)3.1.5. 检查组组成 (49)3.1.6. 报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1. 质量系统 (51)5.2. 厂房设施和设备 (51)5.3. 物料系统 (51)5.4. 生产系统 (52)5.5. 包装和贴签系统 (52)5.6. 实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR) 。

FDA 发布药械组合产品检查合规手册

FDA 发布药械组合产品检查合规手册美国 FDA 于 6 月 4 日发布了新的合规项目指南手册（CPGM）7356.0000《检查 CDER 或 CDRH 主管的组合产品》，解释了其对由药品审评与研究中心（CDER）或器械与放射健康中心（CDRH）主管的组合产品制造商的检查方法。

FDA 于 2013 年 1 月颁布组合产品 CGMP 最终规定，2017 年 1 月发布组合产品 CGMP 要求定稿指南，除此之外没有更多有关组合产品 CGMP 的法规和指南澄清。

【FDA发布组合产品CGMP要求定稿指南2017/01/30】（法规和指南中英文内容可登录识林阅览。

）CPGM 是 FDA 指导检查员的工作手册，包含了对 FDA 检查员执行检查的细致考虑和要求，是企业学习的好资料。

这份长达 46 页的文件列出了 FDA 对组合产品合规计划的实施期望；检查执行和报告注意要点；采样和分析检测期望；监管和行政策略；以及对中心职责的解释。

该 CGPM 主要针对具有药物和器械或生物制品和器械组成部分的单体（各组成部分物理上或化学上组合在一起，例如预充针或药物洗脱支架）和组合包装组合产品（例如手术套装或急救箱），不涵盖由 CBER 作为主管中心的组合产品的检查，也不适用于仅生产一种类型的组成部分或产品组件（例如，器械组件或原料药）的设施的检查。

组合产品制造商可以通过以下两种方式证明 CGMP 合规：遵守所有适用的 CGMP 或遵守简化方法。

简化方法允许制造商证明符合药品CGMP 或器械质量体系规范之一，以及除此之外的一些具体 CGMP 规定。

手册在附录中详细给出了具体 CGMP 规定包括哪些条款。

FDA 指出，“由于大多数组合产品制造商使用简化方法，因此该手册侧重于对基本 CGMP 合规性以及 21 CFR Part 4 中规定的具体条款合规性的检查。

”FDA 还解释指出，除手册中提到的“具体产品”合规计划外，组合产品还应遵循主管中心和基本合规计划的要求。

FDA 检查指南说明书

FDA Inspections – Best and Worst Practices Bioresearch Monitoring InspectionsFDA Inspections •Intro•Before FDA arrives•While FDA is on-site•As the inspection closes•Common observations•Following the inspectionBefore FDA Arrives…•Be in compliance!–Have the appropriate staff–Provide training to staff on regulatory requirements, specific protocol requirements, any processes or procedures–Facilitate open communications–Not just the what, but the why compliance matters–Assume all studies conducted will be inspected•Be prepared for an inspection–Have procedures for how to handle an inspection–Mock inspection with staff; use sponsor audits as a toolWhile FDA is on-site•Opening meeting–Scope of inspection–Schedule–Explain roles and responsibilities, study conduct–Explain records, organization, access•Objective is to ensure investigator and site staff have clear communication and expectationsWhile FDA is on-site•During the inspection–Be accessible to answer questions, provide copies–Don’t delay unnecessarily, if time is needed to retrieve records/answer, explain why•Daily wrap up–Questions?–Concerns?–Progress?–Plan for following dayAs the inspection closes•Schedule close out meeting, ensure responsible/knowledgeable parties available•Is there an FDA 483?–Observations clear?–Do you have additional documentation not reviewed during inspection?–Verbal response? Will be included in Establishment Inspection Report –Plan to respond in writing?After the Inspection has Ended•If there was an FDA 483 – should respond in writing –Recap observation–Provide explanation if appropriate–Describe corrective actions considered and when they will beimplemented including any SOP revisions, staff training–Consider impact on any other on-going or future studies•No FDA 483, but discussion items?–Consider any impacts and corrective actions you may need to do –Consider a written response, the items will be reported in theEstablishment Inspection Report and reviewedWritten Responses•Will be reviewed by investigator and center•Will be considered if any regulatory/administrative action is contemplated•Thorough responses help!Common ObservationsWarning Letters and FDA 483s21 CFR 312.60 – General Responsibilities•Failure to Follow the Investigational Plan•Failure to Personally Conduct or Supervise •Failure to Protect Rights, Safety & Welfare of Human Subjects•Failure to Obtain ConsentCommon ObservationsWarning Letters and FDA 483s21 CFR 312.62 - RECORDKEEPINGAND RECORD RETENTION•Inadequate Case Histories•Record Retention•Drug DispositionHow do these Drug findings compare to MedicalDevice Research?•Failure to ensure that an investigation was conducted in accordance with the investigational plan [21 CFR 812.100 & 21 CFR 812.110(b)] was cited in 3 of 3 Warning Letters to Medical Device CIs.•Failure to maintain accurate, complete, and current records of each subject’s case history and exposure to the device [21 CFR 812.140(a)(3)] was included in 2 of 3 Warning Letters issued in 2014 & 2015.Failure to follow the Investigational Plan – WLsspecifically identified•Eligibility Violations - including unacceptable ECG results, a subject previously enrolled in a study and received a treatment that was disqualifying, out of range clinical labs (e.g., liver function, kidney function, hematology), disqualifying medical history, prohibited prior/ConMeds, (+) pregnancy test •Randomization prior to receipt/evaluation of Eligibility DataFailure to follow the Investigational Plan – WLsidentified•Dosing Errors – including overdosing, under-dosing, dispensing wrong drug, wrong sequence of dosing, & failing to follow titration or stopping rules•Missed Efficacy and/or Safety Assessments- blood, urine, and/or stool specimens, ECGs, scans•Out of Window Tests/AssessmentsViolations Can Be Avoided•As I mentioned previously, ensuring staff understand the protocol and regulatory requirements will aid in conducting research in compliance with the regulations•Training–make it effective for your staff–Most sites provide training and yet there are still violations–Not just standard GCP training, but training tailored to the studyrequirementsInvestigator Interaction•Most investigators are well trained professionals…•Each site and study are different, help the investigator understand how your site works and any specific study requirements that may be unique•What to do when there are disagreements between investigator and study staff•Should I fear retaliation?Contacts•FDA 482 will list the geographical district office and phone number•District/Program Division Director, HQ – Deputy Program Director, Program Director•OmbudsmanContacts•Program Director–Chrissy Cochran – Chrissy ***************.gov (301) 796-5663 •Deputy Program Director–David Glasgow –*********************.gov (301) 796-5403 •BIMO East Director–Anne Johnson –********************.gov (215) 717-3003 •BIMO West Director–Eric Pittman –********************.gov (312) 596-4259ORA Ombudsman•Jessica Zeller ********************.gov 240-535-6021•The ORA Ombudsman is dedicated to two primary objectives: –Informally address concerns, complaints, and other issues that arise between ORA and stakeholders outside of the Agency,including industry, governmental organizations (federal, state, territorial, and tribal), and other members of the public; and –Engage in outreach and education for these stakeholders and employees of ORA to enhance communication andtransparency with stakeholders.Questions? •Post Conference Follow-upDavid K. GlasgowDeputy Program Director*********************.gov301-796-5403FDA INSPECTIONSSPONSOR/MONITOR/CROPERSPECTIVE Cassandra KennedyGlobal Head, Regulatory Compliance & Quality AssuranceBest Approaches to InspectionsInspection Preparation begins at the time of study startPosted company policies on photography, internet, guestsCreation of Tried and True Inspection Management Procedures Official Management/Sponsor NotificationsClear Roles and Responsibilities•Inspection Lead•Dedicated Scribe•Document Assembly/Reviewers•Runner•Administrative AssistanceLog of all Document Requested and Provided – Reviewed at least daily Live display of scribe notes to the Prep RoomMaintenance of Duplicate Set of Documents TakenOfficial Daily UpdatesFinal ReportResponse Process including internal/external reviewersResolution and completion of findings (both written and verbal)ConfidentialInspection Lessons LearnedInspection Training – will need to be refreshed often!ReceptionistSecurity GuardsInspection RolesInspection ParticipationSenior Leaders – Not always a good ideaAffiliated representatives (sponsor, CRO, vendor, etc) – Good idea or more to manage??Training opportunity as an observerDon’t lose an inspector within your facility..“Typically”, “Usually”, “I think” – if this is the beginning of your inspection response –STOP The inspection isn’t over until the inspector is gone!ConfidentialFDA Inspections•Philip T. Leese MD•Board Certified in Internal Medicine (1980); I year ER Fellowship. •Investigator for Phase I/II Clinical Research studies (1979-2016) •VP Ph. I for Quintiles’ Phase I CRU in KC (1996-2013)•Retired from Quintiles in Spring of 2016•IRB Board Member for Midlands IRB (MLIRB)- 2016 to present •Consultant for Private Practice Research Initiatives 2016-2018 •Presently consulting with Dept. of Psychiatry Kansas University Medical Center•No Conflicts of Interest to disclose.1572 Investigator Commitments•I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.•I agree to personally conduct or supervise the described investigation(s).•I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.1572 Investigator Commitments•I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.•I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.•I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.•I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.1572Investigator Commitments•I will ensure that an IRB that complies with the requirements of 21 CFR Part 56will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.•I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.The FDA Inspector wants to ascertain•who performed various aspects of the protocol for the study (e.g., who verified inclusion and exclusion criteria, who obtained informed consent, who collected adverse event data);•whether the IRB approved the protocol, informed consent form, and any amendments to the protocol prior to implementation;•whether the clinical investigator and study staff adhered to the sponsor’s protocol and investigational plan and whether protocol deviations were documented and reported appropriately;•whether informed consent documents were signed by the subject or the subjects’ legally authorized representative prior to entry in the study (i.e., performance of any study related procedures);•whether authority to conduct aspects of the study was delegated, and if so, how the conduct of the study was supervised by the clinical investigator2 ; •where specific aspects of the investigation were performed;The FDA Inspector wants to ascertain •how the study data were obtained and where the study data were recorded;•accountability for the investigational product, including shipping records and disposition of unused investigational product; •whether the clinical investigator disclosed information regarding his financial interests to the sponsor and/or interests of any sub-investigator(s), spouse(s) and dependent children3 ;•the monitor’s communications with the clinical investigator;•the monitor’s evaluations of the progress of the investigation; and •corrective actions in response to previous FDA inspections, if any, regulatory, sponsor and/or monitor correspondence.Common Clinical Investigator Deficiencies*•Failure to follow the investigational plan/agreement &/or regulations. •Protocol deviations.•Inadequate recordkeeping.•Inadequate subject protection – informed consent issues, failure to report Aes.•Inadequate accountability for the investigational product. •Inadequate communication with the IRB.•Investigational product represented as safe/effective.* Clinical Investigator (CP 7348.811) deficiencies identified in FDA Form 483 issued at close of inspections. 2017 BIMO DataPre-study Preparation•Review past Audits/Inspections: Recommendations and lessons learned?•Identify Study Specific tasks which are potential problem areas. •Are there nuances to the I/E criteria, screening, admission, dosing, safety monitoring procedures which could deep six your study? •Review Training files and update for study specific purposes. •Apply Failure Mode Effect Analysis (FMEA) tool to your study. •Use the SIV to clarify questions/issues which surfaced during the above steps.•Implement Checkoff sheets. Have verifiers for critical steps. •Communicate “knowledge” to your study team- not just by e-mail.During Study preparation •Evaluate FMEA risk mitigation action steps.•Document what is working, what is not working.•Make certain your CAPAs are clearly written.•Make certain you document follow-up on your CAPA action steps. •Document if your action steps worked, needed modifications. •Scrutinize amendments for important changes to I/E criteria, dose instructions or procedures, safety monitoring, stopping thresholds. •Communicate, Communicate, Communicate. (esp. Staff turnover). •Study specific sign off sheets for important delegation: PI and partner/s each sign off on a study specific delegation form.Post study Preparation•Have an internal post study “lessons learned session” and do the same with the CRO/Sponsor.•Use a checklist (e.g. UT Southwestern IRB FDA Inspection Preparation Guide) to scrutinize your study TMF and documents for FDA Inspection preparedness.•Go back to your study specific worksheets, your CAPA documents, your CRA memos, etc. to make certain you have documented follow-up on your action items.•Make your corrections and notes to file now, not months or years later when your are preparing for an audit.•Review page 4 of Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical InvestigatorsFDA Inspections•If you have SOPs- periodically review, revise, and update them and then read them and sign off that you have read them.•Have a “sign off” sheet for critical research documents: IB, Protocol, ICF, amendments, revised consents. Use a master checklist to track that Sub Investigators and other team members are updating their knowledge of the investigation. (Keep good team meeting minutes).•Use I/E exclusion checklists.•Dose escalation, Dose titration checklists- use them.•Subject is lost to follow-up- go the extra mile and find out why? •Train, Train, Train.•Communicate, Communicate, Communicate•Problem anticipate and expect errors. Promptly implement plan to address errors or omissions.•Document, Document, Document.FDA Inspection: “Do”•Have a Procedure for handling Audits/Inspections.a. Audit room, War room, scribes, document request process, etc. •Follow that procedure with the help of your team.•Concisely answer only the question asked.•It’s OK to say- I will get back to you.•Be prompt, accurate, honest, and courteous with your responses. •Ask questions to seek clarity around the Inspector’s observations orconcerns.•Update your team daily as to the flow of the “Inspection”.•Ask for recommendations on how to improve: “What have you seen at other sites that you would recommend for us”.FDA Inspection: “Do Not”•Don’t state you will do something and then fail to follow through.•Don’t try to recreate source documents.•Don’t Back date. Use Note to File.•Avoid saying “We usually do this procedure this way or most of the time”.•Don’t blame others for errors, omissions, protocol deviations.•Don’t fail to implement recommendations from an earlier inspection-esp. from the same inspector•Don’t treat the Inspector as an AdversarySome Relevant References•Howard Lee, Heechan Lee. Failure mode and effects analysis drastically reduced potential risks in clinical trial conduct. Drug Design, Development and Therapy 2017:11 3035-3043.•Robert J. Cody, M.D., M.B.A. Anticipating Risk for Human Subjects Participating in Clinical Research: Application of Failure Mode and Effects Analysis. Cancer Investigation, 24:209–214, 2006•/research/research-administration/irb/•1 U.S. FDA, Inspections, Compliance, Enforcement, and Criminal Investigations,/ICECI/EnforcementActions/Warninglett ers/defauIt.htm•Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical Investigators•/downloads/RegulatoryInformation/Guidances/UCM12 6553.pdfFDA Inspections •Questions?Reasons for Routine PI Federal Inspections•Top Recruiter•PI Reputation (Good or Bad)•Data are inconsistent with data from other sites•Importance of a particular study•Impact of site’s data•Just a chance occurrence•Scheduled pre-planned inspectionReasons for Directed (for cause) Inspection•Suspect false or fraudulent data; outlier data•PI appears to be “outside” his/her specialty•Sponsor appears to have rejected data from the site•Appearance of delay in reporting/submitting safety data (SAE and SUSAR reports are delayed)•Questionable sponsor or PI-sponsor monitoring•Questionable informed consent procedures•Questionable IRB approvals•Study carries significant influence on IP approval•Questionable compliance from the site’s IRBReasons for Direct (for cause) Inspection •Complaint filed by• a subject/patient/family member,• Research team staff, Institution, or• Sponsor•IRB•Concern for conflict of interest (COI) among the research team at the siteFDA Inspections from the IRB PerspectiveDavid BoraskyVice President, IRB ComplianceScope of IRB InspectionsFDA Regs21 CFR 11, 50, and 56Published guidance (not typically held to it)DocumentationIRB recordsRoster and related membership informationWritten procedures i.e., SOPs and controlled documentsProtocol-level documents, correspondence, etc.Inspection guided by BIMO manual Manual should guide the inspectionsCovers all areas of IRB work that fall under FDA regulationCan also be used to self-inspect an IRB or to audit vendorsTypical IRB Experience with BIMO InspectionAnnounced 1 to 3 business days in advance21 CFR 50 and 5621 CFR 11 has not been part of audits even when IRB is on Part 11 system Follow the manualRosters, SOPs, etc1 FDA person on site for2 –3 days2 –3 studies and a sample of approved sitesSite level records including ICFs, approval documentation, correspondenceQuestions for the Panel。

FDA检查员指导手册

原料药生产检查（药物质量保证）目录现场检查汇报规定 (55)第I部分背景 (56)第II部分实行 (57)第III部分检查 (58)第IV部分分析 (63)第V部分法规/行政方略 (65)第VI部分参照资料，附件和联络接触方式 (68)第VII部分中心旳职责 (69)附件A (69)附件B (72)现场检查汇报规定工艺专论汇报在API检查时，要使用下列旳分类进行汇报所检查旳工艺状况1．Non Sterile API by Chemical Synthesis CSN化学合成非无菌原料CSN2．Sterile API by Chemical Synthesis CSS化学合成无菌原料药CSS3．Non Sterile API by Fermentation CFN发酵生产旳非无菌原料CFN4．Sterile API by Fermentation CFS发酵生产旳无菌原料CFS5．Plant/Animal Extraction API CEX植物/动物提取原料药CEX6．Biotechnology API CBI生物技术生产旳原料药CBI第I部分――背景至八十年代后期以来，美国食品与药物管理局以强化了其对原料药(API)生产企业旳检查内容。

从部分方面来说，这归咎于对原料药质量在制剂旳质量、效力、和安全面所起旳重要作用认识旳提高。

例如，在配制成固体口服制剂，混悬剂和局部用药时原料药旳化学特性会对制剂旳溶出度/生物运用度产生不利影响。

此外，原料中旳少许没有鉴别出旳杂质或其特性未知旳杂质会给病人导致旳严重不良反应。

FDA长期以来一直认为，收载在制剂药物生产质量管理规范规定(21 CFR 210 and 211)中旳CGMP概念对原料药生产工艺同样有效。

这些概念包括，与其他一起，产品质量是生产出来旳，雇佣可以胜任和通过培训旳员工，建立合适旳书面程序和管理规定，建立一套在线测试和产品测试系统，工艺验证，和保证原料药在预期旳有效期内质量稳定。

FDA检查员指导手册： 7356.002F中文版

Food and Drug AdministrationCompliance Program Guidance ManualFDA检查员指导手册：7356.002F56002F- Active Pharmaceutical Ingredient Process Inspections (Drug QualityAssurance)56002F-原料药生产检查（药品质量保证）目录现场检查报告要求 (55)第I部分背景 (56)第II部分实施 (57)第III部分检查 (58)第IV部分分析 (63)第V部分法规/行政策略 (65)第VI部分参考资料，附件和联系接触方式 (68)第VII部分中心的职责 (69)附件A (69)附件B (72)现场检查报告要求工艺专论报告在API检查时，要使用下列的分类进行报告所检查的工艺情况1．Non Sterile API by Chemical Synthesis CSN化学合成非无菌原料CSN2．Sterile API by Chemical Synthesis CSS化学合成无菌原料药CSS3．Non Sterile API by Fermentation CFN发酵生产的非无菌原料CFN4．Sterile API by Fermentation CFS发酵生产的无菌原料CFS5．Plant/Animal Extraction API CEX植物/动物提取原料药CEX6．Biotechnology API CBI生物技术生产的原料药CBI第I部分――背景至八十年代后期以来，美国食品与药品管理局以强化了其对原料药(API)生产企业的检查内容。

从部分方面来说，这归咎于对原料药质量在制剂的质量、效力、和安全方面所起的重要作用认识的提高。

例如，在配制成固体口服制剂，混悬剂和局部用药时原料药的化学特性会对制剂的溶出度/生物利用度产生不利影响。

另外，原料中的少量没有鉴别出的杂质或其特性未知的杂质会给病人造成的严重不良反应。

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从部分方面来说，这归咎于对原料药质量在制剂的质量、效力、和安全方面所起的重要作用认识的提高。

例如，在配制成固体口服制剂，混悬剂和局部用药时原料药的化学特性会对制剂的溶出度/生物利用度产生不利影响。

另外，原料中的少量没有鉴别出的杂质或其特性未知的杂质会给病人造成的严重不良反应。

FDA长期以来一直认为，收载在制剂药品生产质量管理规范规定(21 CFR 210 and 211)中的CGMP概念对原料药生产工艺同样有效。

这些概念包括，与其他一起，产品质量是生产出来的，雇佣能够胜任和经过培训的员工，建立适宜的书面程序和管理规定，建立一套在线测试和产品测试系统，工艺验证，和保证原料药在预期的使用期内质量稳定。

FDA在1991年出版的化学原料药检查指南，在1994年经过少量的编辑变化，包含有原料药生产的GMP/验证概念应用和范围方面的基本指南，并包含了FDA对杂质和杂质专论方面的要求。

在对国内和国外原料药进行检查时均必须使用该指南，以促进检查的一致性和均一性。

目前，FDA希望生产企业在API生产的全过程实施CGMP，即从起始原料的使用开始，到对原料药质量和纯度产生影响的关键工艺步骤的验证。

该方法认为所需的控制方法完全依赖于实际的生产工艺且随着合成步骤从早期的中间阶段向最终分离和纯化步骤的延伸控制水平也在不断加强。

该方法允许依据工艺本身（即，化学合成工艺和发酵工艺）及特殊工艺步骤的风险性和关键性采取适宜水平的控制方法。

该“控制所有步骤，验证关键工艺步骤”方法包含在FDA的《原料药制造，加工和储存指南》草案内，其在1996年9月20日公布供公众讨论。

后者可以从CDER的网站下载：/cder/api.htm.。

第II部分实施目的：该符合性程序的主要目的是为对国内和国外各类原料药生产企业的检查提供一份综合性的CGMP检查指南。

程序的管理指导：该程序仅适用于用于制剂的原料药。

原料的定义是任何用于制剂中的物质且当用于制剂生产，加工或包装时，它成为其中的一种有效成分。

虽然，FDA一直用“bulk pharmaceutical chemicals”和“bulk drug substances”来描述这些原料，FDA现已意识到“active pharmaceutical ingredient”这个词汇在国际上得到认同。

从这点上来看为了更清晰，FDA在本符合性程序中采用“active pharmaceutical ingredient”这个词。

国内所有药品生产设施的拥有者或经营者，包括APIs，无一例外的谁都要遵守联邦食品，药品和化妆品法案510(g)部分的管制，作为补充，或者按照21 CFR 207.10的要求进行注册并呈报所进行商业化销售的所有药品清单。

对外国的药品生产商不要求进行注册，虽然也要求他们列出所进口的或向美国进口的药品的清单。

在对外国药品制造商列出药品清单的其他信息请参阅21 CFR 207.40。

虽然，现行的药品生产质量管理规范(CGMP)规定，21 CFR 210 和211，不适用与API，原料药必须符合联邦大法典501(a)(2)(B)部分的要求，即所有的药品均应按照现行药品生产质量管理规范生产。

在符合联邦大法典方面，原料药和制剂没有区别，其中任一个不符合CGMP要求都被视为违背联邦大法典。

因此，在本文件中，CGMP指的是后者，而不是21 CFR 210 和211。

例外：本程序不适用于无菌原料药的灭菌和无菌加工过程，这些过程受符合性程序7356.002A，无菌工艺检查的管理。

FDA一直将无菌原料药视同制剂管理，并要求其遵守制剂的CGMP规定(21 CFR 210 和211)，理由是他们在不需进一步纯化和处理的情况下，在无菌条件下进行分装以后就成了制剂。

第III部分――检查对原料药生产企业的检查，不论是国内还是国外，都应该由在发酵，化学合成，DNA重组和其它生物技术生产方法受过专门教育和/或培训的有经验的检查员来进行。

建议在API检查中配备化学家或微生物学家，特别是在评估实验室操作（如，分析方法评估，分析数据，实验室检测方法和仪器方面），建立杂质专论的分析方法分析，发酵生产工艺，复杂的多步骤化学合成工艺。

从事API检查的检查员应指导原料药生产与制剂生产有本质的区别。

API通常通过化学合成，DNA重组技术，发酵，酶促反应，由天然材料中提取，或上述方法的结合而生产出来的。

API的生产典型的特征是通过不同的化学，物理和生物处理步骤使起始原料和中间体发生重大改变。

纯化是其最终目的。

与此相反，制剂是由原料药配制而成的，其中的原料药通常受到制剂厂家某种程度的质量控制。

最重要的一点是，制剂生产工艺不包括典型的纯化步骤。

因此，原料生产中所用到的生产和质量控制以及他们在整个工艺过程中的应用（即，控制的严格程度，书面指令，过程控制，取样，测试，监测和在早期步骤及分离和纯化阶段用到的文件）与在制剂生产厂所见到的是有很多不同的。

然而，这种不同只是仅仅反应出生产工艺的不同，而不是说这两类产品在执行GMP的重要性方面的固有区别。

因为，原料药生产企业经常被制剂生产者引用，每一次检查都应尽可能多的覆盖API的生产工艺。

这一策略会最大效率的利用FDA的资源并可避免对同一个生产厂重复检查，这样可以覆盖在随后的申请中所引用的不同的API类型。

因次，随着本符合性程序的修订版的生效，对所有API生产企业的检查，不论它们是如何生产的，都应是“对符合GMP情况进行确认的检查”。

检查应覆盖所指定的特殊的API检查及在过去两年没有检查到的API。

对外国API企业来说，检查员应仅检查准备在美国上市或已经在美国上市的原料药部分。

所选择的API范围应包括在制剂申请中引用的那些原料，他们应是有重要治疗价值的，将用于注射剂中的，难以生产的，或那些有符合性方面问题记录的。

然而，这并不阻止选择治疗价值较低的原料药来评估特殊的API工艺，也不限定对该企业的检查深度。

进行API检查的检查员应该知道本程序第II部分所述的通用检查策略。

考虑到API企业的大小不同，操作的多样性，及质量保证系统，检查员应该仔细的计划对每个企业的检查计划。

应特别关注位于发展中国家的API生产企业。

API生产中存在于组分，工艺用水和溶剂中的杂质和污染或被带到原料药中去，而且不论是由API生产者还是制剂生产者进行的测试均不能检测到。

在检查中，检查员应评估用于提取和纯化工序的工艺用水和溶剂质量，该企业防止API污染/交叉污染的方法，控制杂质的方法，和为每一个API 工艺建立完整的杂质专论的程序和测试方法。

这些内容的详细部分在FDA1991年9月出版的化学原料药检查指南及其附件A中。

在检查中，检查员应审查去年所生产的批以确定不仅那些被放行的，还应有所有的被拒绝批的情况。

还应检查该企业关于API再加工和重新加工的政策。

有些批号一开始是药用级，后来又变成技术级。

这可能预示着已验证的工艺存在问题。

另外，也因对设备清洁验证进行审核以确保企业能把杂质，微生物污染，和内毒素去除到用该原料所做的制剂是注射剂或液体口服制剂时可以接受的水平。

对批准前的检查来说，可以参阅CP 7346.832中提供的指南，批准前检查/调查，并评估制剂申请和DMF中数据的真实性和准确性。

按照引用两个符合性程序中的适宜程序分配代码(PACs)报告检查时间，同时应以每个程序的覆盖范围为基础。

国外药品检查程序中的变更从97年开始，为使得符合性检查过程合理化，CDER同意对国外药品检查程序做几处变更。

紧急和调查行动处(ORO/DEIO)将继续同外国政府一起制定国外检查计划，为检查组做旅行安排，解决后勤方面的问题。

然而，新的程序对处理外国企业对FD-483的回复，呈报现场检查报告，和评论外国企业对FD-483的回复是有效的。

检查员应指导外国企业将FD-483的书面回复原件直接交给CDER的符合性办公室，同时给检查组组长一份复印件。

文件的回复应交到以下地址：Food and Drug AdministrationForeign Inspection Team, HFD-322Division of Manufacturing and Product QualityCenter for Drug Evaluation and Research7520 Standish PlaceRockville, Maryland 20855-2737检查员和分析员应该将关于外国企业对FD-483回复的评论直接交到CDER的国外检查组(FIT)。

在相关的地区办公室审查并认可后，所有的国外检查现场报告(EIRs)将立即送至FIT供评审和最后分类。

FIT将继续向外国企业签发警告信，无标题信件和其它信件。

FIT也会建议自动延迟外国企业/产品，向评审单位提供建议，适宜时，并要求跟踪检查。

检查参阅1991年9月FDA的化学原料药检查指南，（1994年修订）以熟悉进行API检查时应考虑不同的区域和原料药品。

本符合性程序的附件A是对API检查中所覆盖的区域总结。