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1、1美國美國FDA原料藥查廠重點經驗分享原料藥查廠重點經驗分享2Chemical SynthesisSterile2%FermentationNonsterile6%Crude Bulk NEC7%Others3%Biotech/Crude Drug1%Chemical SynthesisNonsterile81%Processes Covered During API Inspections Abroad- FY 2001Initial inspection on ECIC3ICH Quality Topics ChecklistAPI Inspection GuideQ1: Stabilit
2、y Q1A(R): Stability Testing of New Drugs and Products (Revised) Q1B: Photostability Testing Q1C: Stability Testing for New Dosage Forms Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products Q2: Analytical ValidationQ2A: Text on Validation of Analytical Proc
3、eduresQ2B: MethodologyQ3: Impurities Q3A(R): Impurities in New Drug Substances (Revised) Q3B(R): Impurities in New Drug Products (Revised) Q3C: Impurities: Residual SolventsQ4: PharmacopoeiasQ4: Pharmacopoeial HarmonisationQ5: Biotechnological Quality Q5A: Viral Safety EvaluationQ5B: Genetic Stabili
4、tyQ5C: Stability of ProductsQ5D: Cell SubstratesQ6: SpecificationsQ6A: Chemical Substances with its Decision TreesQ6B: Biotechnological Substances Q7: GMP Q7A: GMP for Active Pharmaceutical Ingredients4Six Systems QUALITY SYSTEM FACILITIES AND EQUIPMENT SYSTEMS PRODUCTION SYSTEM LABORATORY CONTROL S
5、YSTEM PACKAGING AND LABELING MATERIALS SYSTEMS5QUALITY SYSTEM(FDA Compliance Reference Program Guidance)1.Evaluation of whether The Quality Unit (QA) is reviewing and approving all SOPs related to production, QC, and QA.2.Seek assurance that the SOPs are adequate for their intended use.3.This also i
6、ncludes a review of the associated record keeping as well.6QUALITY SYSTEM(FDA Compliance Reference Program Guidance)4.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. vA
7、nnual Product reviewvComplaint ReviewsvDiscrepancy and Failure Investigations related to both the manufacturing and testing. “ documented, evaluated, investigated in a timely manner; includes corrective action where appropriate.”7QUALITY SYSTEM(FDA Compliance Reference Program Guidance)vChange Contr
8、ol: “documented; evaluated; approved; and need for revalidation assessed.”vValidation: status of required validation/ revalidation for computer uses, manufacturing process, and laboratory methods.vTraining/qualifications of employees in the quality (QA) unit. 8QUALITY SYSTEM(FDA Compliance Reference
9、 Program Guidance)5.SOPs for:vReview and approval by QA of all production and process control procedures and all laboratory control mechanisms, specifications, standards, sampling plans, test procedures.vAdequate review and approval by QA of production and control records for each batch before relea
10、se and distribution.vAdequate annual product review procedure and for reviews being performed including OOS and DIR reviews.9QUALITY SYSTEM(Change Control Procedure)10FACILITIES AND EQUIPMENT SYSTEMS(FDA Compliance Reference Program Guidance)1.Description and layout of any specialized air-handling s
11、ystems including IQ/OQ and records of maintenance and filter changes if applicable.2.IQ/OQ for all major manufacturing equipment, purified water system QC laboratory test equipment (HPLCs and GCs), refrigerators, freezers, stability chambers, etc. and major utilities.3.Proper calibrations of equipme
12、nt, gauges, temperature indicators, pH probes, etc.11FACILITIES AND EQUIPMENT SYSTEMS(FDA Compliance Reference Program Guidance)4.Documentation of cleaning procedures.5.Cleaning validation for final-step production equipments.6.Validation of purified water system.7.SOP for maintenance and checking o
13、f water system on a daily basis for operation and leaks.8.Equipment calibration, maintenance, and usage log books.12FACILITIES AND EQUIPMENT SYSTEMS(FDA Compliance Reference Program Guidance)9.SOP for action to be taken if an out of calibration situation is found.10. Appropriate equipment identifica
14、tion and status.11. Qualification/Validation and security of computerized or automated data handling systems.13FACILITIES AND EQUIPMENT SYSTEMS(Purified Water System)Purified Water14PRODUCTION SYSTEM API Vs. Drug Product15PRODUCTION SYSTEM(FDA Compliance Reference Program Guidance)1.Training/qualifi
15、cation of personnel2.Control system for implementing changes in the process3.Adequate procedures and practices for charging of components4.Identification of equipment with contents and where appropriate phase of manufacturing and status.16PRODUCTION SYSTEM(FDA Compliance Reference Program Guidance)5
16、.Validation/verification of cleaning procedures.6.Calculation and documentation of actual yields and percentage of theoretical yields. 7.Established time limits for completion of phases of production.8.Implementation and documentation of in-process controls, tests, and examinations (e.g., pH adequac
17、y of mixing, weight variation, clarity.)17PRODUCTION SYSTEM(FDA Compliance Reference Program Guidance)9.Justification and consistency of in-process specifications and drug product final specifications.10. Equipment cleaning and usage logs.11. Master production and control records12. Issuance of batc
18、h production records18PRODUCTION SYSTEM(In-Process Sampling & Controls) Less stringent in-process controls may be appropriate in early processing steps Tighter controls may be appropriate for later processing stepsEarly stepsABCDEFAPIDEFAPIIncreasing GMPs19PRODUCTION SYSTEM(Examples of Process Param
19、eters) Temperature Pressure Vacuum Time (Duration) Flow Rate Cooling Rate Agitation Speed20PRODUCTION SYSTEM(清潔方法的維護與確效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*測試通過確效報告*撰寫*核准定期監測變更管制再確效事件調查YesNo發展階段計劃階段執行階段維護階段21LABORATORY CONTROL
20、SYSTEM(FDA Compliance Reference Program Guidance)1.Training/qualification of personnel2.Calibration and maintenance programs for major analytical instruments and equipment.3.SOP for action to be taken if an out of calibration situation is found.4.Reference standards: source, purity and assay, and te
21、sts to establish equivalency to current official reference standards.5.System suitability checks on GC and HPLC systems.22LABORATORY CONTROL SYSTEM(FDA Compliance Reference Program Guidance)6.Specifications, standards, and representative sampling plans.7.Adherence to the written methods of analysis8
22、.Validation/ verification of analytical methods9.Control system for implementing changes in laboratory operations10. Required testing is performed on the correct samples.23LABORATORY CONTROL SYSTEM(FDA Compliance Reference Program Guidance)11. Documented investigations into unexpected discrepancies
23、specifically out of specification results (OOS).12. SOP for dealing with OOS results that includes timely completion of the investigation.13. Quality and retention of raw data (e.g. chromatograms and spectra.)14. SOP for handling voided chromatograms and other data.24LABORATORY CONTROL SYSTEM(FDA Co
24、mpliance Reference Program Guidance)15. Adequate reserve samples.16. SOP for examination of reserve samples on a regular basis along with the appropriate documentation.17. Stability testing program including demonstration of the stability indicating capability of the test methods25LABORATORY CONTROL
25、 SYSTEM(OOS Procedure)Sample testOut of specificationSample retest Re-sampling test (Analyst 1)Re-sampling test (Analyst 2)ReleaseRejectfailpassRe-sampling testRejectRejectReleasepasspasspassfailfailfail26PACKAGING AND LABELING(FDA Compliance Reference Program Guidance)1.Control system for implement
26、ing changes in packaging components or labels.2.Control of issuance of labels examination of issued labels and reconciliation of used labels.3.Examination of the labeled finished product.4.If required, destruction of either unused labels, or labels that need to be destroyed.27MATERIALS SYSTEMS API V
27、s. Drug Product28MATERIALS SYSTEMS(FDA Compliance Reference Program Guidance)1. Identification of Components2. Inventory of components 3. Appropriate quarantine storage4. Raw material sampling and testing procedures5. Appropriate retest times and SOPs in place29MATERIALS SYSTEMS(FDA Compliance Refer
28、ence Program Guidance)6.Finished product distribution records by lot.7.Adequate written procedures for storage, handling and quarantine of materials. 8.Adequate identification of components, containers, and closures.9.Adequate storage conditions.30MATERIALS SYSTEMS(FDA Compliance Reference Program G
29、uidance)10. Storage under quarantine until tested, or examined and released.11. Use of FIFO system.12. Adequate quarantine of rejected materials/components13. Adequate inventory/usage records for raw materials and components. 31Preparations for FDA Inspection1.Diagram of the Purified water system sh
30、owing location of filters, sampling points.2.Diagram of the HVAC system, especially for the clean room. 3.Process Flow diagram4.Organization Chart5.Development report6.Validation documents7.List of SOPs32 Inspection Guide Inspection was conducted in conjunction with the review of DMF and ANDA. GMP i
31、nspection was conducted in accordance with ICH Q7A guidance. 33FDA Findings DMF Content Validation data Deviations FDA 483 Record keeping Corrective actions34FDA Findings Hotel arrangement Equipment maintained and calibrated Process Validation Method Validation Test results of finished product Stand
32、ards Instrument calibration35FDA Findings In-Process Control. Stability data check Analyses of raw materials Computer security Personnel training files House keeping Purified Water Validation36Discussion 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. 37Conclusion38Thanks for your attention