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July 2001

CONTINUOUS QUALITY VERIFICATION (CQV) G.K.Raju, Ph.D. Pharmaceutical Manufacturing Initiative (PHARMI), MIT Program on the Pharmaceutical Industry, Massachusetts Institute of Technology July 2001 MIT Pharmaceutical Manufacturing Initiative Objective: To Describe the Opportunity to Improve

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July 2001

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  1. CONTINUOUS QUALITY VERIFICATION(CQV) G.K.Raju, Ph.D.Pharmaceutical Manufacturing Initiative (PHARMI),MIT Program on the Pharmaceutical Industry,Massachusetts Institute of Technology July 2001

  2. MIT Pharmaceutical Manufacturing Initiative Objective: To Describe the Opportunity to Improve Pharmaceutical Manufacturing Performance Research Marketing Development Manufacturing

  3. Pharmaceutical Manufacturing Research Marketing Development Manufacturing Inbound Logistics Bulk Active Bulk Formulation Filling & Finish Outbound Logistics Packaging

  4. Bulk Formulation Filling/ Tableting Packaging/ Finishing Bulk Active STUDYING PHARMACEUTICAL MFG: VERTICAL VS. HORIZONTAL APPROACH VERTICAL APPROACH HORIZONTAL APPROACH Plant A Plant A Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Plant B Plant B Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing

  5. Packaging/ Finishing Filling/ Tableting/ etc. Bulk Active Bulk Formulation PHARMACEUTICAL MANUFACTURING THE HORIZONTAL APPROACH Company A Packaging/ Finishing Filling/ Tableting/ etc. Bulk Active Bulk Formulation Company B Packaging/ Finishing Filling/ Tableting/ etc. Bulk Active Bulk Formulation Company C

  6. CONTINUOUS QUALITY VERIFICATION (CQV) DESCRIBING THE OPPORTUNITYIN ROUTINE MANUFACTURING

  7. WHICH PROCESSES? PROCESS CYCLE TIMES In Process Development In Routine Manufacturing Biggest Impact Here?Time-to-marketEnablingPotent Products Place forValidation?Potent ProductsDifficult ProcessesHigh Volume ProductsProducts with Tough QC TestsGeneric Competition

  8. PROCESS A WITH QC TESTS BLEND DRY MIX STEP FB DRY WEIGHING WET GRANULATION STEP SIEVE ENCAPSULATE QC1 QC2 QC3 QC4 • API • MICRO • LOD • Particle Size • Description • ID • Assay • CU • Impurity • Dissolution • MICRO

  9. PROCESS A WITH CYCLE TIMES < 3 DAYS BLEND DRY MIX Processing FB DRY SIEVE STEP WEIGH WET GRANULN ENCAPSULATE 7 DAYS 13 DAYS QC2 QC3 QC1 QC4 • LOD • Particle • Size • API • MICRO • Description • ID • Assay • CU • Impurity • Dissolution • MICRO

  10. PROCESS B WITH QC TESTS CHEMICAL WEIGHING BLEND FILL CAPSULES BOTTLE PACKAGING QC1 QC2 • API • OVI • Description • ID • Assay • CU • Impurity • Dissolution

  11. PROCESS B WITH CYCLE TIMES 17 DAYS CHEMICAL WEIGHING BLEND FILL CAPSULES BOTTLE PACKAGING 14 DAYS 7 DAYS QC1 QC2 • API • OVI • Description • ID • Assay • CU • Impurity • Dissolution

  12. PROCESS C WITH QC TESTS FILM COATING BOTTLE PACKAGING COMPRESS GRANULATION STEP WEIGHING FB DRY BLEND QC1 QC2 QC2 • API • Particle Size • LOD • Description • ID • Assay • CU • Impurity • Dissolution

  13. PROCESS C WITH CYCLE TIMES 21 DAYS BOTTLE PACKAGING GRANULATION STEP COMPRESS FB DRY BLEND FILM COATING 14 DAYS WEIGHING 6 DAYS QC1 QC2 • Description • ID • Assay • CU • Impurity • Dissolution • API

  14. PROCESS D WITH QC TESTS FILM COATING GRANULATION STEP CHEMICAL WEIGHING Processing BLEND 1: BLEND 2: PRE- BLEND FINAL BLEND COMPRESS BOTTLE PACKAGING QC1 QC2 QC3 • API • Particle Size • LOD • Description • ID • Assay • CU • Impurity • Dissolution

  15. FILM COATING BOTTLE PACKAGING PROCESS D WITH CYCLE TIMES 20 DAYS 15 DAYS BLEND 2: PRE-BLEND GRANULATION STEP CHEMICAL WEIGHING PROCESSING BLEND 1: COMPRESS FINAL BLEND 10 DAYS 15 DAYS QC1 QC2 QC3 • API • Particle Size • LOD • Description • ID • Assay • CU • Impurity • Dissolution 60 DAYS

  16. FILM COATING BOTTLE PACKAGING PROCESS D WITH QC TESTS:Cycle Times includingBULK ACTIVE 20 DAYS 15 DAYS BLEND 2: PRE-BLEND GRANULATION STEP CHEMICAL WEIGHING BLEND 1: COMPRESS FINAL BLEND PROCESSING 10 DAYS 15 DAYS QC1 QC3 QC2 60 DAYS 21-90 DAYS

  17. 20 15 FILM COATING Actual 10 Target 20 DAYS Potential 15 DAYS 5 BOTTLE PACKAGING 0 BLEND 2: PRE-BLEND QC1 PFD QC3 Release GRANULATION STEP CHEMICAL WEIGHING PROCESSING BLEND 1: COMPRESS FINAL BLEND 10 DAYS 15 DAYS QC1 QC3 QC2 60 DAYS PROCESS D WITH QC TESTSCycle Times

  18. 20 15 Actual 10 Target Potential 5 0 QC1 PFD QC3 Release WHAT DRIVES THE QC TESTING TIMES? 2% • Sampling • Batching • Other Products • Waiting • Coordinating TEST • Other Products • Other Paperwork • Waiting • Coordinating

  19. WHICH PROCESSES? PROCESS CYCLE TIMES In Process Development In Routine Manufacturing Biggest Impact Here?Time-to-marketEnablingPotent Products Place forValidation?Potent ProductsDifficult ProcessesHigh Volume ProductsProducts with Tough QC TestsGeneric Competition

  20. LOD PROCESS E WITH QC TEST POINTS ACTIVE INITIAL GRANULATION STAGE MILL QC1 WEIGH DRY MIX WET GRANULN WET GRANULN FL BED DRY MILL SECOND GRANULATION STAGE COATING STAGE LOD LOD COAT MILL MILL QC4 QC2 QC3 WET GRAN DRY SIFT STORE MIX MIX DRY STORE SIFT&BLEND STAGE BLEND&FILL STAGE STORE SIFT BLEND BLEND BLEND BLEND STORE BOTTLE FILL LOD MIX MIX GRANUL DRY MILL EXCEPIENT PREPARATION STAGE

  21. PROCESS E WITH QC TEST TIMES 7 days 3 days 7 days 7 days QC1 QC2 QC3 QC4 ACTIVE < 1 day < 1 day 1-2 days < 1 day < 1 day < 1 day SECOND GRAN SIFT& BLEND BLEND FILL FIRST GRAN COAT

  22. WHICH PROCESSES? TOWARDS PARAMETRIC RELEASE In Process Development In Routine Manufacturing Biggest Impact Here?Time-to-marketEnablingPotent Products Place forValidation?Potent ProductsDifficult ProcessesHigh Volume ProductsProducts with Tough QC TestsGeneric Competition

  23. PROCESS F: LIQUID LINE • ENVIRO. MONITORING • WFI TESTING • Endotoxin • TOC • QC Check WASH AUTOCLAVE WFI STOPPERS • QC Check • QC Check WEIGH WASH DEPYROGEN SEALS BUFFER VIALS TERMINAL STERILIZATION WEIGH • ID pH ADJ COMPOUND FILL STOPPER CAP WEIGH FILTER LABEL/PKG • Appearance • ID • Assay • Impurity • Fill Vol, Osmolarity, Partic. • Endotoxin • STERILITY TESTING • ID • pH • BIOBURDEN • Wt Check • Visual Check

  24. PROCESS F: LIQUID LINE WITH CYCLE TIMES • ENVIRONMENTAL MONITORING 7 days 10 days • WFI TESTING 3-4 days 3-4 months • STERILITY TESTING 17-20 days 7 days • BIOBURDEN TESTING

  25. PERCEIVED PROCESS CYCLE TIMES:SUMMARY

  26. CYCLE TIME COMPONENTS

  27. ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES On-line LIF, NIR, Pattern Recognition, etc.

  28. CQV OPPORTUNITY IN ROUTINE MANUFACTURING SUMMARY • Quality Monitoring is Discontinuous • QC testing times are approximately = 1 month • Factor of 20-25 opportunity in cycle time: Process • Factor of 20-25 opportunity in cycle time: QC • QC Cycle Times >= Process Cycle Times • Time is driven by off-line nature of test • Exception is MICRO test

  29. CONTINUOUS QUALITY VERIFICATION (CQV) DESCRIBING THE OPPORTUNITYIN PROCESS DEVELOPMENT

  30. Company A Bulk Active Bulk Formulation Filling & Finish Packaging Company B Bulk Active Bulk Formulation Filling & Finish Packaging Company C Bulk Active Bulk Formulation Filling & Finish Packaging THE VERTICAL APPROACH Blending Drying Granulation Flow Tableting Transport Rapid Microbial Detection Fermentation

  31. VERTICAL ANALYSIS I: BLENDING UNIT OPERATION Company A Bulk Active Bulk Formulation Filling & Finish Packaging Company B Bulk Active Bulk Formulation Filling & Finish Packaging Company C Bulk Active Bulk Formulation Filling & Finish Packaging Eg. Blending

  32. WHICH PROCESSES? PROCESS CYCLE TIMES In Process Development In Routine Manufacturing Biggest Impact Here?Time-to-marketEnablingPotent Products Place forValidation?Potent ProductsDifficult ProcessesHigh Volume ProductsProducts with Tough QC TestsGeneric Competition

  33. FOCUS MIT Pharmaceutical Manufacturing Initiative Explore the Potential Impact of On-line Monitoring Technology on Blending Process Development

  34. 8 8 8 Active ingredient Excipients Raw material load Mixing Sampling Homogeneity test OK? Analysis Transporting Results & Decision Making Blending Operation Model Undermixed mix-longer Blender cleaning Homogeneous Next batch Discarded Next batch

  35. PHARMACEUTICAL MANUFACTURING: LIF FOR ON-LINE MONITORING OF BLENDING LIGHT INDUCED FLUORESCENCE SYSTEM FOR THE DETERMINATION OF THE HOMOGENEITY OF DRY POWDER BLENDING

  36. LIF VERIFICATION STUDIES Established a correlation between LIF assessment of homogeneity and thief-sampling with off-line analysis

  37. PROCESS D: BLENDING PROCESS DEVELOPMENT FILM COATING GRANULATION STEP CHEMICAL WEIGHING Processing BLEND 1: BLEND 2: PRE- BLEND FINAL BLEND COMPRESS BOTTLE PACKAGING • OFF LINE QC TEST • ON LINE SENSOR

  38. Blending Operation: Two Technologies, Two Approaches Process Development, Validation and Manufacturing Transport Raw Materials Blending Sampling Analysis Process knowledge Results & Decision making Waiting Stock Information Flow Materials Flow R/D/W a- Process Development b- manufacturing Discarded Reprocessed Well Blended Well Blended Blending Raw Materials Analysis & Decision making Discarded On-line Information Feedback OFF LINE ON LINE

  39. Low Medium High Cleaning time (min) 20 250 480 Loading time (min) 10 35 60 Discharge time (min) 6 18 30 Sampling time (min) 60 90 120 Transport time (min) 6 30 60 QC Testing time (min) 20 250 480 2 25 48 QC Holding time (min) Blending Data Collected from CAMP Companies Operation Characteristics

  40. Results Blending Performance Process Development and Validation 6% no wait between blends 1 Blend 2 Blends 3 Blends Best 2.32 0.36 4.96 0.68 8.45 1.07 Med. 13.19 1.31 23.45 1.93 30.65 2.41 Time (days) Worst 25.82 2.57 43.40 3.56 56.17 4.46

  41. Blending Performance Process Development and Validation

  42. Current Approach Proposed Approach 1a 2a Process Development x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 1b 2b Commercial Production x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x APPROACH TO LEARNING: Consequences on Process Development & Commercial Production

  43. CQV Opportunity in Process Development SUMMARY • Process development can be on the critical path • Factor of 10-15 reduction in cycle time in blend • process development (maybe more..) • Variability reduction in blend process dev. time • independence of organization/product -> predictability… • Benefits not restricted to use of new on-line sensors • improvement data analysis of existing sensor data • use of this for experimental design

  44. CONTINUOUS QUALITY VERIFICATION (CQV) WHAT ARE THE IMPLICATIONS?

  45. Consortium for the Advancement of Manufacturing in Pharmaceuticals (CAMP) Pharmaceutical Companies • Hoffmann-La Roche • Glaxo SmithKline • Wyeth-Ayerst • Abbott • Aventis • Bristol-Myers Squibb • Johnson & Johnson FDA CAMP Vendors MIT Purdue

  46. PROCESS A WITH CURRENT QC TESTS AND NEW POSSIBILITIES BLEND DRY MIX STEP FB DRY WEIGHING WET GRANULATION STEP SIEVE ENCAPSULATE QC1 QC2 QC3 QC4 • API • MICRO • LOD • Particle Size • Description • ID • Assay • CU • Impurity • Dissolution • MICRO

  47. Need to Focus on Both Material Flow and Information Flow INFORMATION FLOW MATERIAL FLOW

  48. 10% 5% 1% 0.5% 0.1% Manufacturing Information Management: Has Hardware and Software Components • Fast Response • On-Line • Real-Time • Accurate • Robust • Rapid Rate of Learning • Short Cycle Times • Benchmarking • Modeling • Continuous Problem Solving

  49. HORIZONTAL AND VERTICAL APPROACHES Company A High Vol Bulk Active Bulk Formulation Filling & Finish Packaging Company B Variable Bulk Active Bulk Formulation Filling & Finish Packaging Company C Bulk Active Bulk Formulation Filling & Finish Liquids Packaging Blending Drying Granulation Flow Tableting Transport Rapid Microbial Detection Fermentation

  50. CQV: BENEFITS • Data Mining of Process Data • Data -> Information -> Knowledge • Rationale for New Sensors • Variable Categorization: PCCPs, etc. • Basis for Specifications, Batch Record Design • Basis for Experimental Design, Etc. …

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