FDA检查员指导手册： 7356.002F中文版
FDA检查员指导手册药品生产检查程序制度范本格式
FDA检查员指导手册CP ：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…………………………………………………………………36.目的……………………………………………………………………36.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………………….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……………………………………………………………………41.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…………………………………………………5.质量系统………………………………………………………………51.厂房设施和设备………………………………………………………51.物料系统……………………………………51………………………….生产系统………………………………………………………………52.包装和贴签系统………………………………………………………52.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查厂应对准备
• 查厂:
– 1. 全面性查厂
• 针对首次查厂 • 六大系统中至少查四个, 其中含Quality System
– 2. 简易式查厂
• 例行性查厂 • 六大系统中至少查二个, 其中含Quality System
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查厂前:完成 FDA Inspection Checklist - QUALITY SYSTEM
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没有符合FDA的影響
• • • • • 收到FDA的警告信 公司面臨财政灾难 新产品的批准延迟 货物停止生产、产品召回 输入到美国的药物、原料药、医学器材 将会被取消
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常見違反FDA标准的主要行为
1. 没有SOP或者SOP不充分，或者SOP没有被批准 2. 没有管理审查(review) 3. 质量控制单位的责任没有明确定义，或者质量控 制单位没有依照正常手续 4. 没有内部审查 (internal audit) 5. 没有职员培训或者培训不够充分 (no training) 6. 制造工艺流程没有经过验证 (no validation) 7. 实验室控制管理不够充分 (management) 8. 没有设备维护和清洁或者这方面不够充分 (maintenance and cleaning)
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如何接待FDA审查人员
1. 负责人员向其询问与其他参观者相同的问题，如身 份证、FDA证件、姓名、单位、地址和电话号码。 2. 若由其他人员陪同审查员，询问原因和陪同人员的 职责。 3. 通报公司的业主，将审查人员的时间。 5. 然后可以与审查团共同拟订一个日程表。 6. 尽可能很快的答复提出的问题和提供需要的文件 7. 避免与审查人员就调查发生冲突 8. 全天候陪护审查人员，使他们在指定地点内活动 9. 记录所有的问题和答复
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 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CP药品生产检查程序
F D A检查员指导手册C P药品生产检查程序Document serial number【NL89WT-NY98YT-NC8CB-NNUUT-NUT108】FDA检查员指导手册CP ：药品生产检查程序目录对现场报告的要求………………………………第一部分背景………………………………第二部分执行…………………………….目的……………………………….策略……………………………………………………………………36对生产企业两年一度的检查（包等）…系统性检查………………………………对原料药及制剂生产的系统性检划…………………………….质量系统……………………………….厂房设施与设备系统……………………………….物料系统……………………………….生产系统……………………………….包装和贴签系统……………………………….实验室控制系统……………………………….程序管理指导………………………………定义……………………………….监督性检查……………………………….达标检查……………………………….受控状态……………………………….药品工艺……………………………….药品生产检查………………………………第三部分检查……………………………….检查活动………………………………总则………………………………检查方法……………………………….全面性检查的选择……………………………….简略性检查的选择……………………………….综合性检查范围………………………………系统性检查范围……………………………….质量系统……………………………….厂房设施与设备系统……………………………….物料系统……………………………….生产系统……………………………….包装和贴签系统……………………………….实验室控制系统………………………………取样………………………………检查组组成………………………………报告………………………………第四部分分析………………………………第五部分法律性/行政性策略……………………………….质量系统……………………………….厂房设施和设备……………………………….物料系统……………………………….生产系统……………………………….包装和贴签系统……………………………….实验室控制系统………………………………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： 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。
FDA检查员指导手册C ：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）…3 62.2.2.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……………………………3 82.2.3.1.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.程序管理指导…………………………………………………………392.3.1.定义……………………………………………………………………392.3.1.1.监督性检查……………………………………3 9………………………2.3.1.2.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……………………………………4 3…………………3.1.3.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 0………………………………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检查员手册
FDA检查员指导手册7356.002F原料药生产检查（药品质量保证）第一部分背景总则法案的501(a)(2)(B)条款要求所有药品的生产都必须遵守现行GMP的要求，而原料药也不例外。
对于原料药和制剂这两者的要求，法案并没有区别对待，而任何原料药或制剂方面的GMP缺陷都构成了对法案的偏离。
对于原料药或药物成分来说，FDA并没有为此而专门发布cGMP法规文件（就像我们现在有的制剂cGMP法规一样）。
因此，本文提到的“cGMP”指的是法案要求，而并非美国联邦法规（CFR）第21部分210和211条款中关于制剂的要求。
其实，FDA早就意识到cGMP对制剂的要求（美国联邦法规第21部分210、211条款）在理念上对于原料药生产来说同样适用且有效。
这些理念包括使用合适的设备；聘用经过培训且通过资质确认的人员；建立充分合理的书面程序和控制，确保生产工艺和控制的有效性，从而保证产品质量；建立一套中间体和最终药品检测方法的体系，确保药品在规定的使用期限内保持质量的稳定性。
2001年，FDA在人用药物注册技术要求国际协调会议（ICH）上与其他政府监管部门共同努力，采用了针对API行业cGMP的国际性指南，也就是ICH Q7A，活性药物成分的药品质量管理的指南。
ICH Q7A正体现了FDA对于原料药现行GMP体系的要求。
因此，遵循该指南要求的API及其相关生产和检验设施是符合法定cGMP要求的。
然而，只要是能符合法案501(a)(2)(B)的要求，并能确保API符合其纯度、均一性和质量特性的方法都可以采用。
在本程序中所使用的术语“活性药物成分”（原料药）的含义与ICH Q7A 中的定义一致。
在ICH Q7A中活性药物成分被定义为“旨在用于药品生产的任何物质或混合物，当用于药品生产时，这些物质即成为药品中的活性成分。
这种物质被用来提供药学活性或在诊断、治疗、止痛、缓解、处理或疾病预防中起着直接作用或用于影响机体结构和功能。
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导…………………………………………………………92.3.1.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.综合性检查围………………………………………………………433.1.3.系统性检查围………………………………………………………433.1.3.1.质量系统………………………………………44………………………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官员灭菌药物检查指南手册7356[1].002A
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CHAPTER 56 - DRUG QUALITY ASSURANCESUBJECT:STERILE DRUG PROCESS INSPECTIONS IMPLEMENTATION DATE *Upon Receipt*COMPLETION DATE9/30/93DATA REPORTINGPRODUCT CODES PRODUCT/ASSIGNMENT CODESIndustry codes 560O2A 54, 56,and 60-66 inclusive.FIELD REPORTING REQUIREMENTSForward a copy of each Establishment Inspe ction Report to H#-30O Attention: Division of Drug Quality Evaluation. Copies of Samples of Collection Reports and Analyst Worksheet for all samplesexcept those which are classified "1"should also be sub m itted.(This material will be used in evaluating the program).*As soon as the district becomes aware of any significant adverse inspectional, analytical, or other information which could orshould affect the agency's new product approval decisions withrespect to a firm, the district should i mm ediately notify HFC-120, Medical Products Quality Assurance Staff, via EMS or fax,and they will, i n turn, convey the information by fax orequivalent expeditious means to the appropriate Center regulatory units.*NOTE: Districts should assure that each operation performed bydirection of of this program circular is entered against thecorrect Product Code and Program/Assignment Code (P/AC).*Current Changes*TRANSMITTAL N#.90-68 (03/05/90)PARTI-BACKGOUND*This program is intended to cover the manufacture of all sterile drug products, including sterile bulk drugs, ophthalmic and o phthalm tic dosage forms, S mall Volume Parenteral (SVP) products, La rge Volume Parenteral ( LVP) products, and any other drug products required to be sterile.Biologicals, veterinary drug products, and bioassay drugs are excluded from coverage under this program.**Current Change*PART II - IMPLEMENTATIONOBJECTIVES*To provide guidance for conducting inspections of manufacturers of sterile bulk and finished dosage form drug products todetermine compliance with the Food, Drug, and Cosmetic Act andthe Good Manufacturing Practice Regulations (GMPs), Title 21, CFR Parts 210 and 211.*To initiate appropriate action against those manufacturers found to be out of compliance.To obtain information on key practices, to identify practiceswhich need correction or improvement, and to evaluate currentgood manufacturing practices in the #sterile drugs industry.PROGRAM #AGEMENT INSTRUCTIONS*I nspections of sterile product manufacturing firms will beperformed as either Full Inspections or Abbreviated inspections.In the Abbreviated Inspection, coverage will be directed to keypoints in the major systems affecting the production of thesterile drug product. If the information collected indicatesthat the firm's practices are in compliance with C GM Ps, theinspection may be concluded at this point.It should be pointed out that inspectional coverage under thisoption is not intended to limit the investigator ' s initiativein any way. If questionable practices are observed in areasoutside of the systems delineated under this option, theinvestigator is urged to expand the inspection to cover theseareas to his/her satisfaction.The Full Inspection Option involves an in depth inspection of key manufacturing systems and processes and their validation in order to maintain surveillance over the firm's activities.See Part III - inspectional and Attachment A for a completediscussion of the coverage requested under these inspectionoptions.*Current Change*This program is to be carried out when firms are inspected aspart of the regular statutory inspection cycle in accordance with the current ORA workplan. If the sterile drug products to beinspected are radioactive drugs, then CP735G.OO2C, "Radioactive Drugs", should be followed as supplementary guidance.*o Consider using a team approach in conducting theseinspections, utilizing investigators familiar with theseprocesses, and chemists, microbiologists, and engineers, asappropriate.o*Investigators or team members should be well qualified in sterile product production experience and preferably havecompleted formal training courses in parenteral drugmanufacture, sterilization methods, procedures andequipment. Microbiologists involved should have experiencein sterility/pyrogen testing and some experience in sterileproduct inspections.**Current Change*PART III - INSPECTIONAL*Refer to CP 7356.002, Drug Process inspections, for generalinformation on CGMP inspections. Refer to CP 7356.OO2C,"Radioactive Drugs" for supplemental instructions specific tora d iopharmaceutical drug products.Foreign inspections should be conducted using the guidance inthis program, taking into account the time limitation on theseinspections.This program provides two inspectional options: an Abbreviatedinspectional Option and a Full Inspectional Option. To determine which option should be used an evaluation of the following isappropriate:1. Review and EvaluationA full inspection should be conducted for initial inspections andmay also be conducted on a surveillance basis at the District 's discretion. Although it is not anticipated that full inspections will be conducted every two years, they should be conducted atless frequent intervals, perhaps at every third or fourthinspection. Also, whenever information becomes known which would question the firm's ability to produce quality products, anappropriate in-depth inspection should be performed.An abbreviated inspection should not be conducted for the initial inspection of a facility, nor when the firm has a past history of fluctuating into and out of compliance. The District shouldutilize all information at their disposal such as past historyresults of sample analyses, complaints, recalls, etc. todetermine if coverage under the abbreviated inspectional optionis appropriate for the specific firm.a. Determine if changes have occurred by comparing currentoperations against the EIR for the previous full inspection.The following type of changes are typical of those thatwould warrant the Full Inspection Option:1.New potential for cross-c ontamination arising throughchange in process or product line.e of new technology requiring new expertise,significantly new equipment or new facilities.**Current Change**b.Review the firm's complaint file, DPPRs, annual product reviews, etc. and determine if the pattern of complaints(or other information available to the District) as well asthe firm's records of internal rejection or reworking ofbatches warrant expanding the inspection to the pu11Inspection Option to look for weaknesses in the firm'sprocesses, systems or controls.c. If no significant changes have occurred and no violativeconditions are observed, the Abbreviated Inspection Optionmay be adequate.d. If significant changes have occurred, or if violative orpotentially violative conditions are noted, the inspectionshould be expanded to the Full Inspection Option to provideappropriate coverage.e. If an inspection needs to be expanded to the Full InspectionOption, it need be expanded only for the applicable generalproduct or process area in question.2.Abbreviated Inspection OptionThis option involves a more limited inspection of themanufacturer to maintain surveillance over the firm'sactivities. An Abbreviated Inspection as described below isadequate for routine coverage and will satisfy the biennialinspection requirement. The use of this option will saveinspectional and clerical resources.a. Inspections performed under this option should cover thoseitems delineated under the Fu11 Inspection Option with theexception that validation need not be covered for thosesystems and processes that have previously been coveredunder the Full Inspection Option.Perform an inspection of the firm's manufacturing facilityincluding a review of a representative number of Master andBatch Production Records (minimum of 5 batches) on productsmanufactured by the firm. Products that appear in thefirm's inspectional history of previous problems should beincluded. A brief inspection of the laboratory shouldinclude a spot c heck of a limited number of test records (atleast 10) to assure that batches are being subjected toadequate testing for conformance to specifications.**Current Changes**Special note should be taken of the firm's packaging andlabeling controls. Any observation of inadequate controlswill indicate that a Full inspectional Option should beperformed. If the following type of procedures areencountered, in-depth inspectional coverage should be givento the firm's Labeling systems:- The use of labels which are similar in size, shape,and color for different products.- The use of cut labels which are similar in appearancewithout some type of 100 percent electronicverification system for the finished product.- If the use of gang printing of cut labels is notminimized as required by current regulations.- If the firm has had more than one mislabeling recallin the past two years.- If the firm fills product into unlabeled containerswhich are later labeled under multiple private labels.If the abbreviated inspection reveals no significantobjectionable conditions, and there are no other factorsrequiring the use of the Full Inspection Option, use of theAbbreviated Inspection Option 18 adequate.Refer to the "Guide to Inspection of Bulk Pharmaceutical Chemical Manufacturing" for guidance on the applicability of CGMPs to bulk operations.3. Full Inspection OptionThe Full Inspection Option will be implemented when: (1) this is the initial inspection of the drug firm; (2) this is the firstinspection performed following a regulatory action against thefirm; or (3) the information collected under the AbbreviatedInspection indicates that the firm's practices are or may bedeficient in one or more system areas. An in-d epth inspection of all manufacturing, support, and documentation systems at the firm in question should be initiated. However, this in-depthinspection may be limited - at the discretion of the investigator - to only that system area that appears to be deficient.It is not expected that inspections performed under this optionwill necessarily result in the preparation of regulatory actionrecommendations. **INSTRUCTIONSThe inspection will focus on the major systems that impact on the safety and effectiveness of all sterile products manufactured by the firm:-sterilization procedures applied to the drug product;components; container/closures; product contact equipmentand surfaces- water systems- air handling- environmental monitoring- handling of incoming components- packaging and labeling- laboratory- lyophili z ation (where applicable)2.It is suggested that one drug product be selected and followedthroughout; if the firm utilizes more than one type of drugproduct sterilization process, one drug product representing each type of sterilization process should be selected.When selecting a drug product for review, drugs that are thesubject of DPPRs or listed in the firm's complaint files shouldbe considered.Drug product information to be reported:A. Name of Selected DrugB. Dosage SizeC. StrengthD. itch sizesE. Nu mber of batches per yearDescribe what type of sterile drug products are manufactured bythis firm:F. SVP6. LVP#. O p hthalmicsI. Sterile OticsJ. Sterile BulkK. Other (identify)Please indicate whether any of these products are lyophilized.The report should include separate sections for each unique drug product and sterilization process investigated.3.Attachment A has been provided as a reference guide for the typeof information that should be evaluated in a sterile processinspection.SAMPLE COLLECTIONCollect *documentary or physical* samples, including 'in-process samples where possible, to document any suspected adulterationand misbranding problems encountered during the inspection.If microbiological contamination is suspected, document wherepossible the conditions which could contribute microbiologicalcontamination to the product *both by collecting records andphysical samples taken aseptically at points where suchcontamination might occur, such as from the WFI system. Products found positive on initial sterility testing should also beconsidered for sampling.Physical samples should not be collected if the estimated levelof microbial contamination is low.*Collect samples for particulate matter contamination whereinspectional observations indicate poor manufacturing practiceshave possibly contributed to the introduction of particulatematter into these products or where finished product controls are inadequate to assure rejection of such units.Sample SizeFor guidance in determining sample sizes for endotoxin andsterility evaluation, refer to the respective Drug SurveillanceRequest (DSR). Such sampling may be accomplished to meet District obligations under that program, a s appropriate.Reporting*The investigator will utilize sections 590, 591, and 592 of the IOM for guidance in reporting inspectional findings.For inspections made pursuant to specific assignments from HFD-33G, all appropriate program areas should be fully reviewed andreported for all firms inspected, regardless of EIclassification.Attachment of standard operating procedures (SOPs),specifications, or other documentation in response to a question and/or to illustrate a deficiency is acceptable provided theresponse/deficiency is clearly described in all accompanyingnarrative.*Notify supervisors immediately if potentially serious healthhazards exist.*Current ChangePART IV - ANALYTI CA L*ANALYZING LABORATORIES1.Routine chemical analyses : all District laboratories exceptW#C and M L MI.2.Sterility Testing:Region Examining LaboratoryNE, MA NYK-RLSE SE-RLMW MLMISW, PA SAN-DO3.Other microbiological examinations : WEAC, NYK-RL (FOR NYKand BUF), SJN, BLT, SE-RL, CIN (for NWK and CIN), LOS, SAN,SEA, DAL and DEN (for DAL and DEN).Salmonella Serotyping Lab : MLMI.4.Chemical cross-contamination analyses by mass spectrometry(MS) : NYK-RL, DAL, SE-RL, DET, DEN, and LOS. Non-massspectrometry laboratories should call one of their ownregional MS labs and/or Division of Field Science (HFC-142)to determine the most appropriate MS lab for thedeterminations to be performed.5.Chemical cross-contamination analyses by Nuclear MagneticResonance (NMR) spectroscopy : SE-RL, NYK-RL, PHI and DET.Non-NMR laboratories should call one of their own regionalNMR labs and/or Division of Field Science (HFC-142) todetermine the most appropriate NMR lab for thedeterminations to be performed.6.Antibiotic Analyses:Examining Laboratory Drug ProductDEN-DO TetracyclinesErythromycinsNYK-RL PenicillinsCephalosporinsDivision of Drug All Other AntibioticsBiology, AntimicrobialDrugs Branch, HFD-178*7.Bioassys : Division of Research and Testing (HFD-470)8.Particulate Matter in Injectables: MLMI (HFD-470).**Current Change*ANALYSIS1.Samples are to be examined for compliance with applicablespecifications. Check analyses will be by the officialmethod, or when no official method exists, by othervalidated procedures. See CPG 7152.012.The presence of cross-contamination must be confirmed by asecond method. Spectroscopic methods, such as MS, NMR, UV-visible, or infrared are preferred. However, a secondchromatographic method may be employed, provided thechromatographic mechanisms are different (e.g., ion-pairingvs. conventional reverse phase HPLC).3.Sterility testing methods should be based on USP XXI and theSterility Analytical Manual, 1981. Other microbiologicalexaminations should be based on appropriate sections of USPXXI and BAM, 6th Edition, Chapter VII, Salmonella andcurrent supplement*Current Change*PART V - REGULATORY/ADMINISTRATIVE S#TEGYThe therapeutic significance of the drug product and thepotential adverse effect of the GMP deviation on the finishedproduct must be considered in determining whether or not aregulatory action and/or administrative action (e.g., withholding NDA/##, G#QAP non-acceptance) is indicated.When the nature of the deviations is considered in relation tothe therapeutic significance of the product(s) and it isdetermined that they pose a minimal risk to the consumer,voluntary correction by management should be sought as theprimary action. *However, this is not to imply that regulatoryaction will never be taken in such cases.* The district shouldrequire that all comm u nications for achieving voluntarycompliance by firm management be submitted in writing and containa time schedule for completion. *The field should determine ifthe schedule is a reasonable time frame and should monitor their progress.*When voluntary action is not accomplished or when the deviations observed pose a threat to the consumer, formal regulatory and/or administrative action should be recommended. When deciding thetype of action to recommend, the initial decision should be based on the seriousness of the problem and the most effective way toprotect the consumer (i.e., when non-sterile injectables arefound, injunction/recall would be the action(s ) of choice ).Outstanding instructions in the Regulatory Procedures Manual(RPM) should be followed.NOTE:The lack of a violative physical sample is not a bar to pursuing regulatory and/or administrative action providingthe GMP deficiencies have been well documented. Physicalsamples found to be in compliance likewise are not a bar topursuing action under UP charges.*The following list represents examples of deficient practiceswhich the Center believes could warrant regulatory and/oradministrative action:1.Contamination with filth, objectionable microorganisms,toxic chemicals or other drug chemicals ; or a reasonablepotential for contamination by same, with demonstratedavenues of contamination such as contact with uncleanequipment or through airborne contamination.2.Failure to assure that each batch conforms to establishedspecifications, such as NDA, USP, customer specifications,and label claims.3.Distribution of product which does not conform toestablished, specifications.**e of test methodology which is not adequate or validated.5.Deliberate blending for the purpose of diluting and hidingpyrogenic, microbiological or other noxious contamination, or where blending of a non-standard batch with one meeting specifications results in one blended batch meeting minimum specifications.6.Failure to assure that each batch is of uniform characterand quality (homogeneous).7.Conducting packaging and labeling operations in such amanner as to introduce a significant risk of mislabeling,for example, the use of cut labels which are similar inappearance without some type of 100 percents electronicverification system for the finished product.8. Failure to keep adequate records, including:o Date(s) of manufactureo QU antity manufacturedo Lot numbero T e st results and dateso L a beli i ng records and specimen of label usedo signature of person(s) responsible for accomplishing significant steps including:(1) determining yield(2)examining labeled containers for correctness oflabel(3)testing for conformance to specifications(4)blending, if required(5)assuring conformance with established manufacturingproc e dure(6)reviewing production and testing records andauthorizing release for distribution9.Failure to record distribution by lot n umb er in a mannerwhich would permit prompt recall.10.Failure to have any information which would establishstability for the intended period of use.*PART VI - REFERENCES, ATPACHMENTS, AND PROGRAM CONTACTS REFERENCES OR AIDSA.Inspection Operations Manual, Chapter 5, Part 542.58 - SterileProducts.B.Proposed CGMP's For Large Volume Parenterals published in theFederal Register, June 1, 1976.C.United States Pharmacopeia, latest revision and its supplements.D.*"Guideline on Validation of the Limulus Amebo cy te Lysate T e st asan End-Product Endotoxin T e st for Human and Animal ParenteralDrugs, Biological Products, and Medical Devices," December,1987.*E.Inspectors T e chnical Guide, Number 1, 1/9/13, "SterilizingSymbols (D, z,F."Understanding and Utilizing Values", Akers, Attia and Avis,"Pharmaceutical Technology", May 1978, pages 31-35.G.*Inspectors T e chnical Guide, Number 5, 6/9/72, "Ethylene Oxide aSterilizations, I. Calculation of Initial Gas Concentration". H.*Principles and Methods of Sterilization in Health Sciences,Charles C. Thomas Co., (1969), p. 508.*I.*Inspectors T e chnical Guide, Number 6, 4/28/72, "Leak-TestingSealed Am puls of Parenteral Solutions"*J.*"Parenteral Preparations", Avis, Chapter 36, pp. 498-524 in Remington's Pharmaceutical Sciences; Edit. Martin; MackPublishing Co., (1965).*K.*Inspectors Technical Guide, Number 24, 7/30/76, "Air Velocity Meters".*L.*Inspectors Technical Guide, Number 25, 9/1/76, "Ethylene Oxide Sterilizations, II. Graphical Aid to Determine GasConcentration".*M.*Inspectors Technical Guide, Number 32, 1/12/79, "Pyrogens, Stilla Danger".*N.Inspectors Technical Guide, Number 36, 10/21/80, "Reverse Osmosis".0.*Inspectors Technical Guide, Number 41, 10/18/85, "ExpirationDating and Stability Testing for Human Drug Products".*P.*Inspectors Technical Guide, Number 43, 4/18/86,."Lyophilization of Parenterals".*Q.Federal Standard 209, #current revision,*R.Remington's Pharmaceutical Sciences, *Current Edition*S.*"Guideline on Sterile Drug Products Produced by Aseptic Processing, # June 1987.*T.*"Guideline on General Principles of Process Validation," May 1987.*U.*Regulatory Procedures Manual, Part 8.*V."Guideline to Inspection of Bulk Pharmaceutical Chemical Manufacturing, Revised November 1987.ATTACHMENTSA-Reference points to be covered as appropriate to thetype of inspection being performed, and the type ofproduct and/or manufacturing system being evaluated.B-To be completed for each type of Biological Indicator and/or Product.CONTACTS*The area code for commercial calls to all headquarters contacts is 301.* A. ORA1.Jay S. AllenInvestigations Operations Branch/DFI/ORO (HFC-l33) Telephone: FTS 443-33402.Methods InquiryDivision of Field Science/ORO (HFC-l40), #lephone: FTS443-*3007*B. CDER*Manufacturing Surveillance Branch (HFD-336)Division of Drug Quality EvaluationTelephone: 8-295-8107**Current Change*PART VII - CENTER RESPONSIBILITIESThe Division of Drug Quality Evaluation (HFD-330) will evaluate all reports. Results 0f these evaluations will be shared with the field, ORA, and interested headquarters units.*Current Change*GUIDE TO EVALUATION OF STERILE PROCESS INSPECTIONSThe following reference questions are provided for evaluation of specific drug products, manufacturing systems, and quality control procedures.The points have been numbered for easier reference in the EIR narrative.COMPONENT STORAGE AND PREPARATION1.Does the firm have adequate written procedures describing thereceipt, handling, that are represented to be sterile and/orpyrogen free? (per 21 CFR 211.80 - 211.94; 211.184)2.Have these procedures been followed for the selected drugproduct?3. Are any colorants used (none are permitted)?4.Does the firm have written control procedures that adequatelydescribe the receipt, storage, sampling, issuance, andreconciliation of labeling and packaging materials? (per 21 CFR211.122 - 130; 211.134 and 211.137).5.Does the firm use cut or rol1 labels?6.Are the labels similar in color, shape, size and format fordifferent products or potencies?7.Does the firm use any type of electronic label verificationsystem (bar codes, machine vision systems, etc.)? Describe8.Is the label verification on receipt, on line, or both?9.Is any printing done on line of label text, lot number,expiration date, etc.?10.Does the firm use dedicated packaging lines?11.Are the samples of labels used for acceptance (proofing) oflabels from vendors based on a statistical plan? Describesampling plan.12.Are labels printed by the firm or by an outside vendor?13.Have these procedures been completely and accurately followed forthe subject drug product?EVALUATION SYSTEMS14.Does the firm have an SOP on vendor audits?15.Has the firm audited the (a) component, (b) container, (c) closure, and (d) label vendors? Report the dates of last audits.16.Does the firm have written procedures for the production andprocess control of drug products? (per 21 CFR 211.100, - 211.115;211.186; 211.188; 211.192)17.Have these production and process control records been approvedby the firm's quality control unit and by designatedorganizational units?18.Have these process control records been completely and accuratelyprepared for the subject drug product?19.Briefly describe the firm's procedures for changing any of thestandard operating procedure documents described above.20.Does the firm have written procedures for the review and approvalof all drug production and control records before release of the batch for distribution? (21 CFR 211.192)21.Were these procedures followed in the review of the selected drugproduct?22.What are the firm's procedures for the investigation to be madefollowing any unexplained discrepancy found in batch productionrecords, or the failure o f a batch or any of its components tomeet specifications? (21 CFR 211.192)23.Were these procedures followed accurately and thoroughlyconcerning any batch discrepancies/failures of the selected drug?24.Does the firm have written laboratory control mechanisms,including change control procedures, which describe conformanceto established specifications and standards for the selected drug product? (21 CFR 211.160-167)25.Were all specified in-process and end product tests performed onthe selected drug product?26.Were all specifications met?*Current Change*MAJOR SYSTEMS AND PROCESSESMonitoring of Environment27.Is the air supplied to critical areas (exposed product/fillingareas) filtered through HEPA filters under positive pressure? 28.Is the air flow in critical areas laminar when delivered to thepoint of use? At what velocity? Is velocity determined at thecritical area or at the filter face?29.How is the air filtered that is s upplied to controlled areas(where unsterilized product, in-process materials, andcontainer/closures are prepared)?30.What are the firm's air quality classifications for:a.exposed product areasb.filling areac.surrounding plant areas31.Is room classification system based upon Federal Standard 209d orother?32.Are HEPA filters efficiency tested?33.How often are HEPA filters integrity tested? What test method isused?34.How often are air flow velocities checked for each HEPA filter?35.Does the firm have a written monitoring program for classifiedareas that included a scientifically sound sampling schedule that describes sampling locations, their relation to the workinglevel, and frequency? Describe the basis for the samplingprogram. (21 CFR 211.160)36.Are both viable and non-viable particulate samplings performed inall classified areas during production?37.Report the frequency of viable sampling using "active" samplingmethods for:a.exposed product areasb.filling areasc.surrounding areas38.Report the limits used, length of sampling period, and ifsampling is done during production or at rest.39.Report the type of viable sampling equipment use (STA,Centrifugal sampler, etc.)。
FDA检查员指导手册--中文译
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.综合性检查范围 (43)3.1.3.系统性检查范围 (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官员原料药检查指南7356.002F(2003年版翻译中文)排版打印
FDA检查员指导手册7356.002F(2003年版)原料药生产检查（药品质量保证）第一部分背景总则法案的501(a)(2)(B)条款要求所有药品的生产都必须遵守现行GMP的要求，而原料药也不例外。
对于原料药和制剂这两者的要求，法案并没有区别对待，而任何原料药或制剂方面的GMP缺陷都构成了对法案的偏离。
对于原料药或药物成分来说，FDA并没有为此而专门发布cGMP法规文件（就像我们现在有的制剂cGMP法规一样）。
因此，本文提到的“cGMP”指的是法案要求，而并非美国联邦法规（CFR）第21部分210和211条款中关于制剂的要求。
其实，FDA早就意识到cGMP对制剂的要求（美国联邦法规第21部分210、211条款）在理念上对于原料药生产来说同样适用且有效。
这些理念包括使用合适的设备；聘用经过培训且通过资质确认的人员；建立充分合理的书面程序和控制，确保生产工艺和控制的有效性，从而保证产品质量；建立一套中间体和最终药品检测方法的体系，确保药品在规定的使用期限内保持质量的稳定性。
2001年，FDA在人用药物注册技术要求国际协调会议（ICH）上与其他政府监管部门共同努力，采用了针对API行业cGMP的国际性指南，也就是ICH Q7A，活性药物成分的药品质量管理的指南。
ICH Q7A正体现了FDA对于原料药现行GMP体系的要求。
因此，遵循该指南要求的API及其相关生产和检验设施是符合法定cGMP要求的。
然而，只要是能符合法案501(a)(2)(B)的要求，并能确保API符合其纯度、均一性和质量特性的方法都可以采用。
在本程序中所使用的术语“活性药物成分”（原料药）的含义与ICH Q7A中的定义一致。
在ICH Q7A中活性药物成分被定义为“旨在用于药品生产的任何物质或混合物，当用于药品生产时，这些物质即成为药品中的活性成分。
这种物质被用来提供药学活性或在诊断、治疗、止痛、缓解、处理或疾病预防中起着直接作用或用于影响机体结构和功能。
CPGM 7356.002A Sterile Drug Process Inspections中文
CPGM 7356.002A 无菌药品生产检查2015/09/11现场报告要求：企业检查报告（Establishment Inspection Reports ，EIRs）通过应用TurboEIR中的特定模块或可被监管事务办公室（Office of Regulatory Affairs，ORA）和药品审评和研究中心（Center for Drug Evaluation and Research，CDER）同时查看的替代性系统，以电子形式进行创建及存档。
对于因未能遵守适用于无菌药品工艺检查的美国联邦法规21卷第210和211部CGMP，而被归为官方行动指示（Official Action Indicated，OAI）的例行商业生产检查，依照监管程序手册（Regulatory Procedures Manual，RPM）的要求，通过MARCS-CMS递交通知、行政或司法行动的建议书。
各区分局需根据现行现场活动合规追踪系统（Field Activities Compliance Tracking System，FACTS）、全景图和CMS程序，立刻报告重大问题，包括快速提交和变更OAI通知。
检查过程中，当获取到有关不恰当的不良事件（Adverse Drug Experience，ADE）报告、未获批药物问题，或批准后报告违规行为（补充申请、现场警示报告（Field Alert Reports，FARs）等）的信息时，应按照适用的合规项目提供的指示以及EIR中单独的说明进行报告。
与这些检查活动相关的数据系统信息应根据单独的项目任务代码（Program Assignment Codes，PACs）报告。
在这些项目中，如扩大覆盖范围进行CGMP检查，应根据此合规项目进行报告。
要求各区分局应用此合规项目进行所有无菌药品工艺检查。
注：各区分局需保证按照此项目通知的指示执行的各项操作，需输入正确的产品编码和项目/任务代码（Program/Assignment Code ，P/AC）。
FDA检查员指导手册CP药品生产检查程序
FDA检查员指导手册CP ：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…………………………………………………………………36.目的……………………………………………………………………36.策略……………………………………………………………………36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）…3 6系统性检查……………………………………………………………3 7对原料药及制剂生产的系统性检查计划……………………………3 8.质量系统………………………………………………………………38.厂房设施与设备系统…………………………………………………38.物料系统………………………………………………………………38.生产系统………………………………………………………………38.包装和贴签系统………………………………………………………38.实验室控制系统……………………………………39………………….程序管理指导…………………………………………………………39定义……………………………………………………………………39.监督性检查……………………………………………………………39.达标检查………………………………………………………………4.受控状态………………………………………………………………4.药品工艺………………………………………………………………4.药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………41.检查活动………………………………………………………………41总则……………………………………………………………………41检查方法………………………………………………………………42.全面性检查的选择……………………………………………………43.简略性检查的选择……………………………………………………43.综合性检查范围………………………………………………………43系统性检查范围………………………………………………………4 3.质量系统………………………………………………………………44.厂房设施与设备系统…………………………………………………44.物料系统………………………………………………………………45.生产系统………………………………………………………………46.包装和贴签系统………………………………………………………47.实验室控制系统………………………………………………………48取样……………………………………………………………………49检查组组成……………………………………………………………49报告……………………………………………………………………49第四部分分析……………………………………………………………………5第五部分法律性/行政性策略…………………………………………………5.质量系统………………………………………………………………51.厂房设施和设备………………………………………………………51.物料系统……………………………………51………………………….生产系统………………………………………………………………52.包装和贴签系统………………………………………………………52.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官员原料药检查指南手册7356.002F
Food and Drug AdministrationCompliance Program Guidance Manual PROGRAM 7356.002F*Current Changes*FORM FDA 2438g (Computer Generated, 05/98)PAGE 1 of 30CHAPTER 56 - DRUG QUALITY ASSURANCE SUBJECT:*ACTIVE PHARMACEUTICAL INGREDIENTS (APIs)*IMPLEMENTATION DATE Upon ReceiptCOMPLETION DATEContinuingDATA REPORTINGPRODUCT CODES PRODUCT/ASSIGNMENT CODESIndustry Codes: 54 and 56 See Below56002F -Active Pharmaceutical Ingredient Process Inspections (Drug Quality Assurance)56008A -Drug Product Surveillance, CDER Initiated 56008H -Drug Product Surveillance, Imported Drugs, CDER and District Initiated Surveys 56R806-Foreign Routine Drug Surveillance Inspections*FIELD REPORTING REQUIREMENTSOAI ALERTSWhen the district becomes aware of any significant adverse inspectional, analytical, or other information that could or should affect the agency's new product approval decisions with respect to an *activepharmaceutical ingredient manufacturer referenced in an application, *the district should immediately notify HFC-240, Medical Products Quality Assurance Staff, via EMS or FAX. HFC-240 will thenconvey the information by FAX or equivalent expeditious means to the *Division of Manufacturing and Product Quality (HFD-320) in CDER's Office of Compliance.*PROCESS PROFILE REPORTING*In December 1995, at the request of CDER, the Medical Products Quality Assurance Staff (HFC-240) added profile classes CSN (Non Sterile API by Chemical Synthesis) and CSS (Sterile API by Chemical Synthesis) to the drug profile classification system. This change was requested because separate profile classes existed for nonsterile and sterile active pharmaceutical ingredients produced by fermentation processes, but the same did not hold true for active pharmaceutical ingredients produced by chemical synthesis processes. In implementing the change, however, MPQAS did not eliminate the profile class "CCS" because deleting the latter would have caused a loss of history in the GWQAP profiling system. Therefore, effective with this program circular, discontinue using Profile class CCS (Chemical Synthesis Crude Drug) and use only the following seven bulk profile classes to report the processes covered during API inspections:*FULL DESCRIPTION PROFILE CLASSNon Sterile API by Chemical Synthesis CSNSterile API by Chemical Synthesis CSSNon Sterile API by Fermentation CFNSterile API by Fermentation CFSPlant/Animal Extraction API CEXBiotechnology API CBICrude Bulk Not Elsewhere Classified (i.e., producers CRU*of bulk intermediates, and contract micronizers of APIs)*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE 2 of 30REPORTING TO FORENSIC CHEMISTRY CENTER (FCC):*In order to assure that foreign firms supply the requested profile samples and documentation (See Page 12, Items 1 & 2), the Forensic Chemistry Center (FCC) should receive a copy of the coversheet for all inspections of foreign active pharmaceutical ingredient manufacturers. The coversheet endorsement should include a phone and fax number of the contact person at the firm. If a sample is not collected by the investigator during the inspection, the coversheet should also state that the manufacturer was instructed to collect and ship a sample and applicable records directly to FCC as per Appendix B. This will permit proper follow-up by FCC and also serve to identify the investigator who will receive a copy of the annotated collection report prepared by FCC. On a quarterly basis, FCC will send a summary of sample testing results to the Foreign Inspection Team (FIT), HFD-322.The container/closure and product information obtained from Appendix B will be included in the Active Pharmaceutical Ingredient Databases and made available to District Import Offices to help prevent counterfeit APIs from entering the United States market.*REPORTING TO CDER S DIVISION OF MANUFACTURING AND PRODUCT QUALITY: For domestic inspections of active pharmaceutical ingredient manufacturers, submit a copy of the EIR coversheet, FD-483, and District issued copy of Warning Letters (after CDER review and concurrence) to CDER's Division of Manufacturing and Product Quality, HFD-320, for review and trend analysis.*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE 3 of 30*Current Changes*FORM FDA 2438g (Computer Generated, 05/98)PAGE 4 of 30PART I - BACKGROUND*Since the late 1980's, the U.S. Food and Drug Administration has intensified its inspectional coverage of active pharmaceutical ingredient (API) manufacturers. This is due, in part, to an increased awareness that API quality plays a potentially significant role in the quality, efficacy, and safety of finished dosage form pharmaceuticals. For example, physical properties of APIs formulated into solid oral dosage forms,suspensions, and topicals may adversely affect drug product dissolution/bioavailability. In addition,extremely small quantities of unidentified or uncharacterized impurities in drugs may cause serious patient side effects.FDA has long recognized that CGMP concepts, embodied in the good manufacturing practice regulations for finished pharmaceuticals (21 CFR 210 and 211), are valid and can be applied to API processes. These concepts include, among others, building quality into the product, employing appropriately qualified and trained personnel, establishing adequate written procedures and controls, establishing a system of in-process and end product tests, process validation, and ensuring stability of APIs for the intended period of use.*The *September 1991 FDA Guide to Inspections of Bulk Pharmaceutical Chemicals, reformatted in May 1994 with minor editorial changes, contains general guidance as to the extent and application ofGMP/validation concepts to API production and agency expectations regarding tests for impurities and impurity profiles. This guide must be used for inspection of both foreign and domestic facilities to promote inspectional consistency and uniformity.**At present, FDA expects API manufacturers to apply CGMPs to all steps of an API process, beginning with the use of starting materials, and to validate critical process steps that impact the quality and purity of the final API. This approach recognizes that the control needed is highly dependent on themanufacturing process and that the level of control increases throughout the synthesis as the processproceeds from early intermediate steps to final isolation and purification steps. This approach also allows appropriate levels of control, depending on the process itself (i.e., fermentation process vs. chemical synthesis) and the risk or criticalness associated with the specific process step being performed.This "control all manufacturing steps, validate critical process steps " approach is embodied in the draft FDA Guidance for Industry on the Manufacture, Processing or Holding of Active Pharmaceutical Ingredients, which was released for public discussion on September 20, 1996. The latter can be obtained from CDER s Drug Information Branch, HFD-210, or can be downloaded from CDER s Home Page at /cder/api.htm.*PART II - IMPLEMENTATIONOBJECTIVEThe primary objective of this compliance program is to provide comprehensive CGMP inspectional coverage of the domestic and foreign active pharmaceutical ingredient (API) industry in all profile classes (processes).PROGRAM MANAGEMENT INSTRUCTIONS*This program circular applies only to active pharmaceutical ingredients intended for use in drug products. An active pharmaceutical ingredient is defined as any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished dosage form of the drug. Although the agency has used the terms bulk pharmaceutical chemicals and bulk drug substances to describe these materials, FDA is aware that the term active pharmaceutical ingredient has international recognition. In light of this and for added clarity, the agency is adopting the term active pharmaceutical ingredient for use in this compliance program.**Owners or operators of all domestic drug establishments, to include APIs, not exempt under section510(g) of the Federal Food, Drug, and Cosmetic Act, as amended, or 21 CFR 207.10 are required to register and to submit a list of every drug in commercial distribution. Foreign drug manufacturers are not required to register, although they are required to list all drugs imported or offered for import into the United States. Refer to 21 CFR 207.40 for additional information on drug listing requirements for foreign drug establishments.*Although the current good manufacturing practice (CGMP) regulations, 21 CFR 210 and 211, do not apply to APIs, active pharmaceutical ingredients are subject to the broad requirement of Section501(a)(2)(B) of the Act in that they must be prepared in conformance with current good manufacturing practice. *No distinction is made between APIs and finished pharmaceuticals in the Act, and failure of either to comply with CGMP constitutes a violation of the Act.* Therefore, in this document, the term CGMP refers to the latter, rather than 21 CFR 210 and 211 provisions.*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE 5 of 30EXCLUSION*This program circular does not apply to the sterilization and aseptic processing steps of sterile active pharmaceutical ingredients, which are covered by Compliance Program 7356.002A, Sterile Drug Process Inspections. The FDA has long maintained that sterile APIs are finished drug products subject to the CGMP regulation for finished pharmaceuticals (21 CFR 210 and 211) because these are repacked as finished dosage forms under aseptic conditions without further purification or processing.**Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE 6 of 30PART III - INSPECTIONAL*Inspections of active pharmaceutical ingredient manufacturers, whether foreign or domestic, should be conducted by experienced investigators with education and/or training in fermentation, chemical synthesis, recombinant DNA, and other biotechnology manufacturing methods. Use of chemists and/or microbiologists during API inspections is recommended, particularly for evaluating laboratory operations (e.g., analytical methods evaluation, analytical data, lab procedures and instrumentation), analytical review of methods used to establish impurity profiles, fermentation manufacturing processes, and complex multi-step chemical synthesis processes.**Investigators conducting API inspections must understand the basic differences between the processes used for the production of APIs and those used for finished dosage forms. APIs are usually produced by chemical synthesis, recombinant DNA technology, fermentation, enzymatic reactions, recovery from natural materials, or combinations of these processes. The production of APIs typically involves significant changes of starting materials or intermediates by various chemical, physical, and biological processing steps. Purification is the ultimate objective.In contrast, finished drug products are formulated from bulk raw materials that are usually subjected to some degree of quality control by the users (dosage form manufacturers). Most important, the manufacturing processes for finished pharmaceuticals typically do not involve purification steps.For these reasons, the manufacturing and quality controls employed in API production and their application throughout the process (i.e., stringency of controls, written instructions, in-process controls, sampling, testing, monitoring, and documentation employed in early processing steps vs. later isolation and purification steps) differ somewhat from those found in finished dosage form plants. These differences, however, are simply reflections of different manufacturing processes, not inherent differences in the importance of GMPs for the two types of production.**Since manufacturers of active pharmaceutical ingredients are often referenced in many drug applications, each inspection should cover as many API processes as is feasible. This strategy will maximize the use of agency resources and avoid repeated visits to the same manufacturing site to cover different API profile classes referenced in subsequent applications. Thus, effective with this CP revision, all inspections of API manufacturers, regardless of how these are initiated, will be "GMP qualifying inspections." Inspections should cover the specific API profile classes referenced in the assignment and all other API profile classes not inspected in the last two years.*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE7 of 30For foreign API firms, investigators should only cover profile classes for APIs intended to be marketed or already marketed in the United States.APIs selected for coverage should include those referenced in drug applications, are therapeutically significant, are intended for use in parenteral drug products, are difficult to manufacture, or those on record as having past compliance problems. However, this does not preclude the selection of less therapeutically significant active pharmaceutical ingredients to evaluate specific API processes (profile classes) not previously given in-depth coverage at the facility.Investigators conducting API inspections should understand the general inspection strategy set forth in Part II of this program. Recognizing that API firms vary greatly in size, diversity of operations, and quality assurance systems, investigators should carefully plan their inspectional strategy at each firm. Of particular concern are API manufacturing operations located in developing countries. *Impurities and contaminants present in components, process water, and solvents used in the production of APIs may carry over into the active pharmaceutical ingredient and may not be detected by analytical tests conducted by either the API manufacturer or the dosage form manufacturer. During inspections, investigators should review the quality of process water and solvents used in isolation and purification steps, the firm's procedures for preventing API contamination/cross-contamination, procedures for controlling impurities, and the procedures and test methods for establishing a complete impurity profile for each API process.* These are covered in detail in the September 1991 FDA Guide to Inspection of Bulk Pharmaceutical Chemicals and its "Appendix A."During inspections, investigators should review the batches manufactured during the last year to determine not only those released, but any rejections. The firm s policy on reprocessing and reworking of APIs should also be examined. Some batches start off as a pharmaceutical grade and then become technical grade. This could indicate a problem with the validated process. In addition, equipment cleaning validation should be reviewed to assure that the firm can remove residues, microbial contamination, and endotoxins to acceptable levels when the end product is intended for parenteral or liquid dosage forms.*For API inspections initiated by a preapproval assignment, review guidance provided in CP 7346.832, Pre-Approval Inspections/Investigations, and assess the authenticity and accuracy of data contained in drug applications and drug master files. Report inspectional time under the appropriate program assignment codes (PACs) referenced in both compliance programs, based on coverage afforded to each program.**Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE8 of 30*CHANGES IN THE FOREIGN DRUG INSPECTION PROGRAMBeginning in FY 97, ORA and CDER agreed to implement several changes to the foreign drug inspection program to streamline the compliance review process. The Division of Emergency and Investigational Operations (ORO/DEIO), will continue to work with foreign governments in scheduling foreign inspections, making travel arrangements for inspection teams, and resolving logistical problems. However, new procedures are in effect for handling a foreign firm's response to an FD-483, submitting establishment inspection reports, and commenting on a foreign firm's response to an FD-483. Investigators should instruct management at foreign firms to submit the original written response to an FD-483 directly to CDER's Office of Compliance with a copy to the lead investigator. The original response with appropriate documentation should be submitted to the following address: Food and Drug AdministrationForeign Inspection Team, HFD-322Division of Manufacturing and Product QualityCenter for Drug Evaluation and Research7520 Standish PlaceRockville, Maryland 20855-2737Investigators and analysts will submit written comments regarding a foreign firm's response to an FD-483 directly to CDER's Foreign Inspection Team (FIT). After appropriate district office review and endorsement, all foreign establishment inspection reports (EIRs) will be promptly forwarded to FIT for review and final classification. FIT will continue to issue Warning Letters, Untitled Letters and other correspondence to foreign firms. FIT will also recommend automatic detention of foreignfirms/products, make recommendations to review units, and request follow-up inspections, as appropriate.*INSPECTIONReview the September 1991 FDA Guide to Inspections of Bulk Pharmaceutical Chemicals, (Reformatted May 1994) to become familiar with the various areas and topics that must be considered when conducting API inspections. Appendix A of this CP program is a summary of areas to be covered during API inspections. Photocopy this appendix and take with you*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE9 of 30during inspections. Also obtain a copy of the drug application and/or Drug Master File (DMF), as applicable, and review these before initiating the inspection.Third (field) copies of applications, *supplements and annual reports* are now required (Refer to 21 CFR 314.440) and such copies are submitted by domestic firms directly to the applicant's home FDA district office. Foreign *applicants* are required to submit third copies of applications to the same headquarters units receiving the first and second copies. These are made available by DEIO to investigators before initiation of foreign inspections.*Investigators should review all available information including prior inspectional information, FD-483s and responses, any Warning Letters, the firm's compliance history, sample analysis results, complaints, recalls, etc., to prepare for the inspection. For domestic inspections, the information is available from the Pre-Approval Monitors (PAMs) at each District Office. For foreign inspections, the information is available from DEIO or FIT.**Additional suggested references that Investigators and Chemists should be familiar with include: the draft Guidance for Industry - Manufacture, Processing or Holding of Active Pharmaceutical Ingredients; USP <1086> Impurities in Official Articles; and the recent changes in tests for the presence of foreign substances and impurities, contained in Page 3636 of USP-NF Supplement 6, effective May 15, 1997. In addition, the Investigator should contact the Forensic Chemistry Center (FCC) to determine which APIs should be sampled, so that duplicates are not collected during different inspections.**The Investigator should consult the CDER Case Officer for clarification of the assignment to assure that they are aware of the previous deficiencies at the firm. During the inspection, assure that all the firm s promised actions are effective at correcting the problems. If the inspection determines that the firm has resolved all the deficiencies, submit the information for input into the CARS computer system.**Conduct a "GMP qualifying inspection" at each API manufacturer covering the products and processes specified in the assignment. In addition, cover in as far as possible, API processes that have not been inspected in the last two years. Also, conduct an in-depth inspection, to include examining pertinent systems and processes, whenever the District receives adverse information regarding a firm's ability to produce APIs of acceptable quality.*During inspections of API manufacturers:*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE10 of 301.*Determine if the firm has made process changes by comparing current operations against the Establishment Inspection Report (EIR) for the previous inspection. Also compare the current operations with those filed in the Drug Master File or the drug application to determine whether the firm is complying with commitments made to the agency. The following changes are typical of those that would warrant *extensive coverage* during the inspection:a.New potential for cross-contamination arising through changes in API processes orproduct lines, to include processing numerous APIs of varying therapeutic significance incommon equipment and/or facilities.e of new technology requiring new expertise, significantly new equipment or newfacilities.c.*Recent changes in starting materials, intermediates, equipment, facilities, supportsystems, processing steps, packaging materials, and computer software that are not referenced in the DMF or application.*2.Verify that the size of the largest batch does not exceed the maximum working capacity of the firm's largest blender that is used for blending of API batches.3.Review the firm's complaint file. Determine whether the pattern of complaints (or other information available to the District) and the firm's records of internal rejection or*reprocessing/reworking* of API batches warrant expanding the inspection. Look for weaknesses in the firm's processes, systems or controls.4.Investigate the return of APIs for any reason. Determine whether the firm conducts investigations on returned products to find out if these APIs failed to meet specifications or were contaminated. Also determine the final disposition of returned APIs, i.e., whether reprocessed or destroyed.5.If the inspection is initiated because the firm *is referenced as an API supplier in a drug application (NDA, ANDA, AADA), evaluate operations against commitments in the application and/or drug master file. Also, verify the authenticity and accuracy of data submitted in the application and/or DMF.**Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE11 of 306.*Obtain a copy of the impurity profile for each active pharmaceutical ingredient process covered during the inspection and compare these to the impurity profiles submitted in the Drug Master File.*All Establishment Inspection Reports for API manufacturers must include:1.History of business, and any corporate affiliations.s, titles, *and complete mailing address of most responsible officials who should receive correspondence from FDA.*3. A list of APIs manufactured (or categories of products if many) along with the general manufacturing process for each (for example, chemical synthesis non-sterile, fermentation, extraction of natural products, etc.).4.*For foreign API manufacturers, the names, titles, complete mailing address, telephone and Fax number of the firm's U.S. Agent, Regulatory Agent, and/or Importer/Broker.*5.*For foreign API manufacturers, a report of all active pharmaceutical ingredients imported into the United States in the last three years, their consignees, and an estimate of the frequency and quantity of shipments to these consignees.*6. A description of areas/processes inspected (i.e., what areas, systems and processes were inspected, who was interviewed, what manufacturing activities were ongoing during the inspection).7. A description of any non-drug manufacturing activities conducted by the firm, such as processing pesticides or other toxic chemicals. If non pharmaceuticals are processed in the same facility and/or equipment with APIs, report precautions taken by the firm to prevent or minimize the potential for cross-contamination.8. A description of all API micronizing or milling operations, whether conducted in-house or by a contract micronizer. Fully describe the precautions taken by the firm to prevent or minimize the potential for cross-contamination. During inspections of contract micronizers,*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE12 of 30obtain a complete list of all active pharmaceutical ingredients micronized and report the source (owners) of these materials.9.*A copy of the firm's process validation protocol. Report the status of all validation efforts. If not completed, obtain and submit the firm's written timetable showing when process validation will be completed.*10. A report of any adverse findings as required by the Investigations Operations Manual (IOM). SAMPLING1.*A profile sample of the active pharmaceutical ingredient should be collected for analysis by the Forensic Chemistry Center, FCC (HFR-MA500) and Northeast Regional Lab (NRL). These samples of the API should not be confused with profile samples of actives collected together with finished product samples under the Pre-Approval Inspections/Investigations Compliance Program, CP 7346.832.Depending upon the cost, the sample should consist of 25 - 50 grams of active drug substance from three different lots, collected in duplicate. Documentation that should accompany the sample must include:- A flowchart and brief narrative description of the API manufacturing process;- A material safety data sheet for the active pharmaceutical ingredient;- A Certificate of Analysis *(COA)* for each lot; *in addition, a description of the computer system that was utilized to generate the COA and the precautions taken by the firm to safeguard the integrity of the computer data against employee manipulation.*- A copy of any potential/established impurity profiles and applicable methodologies;-The analytical methodology (if the inspection involves a new chemical entity).**Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE13 of 302.*During foreign inspections, it is often difficult for the investigator to collect profile samples of APIs. If a sample is not collected, the investigator should identify the lot (s) to be sampled and instruct the manufacturer to collect and ship the sample and applicable records directly to the FCC. The FCC will prepare an annotated collection report and forward the duplicate portion and copy of records to the NRL. An information copy will also be sent to the lead investigator.*3.*When collecting samples for profile analysis, protect these from trace contamination. In all instances, avoid using metal spatulas. Use a plastic container and closure for sampling and submit an empty container as a control sub. If a plastic spatula is used, also submit an unused spatula as asub-sample. Identify each container with the sample number, the product name and lot number, manufacturer, date and initials of the sampler. Wear disposable, talc-free, polyethylene gloves during the sampling activity. The preferred sampling method is by direct transfer and replacing the gloves between each subsample. Multiple product lots may be submitted under one collection report.*4.To establish a labeling/container forensic data base, obtain the following information during inspections of foreign API firms. Identify this information with the firm's name, central file number (CF Number), and street address and send to *FDA/FCC, Bulk Drug Group, HFR-MA500, 1141 Central Pkwy., Cincinnati, Ohio 45202.*plete telephone and FAX number;b.Contact person with title;c.*Decoding of the *lot/batch numbering system;d.*List* of the actual quantities of each lot of API produced for the last three years. Explainany difference between the batch and lot number. The records should reflect the total quantity*produced* and the amount shipped to the U.S.e.Description *and/or* specimen of the container closure systems *(if easily obtained)* forAPIs intended for U.S. distribution, as domestic packaging is often different:*Current Changes*FORM FDA 2438g (Computer Generated, 05/98) PAGE14 of 30。
无菌药品FDA检查员指导手册
无菌药品FDA检查员指导手册FDA检查员指导手册无菌药品工艺检查目录第一部分背景 (4)第二部分实施 (4)2.1 目的 (4)2.2 程序实施指南 (4)第三部分检查 (5)3.1. 审核和评估 (5)3.2. 简略性检查 (5)3.3. 全面性检查 (6)3.4. 附录A (7)3.5 样品采集 (7)3.6 样本大小 (8)3.7 报告 (8)第四部分分析 (8)4.1 分析内容 (8)4.2 分析 (8)第五部分法律/行政策略 (9)第六部分中心的职责 (10)无菌工艺检查的评估指南 (10)A. 组分的储存和准备 (10)B. 评估系统 (11)C. 主要系统和工艺 (12)a. 环境监测 (12)b. 设备清洁/消毒 (13)D. 生产设施 (13)a. 更衣 (13)b. 冻干 (13)c. 冻干验证 (14)E. 辅助系统 (15)F. 除热原 (15)G. 容器和封口材料的完整性 (16)H. 灭菌系统 (17)a. 总则 (17)b. 蒸气灭菌 (17)c. 蒸汽灭菌验证 (18)d. 干热灭菌（不包括除热原） (19)e. 化学灭菌/消毒/ (21)f. 化学灭菌验证 (21)g. 环氧乙烷气体灭菌 (21)h. 环氧乙烷验证 (23)i. 辐射灭菌 (24)j. 辐射灭菌验证 (25)k. 无菌除菌系统 (26)l. 无菌灌装验证 (28)I. 实验室 (29)a. 稳定性和有效期 (29)b. 无菌测试 (29)c. 热源检测 (30)d. 环境 (30)e. 校正 (30)I. 计算机 (30)J. 生物指示剂的用法 (30)。
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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。
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。