GMP Systems Integration–Combine Results and Utilize as a Compliance Tool
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A comprehensive presentation on GMP systems and integration. This includes validations, vendor qualification, preventative maintenance, audits, CAPA, and utilization of system results.

A comprehensive presentation on GMP systems and integration. This includes validations, vendor qualification, preventative maintenance, audits, CAPA, and utilization of system results.

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GMP Systems Integration–Combine Results and Utilize as a Compliance Tool Presentation Transcript

  • 1. GMP SYSTEMS INTEGRATION –COMBINE RESULTS ANDUTILIZE AS A COMPLIANCETOOLBetzaida BigioBristol Myers - Squibb Betzaida Bigio 1
  • 2. We will be Discussing GMP systems – no definitions How they interact Review of recent observations How they can be integrated to establish controls Interactive Exercise Betzaida Bigio 2
  • 3. GMP Systems  Annual Product Reviews (APR)  Change Control  Validations  Equipment qualifications  Vendor Qualifications  Preventive Maintenance (PM’s)  Audits (Internal & External)  Suppliers audits  Stability  Customer complaints  Suppliers complaints  CAPA  Investigations 8/30/2012 3
  • 4. Integration Between Systems  Discussion of Recent observations  Classification of observation  Integration between systems based on each observation 8/30/2012 4
  • 5. Recent Health AuthoritiesFindings  Discussion of 2011- 2012 Warning letters  Eighteen (18) Warning letters  Focused on Pharmaceutical Industries  cGMP for API (Active Pharmaceutical Ingredient)  cGMP for Finished Pharmaceutical  Location of inspected Sites:  India  China  Germany  Poland  UK  Canada  Mexico  Switzerland  Israel  Japan  US 8/30/2012 5
  • 6. Recent Observations - “Hot”Topics Cleaning Validation Investigations Media Fill Laboratory Controls Test Methods Environmental Monitoring Microbiology Contamination Prevention Disinfectant qualification Visual Inspection Qualification Supplier Qualification Reduce testing APR, Record Retention Incoming testing of raw materials 8/30/2012 6
  • 7. Cleaning Validation Use of two equipment parts for the production of multiple drug products without validating the process  Process validation for six (6) products conducted only with one out of two parts  Parts identical in construction but different internal configurations  Failure to demonstrate are identical Not cleaned and maintained equipment at appropriate intervals – holding time 8/30/2012 7
  • 8. Integration Between Systems perObservationValidation/Qualification: Controls Use of two equipment parts for the  Equipment qualification production of multiple drug products without validating the  Process Validation process  Process validation for six (6)  Cleaning validation products conducted only with one out of two parts  Holding time  Parts identical in construction but different internal  Dirty time configurations  Systems:  Failure to demonstrate are identical  Change Control Not cleaned and maintained  Validation equipment at appropriate intervals – holding time 8/30/2012 8
  • 9. Cleaning Validation Failure to have in shared manufactured areas, multi-product equipment:  Well-designed contamination prevention strategy in place  Proper segregation  Or dedicated equipment to a single mfg process No documented evidence of cleaning between batches or between product changeovers occurred on non-dedicated equipment Technology transfer to a facility that was previously used to manufacture without conducting adequate decontamination, renovation, and activation of the facility 8/30/2012 9
  • 10. Integration Between Systems perObservationValidations/Qualifications: Controls Failure to have in shared manufactured areas, multi-product  Equipment qualification equipment:  Process Validation  Well-designed contamination prevention strategy in place  Cleaning validation  Proper segregation  Or dedicated equipment to a  Holding time single mfg process No documented evidence of cleaning  Dirty time between batches or between product changeovers occurred on non-  Systems: dedicated equipment  Change Control Technology transfer to a facility that  Validation was previously used to manufacture without conducting adequate decontamination, renovation, and activation of the facility 8/30/2012 10
  • 11. Investigations Not thoroughly investigated the failure of a batch or any of its components Failure to include other batches in investigations No investigation raw data for a media fill failure Failure to determine root cause on crystals in the vial  Changes to filling process  Changes to filling needles  Vial washers 8/30/2012 11
  • 12. Integration Between Systems perObservationInvestigations: Controls Not thoroughly investigated  Product behavior on APR the failure of a batch or any of its components  Stability Failure to include other  Predictive maintenance batches in investigations  Preventive maintenance No investigation raw data for a media fill failure  Systems: Failure to determine root  Investigations cause on crystals in the vial  CAPA  Changes to filling process  Supplier  Changes to filling needles  Change Control  Vial washers  PM’s 8/30/2012 12
  • 13. Investigations Investigations  Failure to investigate and document contamination of API  Root cause not determined and production continued  No segregation of impacted lots  Failure to extend investigation to other batches  Contaminated lot release and shipped, then recalled – failure to have controls in place to identify material status  Inadequate equipment maintenance program  Firm authorize the use of equipment known to be defective (10 maintenance requests in one year) 8/30/2012 13
  • 14. Integration Between Systems per ObservationInvestigations: Controls Failure to investigate and  Product behavior on APR document contamination of API  Stability  Root cause not determined and  Materials segregation production continued  No segregation of impacted lots  Supplier’s audit  Failure to extend investigation to  Preventive & Predictive other batches maintenance  Contaminated lot release and shipped, then recalled – failure to  Systems: have controls in place to identify  Investigations material status  CAPA  Inadequate equipment maintenance program  Supplier  Firm authorize the use of  Change Control equipment known to be defective  Materials (10 maintenance requests in one year)  PM’s 8/30/2012 14
  • 15. Media Fill Media fill insufficient to establish that the aseptic process is in control  Inadequate reconciliation of filled vials  Filled vials not match with incubated vials  Employee who perform critical duties in your aseptic process did not participate in the simulation process qualification 8/30/2012 15
  • 16. Integration Between Systems per Observation Media Fill: Controls Media fill insufficient to  Manufacturing simulation establish that the aseptic  QC – Microbiology process is in control  Training – Job description, job  Inadequate reconciliation of duties, SOP’s, employee filled vials qualifications, and  Filled vials not match with incubated vials certifications aligned  Employee who perform  Systems: critical duties in your aseptic  Manufacturing process did not participate in  Training the simulation process qualification  QC - Microbiology 8/30/2012 16
  • 17. Laboratory Controls Test Methods  Not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures design to assure that components, in-process materials, and DP conforms with standards  Validation data for laboratory methods incomplete or not available  Validation method approved without the complete data in place Equipment qualification – all instruments whether newly purchased or already in use , be qualified prior to being release for use 8/30/2012 17
  • 18. Integration Between Systems per Observation Laboratory Controls: Controls Test Methods  Change Control should establish  Not established scientifically sound specific requirements and appropriate specifications,  Appropriate equipment standards, sampling plans, and test procedures design to assure that qualification components, in-process materials,  Documentation approval and DP conforms with standards  Validation data for laboratory  Employee training methods incomplete or not available  Systems:  Validation method approved  Quality Assurance without the complete data in  Quality Control place  Change Control Equipment qualification – all instruments  Validations/Qualification whether newly purchased or already in use , be qualified prior to being release  Training for use 8/30/2012 18
  • 19. Suppliers Qualification Reduce testing  Inadequate sampling process if no evidence of vendor sampling, shipping, and transit process Incoming testing of raw materials  Not conducted at least one specific identification test  Lack of appropriate validation of the supplier test result  Accept CoA of a stopper supplier without conducting adequate vendor qualification  No evidence of how your vendor conducts the sampling (composite, segregation…) 8/30/2012 19
  • 20. Integration Between Systems per Observation Supplier’s Qualification: Controls Reduce testing  Material qualification  Inadequate sampling process if  Supplier audit no evidence of vendor sampling,  Quality agreement shipping, and transit process  Testing of components & Incoming testing of raw materials material  Not conducted at least one specific identification test  Comparison between CoA and  Lack of appropriate validation of test results the supplier test result  Systems:  Accept CoA of a stopper supplier without conducting adequate  Quality Assurance vendor qualification  Quality Control  No evidence of how your vendor conducts the sampling (composite, segregation…) 8/30/2012 20
  • 21. Shutdown/Start-up Inadequate aseptic and support area sanitization following maintenance shutdown  Assure to complete:  Media fill  Smoke studies  QA authorization to resume activities  NO failure on Media fill results (this was the case in the warning letter, two contaminated units, not adequate investigated root cause) 8/30/2012 21
  • 22. Integration Between Systems per Observation Shutdown/Start-up: Controls  Cleaning Inadequate aseptic and  Change Control should establish specific requirements support area sanitization  Asceptic Techniques following maintenance  Assure to complete: shutdown  Media fill  Smoke studies  NO failure on Media fill  QA authorization to results (this was the case resume activities in the warning letter, two  Systems: contaminated units, not  Quality Assurance adequate investigated  Quality Control  Manufacturing root cause) 8/30/2012 22
  • 23. Microbiology ContaminationPrevention Disinfectant qualification  Not establish a schedule for the cleaning with agent design to kills spores – mold found  Disinfectant rotation – efficacy studies not completed for three of the disinfectant  Failed to demonstrate that is suitable and effective to remove microorganism from different surfaces  Failure to challenge with multiple organisms 8/30/2012 23
  • 24. Integration Between Systems per Observation Microbiology Contamination Prevention: Controls Disinfectant qualification  Quality Control – Micro  Not establish a schedule for the  Robust Qualification of cleaning with agent design to disinfectant kills spores – mold found  Disinfectant rotation – efficacy  Systems: studies not completed for three  Quality Assurance of the disinfectant  Quality Control  Failed to demonstrate that is suitable and effective to  Qualification remove microorganism from different surfaces  Failure to challenge with multiple organisms 8/30/2012 24
  • 25. Microbiology ContaminationPrevention Smoke studies  No evidence of smoke studies  Failure to demonstrate that appropriate design & controls are in place to prevent turbulence and stagnant air in critical areas 8/30/2012 25
  • 26. Integration Between Systems per Observation Microbiology Contamination Prevention: Controls  Robust Smoke studies Smoke studies  Air velocities/pressure & air  No evidence of smoke changes data studies  Multidisciplinary team to  Failure to demonstrate evaluate smoke studies that appropriate design  Systems:  Quality Assurance & controls are in place  Quality Control to prevent turbulence  Engineering and stagnant air in critical areas 8/30/2012 26
  • 27. Microbiology ContaminationPrevention Environmental Monitoring (EM)  Poor routine examination of facilities (mold in class 100 production  Poor condition of walls  Poor aseptic techniques  Personnel sampling areas (hands, chest, gowning, hood, goggles, sleeves)  Gowned employee not monitored by a second qualified person  EM performed at the end of the shift  Operators sanitizing his hands immediately prior to conducting his own personnel monitoring sampling  Operator spraying his hands directly over the air viable microbial plate. Results may not reflect microbiology environment of the class 100 room. 8/30/2012 27
  • 28. Integration Between Systems per Observation Microbiology Contamination Prevention: Controls Environmental Monitoring (EM)  Aseptic techniques  Poor routine examination of facilities  Personnel training and (mold in class 100 production qualification  Poor condition of walls  Poor aseptic techniques  Engineering controls  Personnel sampling areas (hands,  Facilities walk tru chest, gowning, hood, goggles, sleeves)  Internal audits  Gowned employee not monitored by a second qualified person  Preventive maintenance  EM performed at the end of the shift  Systems:  Operators sanitizing his hands  Quality Assurance immediately prior to conducting his own personnel monitoring sampling  Quality Control  Operator spraying his hands directly  Engineering over the air viable microbial plate.  Internal audits Results may not reflect microbiology environment of the class 100 room.  Training 8/30/2012 28
  • 29. Microbiology ContaminationPrevention Environmental Monitoring (EM)  EM trends not analyzed – failure to address increased adverse trends observed  Not establish a schedule for the cleaning with agent design to kill spores although mold was detected in class 10,000 area 8/30/2012 29
  • 30. Integration Between Systems per Observation Microbiology Contamination Prevention: Controls  Aseptic techniques Environmental Monitoring (EM)  Personnel training and qualification  EM trends not analyzed – failure to address  APR increased adverse  Systems: trends observed  Quality Assurance  Not establish a schedule  Quality Control for the cleaning with  Training agent design to kill spores although mold was detected in class 10,000 area 8/30/2012 30
  • 31. Visual InspectionQualification Defect in include visual inspection program Inspectors qualification failure  Visual inspection certification program does not adequately challenge the technician performing the inspection  SOP should include all possible defects- inspector should be capable to detect all possible critical defects, challenge vial selected, and rotated to ensure that each inspector is challenged to detect each critical defect 8/30/2012 31
  • 32. Integration Between Systems per Observation Visual Inspection Qualification: Controls Defect in include visual inspection  Visual Inspection Certification program Program Inspectors qualification failure  Personnel training and  Visual inspection certification program does not adequately qualification challenge the technician performing the inspection  SOP should include all possible  Systems: defects- inspector should be capable to detect all possible  Quality Assurance critical defects, challenge vial  Qualification selected, and rotated to ensure  Training that each inspector is challenged to detect each critical defect  Manufacturing 8/30/2012 32
  • 33. APR & Record Retention APR  Quality Unit does not perform an annual evaluation of the process  This is the process to assure that changes were effective and the process remains in a validated state Record Retention  Records destroyed  No evidence of qualification and validation records resulted in a not validated process, and/or not qualified equipment 8/30/2012 33
  • 34. Integration Between Systems per Observation APR/Record Retention: Controls  APR program in place APR  Quality Unit does not perform  Record Retention based on an annual evaluation of the criticality and risk process  Change controls,  This is the process to assure that Qualifications/validations - changes were effective and the never are destroyed process remains in a validated state Record Retention  Systems:  Records destroyed  Quality Assurance  No evidence of qualification  APR and validation records resulted  Validation in a not validated process,  Record Management and/or not qualified equipment 8/30/2012 34
  • 35. Interactive Exercise 8/30/2012 35
  • 36. Instructions Evaluate recent Observations to different systems and relate each of different GPM Systems Identify your opportunities Identify controls that should be in place in each system to avoid the out of compliance situation and establish communication among them Assure that your control address post implementation sustainability Identify & avoid Road blocks to maintain compliance 8/30/2012 36
  • 37. 38/30/2012 7
  • 38. 38/30/2012 8