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1、1,美國FDA原料藥查廠重點經驗分享,2,Processes Covered During API Inspections Abroad,- FY 2001,Initial inspection on ECIC,3,ICH Quality Topics Checklist,API Inspection Guide,4,Six Systems,QUALITY SYSTEM,FACILITIES AND EQUIPMENT SYSTEMS,PRODUCTION SYSTEM,LABORATORY CONTROL SYSTEM,PACKAGING AND LABELING,MATERIALS SYS
2、TEMS,5,QUALITY SYSTEM(FDA Compliance Reference Program Guidance),Evaluation of whether The Quality Unit (QA) is reviewing and approving all SOPs related to production, QC, and QA.Seek assurance that the SOPs are adequate for their intended use.This also includes a review of the associated record kee
3、ping as well.,6,QUALITY SYSTEM(FDA Compliance Reference Program Guidance),The FDA considers the following SOPs to be critical and will want to review them to see if they are written, and if they are being followed as written where there use is required. Annual Product reviewComplaint ReviewsDiscrepa
4、ncy and Failure Investigations related to both the manufacturing and testing. “ documented, evaluated, investigated in a timely manner; includes corrective action where appropriate.”,7,QUALITY SYSTEM(FDA Compliance Reference Program Guidance),Change Control: “documented; evaluated; approved; and nee
5、d for revalidation assessed.”Validation: status of required validation/ revalidation for computer uses, manufacturing process, and laboratory methods.Training/qualifications of employees in the quality (QA) unit.,8,QUALITY SYSTEM(FDA Compliance Reference Program Guidance),SOPs for:Review and approva
6、l by QA of all production and process control procedures and all laboratory control mechanisms, specifications, standards, sampling plans, test procedures.Adequate review and approval by QA of production and control records for each batch before release and distribution.Adequate annual product revie
7、w procedure and for reviews being performed including OOS and DIR reviews.,9,QUALITY SYSTEM(Change Control Procedure),ChangeApplication,ChangeEvaluation,Reject,Approval and Notification,Qualification/Revalidation,10,FACILITIES AND EQUIPMENT SYSTEMS(FDA Compliance Reference Program Guidance),Descript
8、ion and layout of any specialized air-handling systems including IQ/OQ and records of maintenance and filter changes if applicable.IQ/OQ for all major manufacturing equipment, purified water system QC laboratory test equipment (HPLCs and GCs), refrigerators, freezers, stability chambers, etc. and ma
9、jor utilities.Proper calibrations of equipment, gauges, temperature indicators, pH probes, etc.,11,FACILITIES AND EQUIPMENT SYSTEMS(FDA Compliance Reference Program Guidance),Documentation of cleaning procedures.Cleaning validation for final-step production equipments.Validation of purified water sy
10、stem.SOP for maintenance and checking of water system on a daily basis for operation and leaks.Equipment calibration, maintenance, and usage log books.,12,FACILITIES AND EQUIPMENT SYSTEMS(FDA Compliance Reference Program Guidance),SOP for action to be taken if an out of calibration situation is foun
11、d.Appropriate equipment identification and status.Qualification/Validation and security of computerized or automated data handling systems.,13,FACILITIES AND EQUIPMENT SYSTEMS(Purified Water System),Tape Water,Active Carbon bed,Ion Exchange,Reverse Osmosis,Purified Water,14,PRODUCTION SYSTEM API Vs.
12、 Drug Product,15,PRODUCTION SYSTEM(FDA Compliance Reference Program Guidance),Training/qualification of personnelControl system for implementing changes in the processAdequate procedures and practices for charging of componentsIdentification of equipment with contents and where appropriate phase of
13、manufacturing and status.,16,PRODUCTION SYSTEM(FDA Compliance Reference Program Guidance),Validation/verification of cleaning procedures.Calculation and documentation of actual yields and percentage of theoretical yields. Established time limits for completion of phases of production.Implementation
14、and documentation of in-process controls, tests, and examinations (e.g., pH adequacy of mixing, weight variation, clarity.),17,PRODUCTION SYSTEM(FDA Compliance Reference Program Guidance),Justification and consistency of in-process specifications and drug product final specifications.Equipment clean
15、ing and usage logs.Master production and control recordsIssuance of batch production records,18,PRODUCTION SYSTEM(In-Process Sampling & Controls),Less stringent in-process controls may be appropriate in early processing stepsTighter controls may be appropriate for later processing steps,Early steps,
16、A,B,C,D,E,F,API,D,E,F,API,19,PRODUCTION SYSTEM(Examples of Process Parameters),TemperaturePressureVacuumTime (Duration)Flow RateCooling RateAgitation Speed,20,PRODUCTION SYSTEM(清潔方法的維護與確效),計劃書之發展*撰寫*核准*訓練,設備*取樣位置選擇*表面積計算*概要圖,分析標的物選擇及允收標準*活性成份*賦形劑*清潔劑,清潔SOP*撰寫*核准*訓練,分析方法發展,分析方法確效,計劃書執行*清潔*樣品*測試,通過,確效
17、報告*撰寫*核准,定期監測,變更管制,再確效,事件調查,Yes,No,發展階段,計劃階段,執行階段,維護階段,21,LABORATORY CONTROL SYSTEM(FDA Compliance Reference Program Guidance),Training/qualification of personnelCalibration and maintenance programs for major analytical instruments and equipment.SOP for action to be taken if an out of calibration si
18、tuation is found.Reference standards: source, purity and assay, and tests to establish equivalency to current official reference standards.System suitability checks on GC and HPLC systems.,22,LABORATORY CONTROL SYSTEM(FDA Compliance Reference Program Guidance),Specifications, standards, and represen
19、tative sampling plans.Adherence to the written methods of analysisValidation/ verification of analytical methodsControl system for implementing changes in laboratory operationsRequired testing is performed on the correct samples.,23,LABORATORY CONTROL SYSTEM(FDA Compliance Reference Program Guidance
20、),Documented investigations into unexpected discrepancies specifically out of specification results (OOS).SOP for dealing with OOS results that includes timely completion of the investigation.Quality and retention of raw data (e.g. chromatograms and spectra.)SOP for handling voided chromatograms and
21、 other data.,24,LABORATORY CONTROL SYSTEM(FDA Compliance Reference Program Guidance),Adequate reserve samples.SOP for examination of reserve samples on a regular basis along with the appropriate documentation.Stability testing program including demonstration of the stability indicating capability of
22、 the test methods,25,LABORATORY CONTROL SYSTEM(OOS Procedure),Sample test,Out of specification,Sample retest,Re-sampling test (Analyst 1),Re-sampling test (Analyst 2),Release,Reject,fail,pass,Re-sampling test,Reject,Reject,Release,pass,pass,pass,fail,fail,fail,26,PACKAGING AND LABELING(FDA Complianc
23、e Reference Program Guidance),Control system for implementing changes in packaging components or labels.Control of issuance of labels examination of issued labels and reconciliation of used labels.Examination of the labeled finished product.If required, destruction of either unused labels, or labels
24、 that need to be destroyed.,27,MATERIALS SYSTEMS API Vs. Drug Product,28,MATERIALS SYSTEMS(FDA Compliance Reference Program Guidance),Identification of ComponentsInventory of components Appropriate quarantine storageRaw material sampling and testing proceduresAppropriate retest times and SOPs in pla
25、ce,29,MATERIALS SYSTEMS(FDA Compliance Reference Program Guidance),Finished product distribution records by lot.Adequate written procedures for storage, handling and quarantine of materials. Adequate identification of components, containers, and closures.Adequate storage conditions.,30,MATERIALS SYS
26、TEMS(FDA Compliance Reference Program Guidance),Storage under quarantine until tested, or examined and released.Use of FIFO system.Adequate quarantine of rejected materials/componentsAdequate inventory/usage records for raw materials and components.,31,Preparations for FDA Inspection,Diagram of the
27、Purified water system showing location of filters, sampling points.Diagram of the HVAC system, especially for the clean room. Process Flow diagramOrganization ChartDevelopment reportValidation documentsList of SOPs,32,Inspection Guide,Inspection was conducted in conjunction with the review of DMF an
28、d ANDA. GMP inspection was conducted in accordance with ICH Q7A guidance.,33,FDA Findings,DMF ContentValidation data DeviationsFDA 483Record keepingCorrective actions,34,FDA Findings,Hotel arrangementEquipment maintained and calibratedProcess ValidationMethod ValidationTest results of finished produ
29、ctStandardsInstrument calibration,35,FDA Findings,In-Process Control.Stability data checkAnalyses of raw materialsComputer securityPersonnel training files House keepingPurified Water Validation,36,Discussion with management,At the end of every day of the inspection, a brief discussion was held with management and findings were discussed. Observations were pointed out as they were noted during the inspection.,37,Conclusion,More Recognition,More Confidence,38,Thanks for your attention,
