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November 16 th 2001

PHARMACEUTICAL MANUFACTURING: NEW TECHNOLOGY OPPORTUNITIES.. G.K.Raju, Ph.D. Executive Director, Pharmaceutical Manufacturing Initiative (PHARMI), MIT Program on the Pharmaceutical Industry, Massachusetts Institute of Technology. November 16 th 2001. OUTLINE.

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November 16 th 2001

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  1. PHARMACEUTICAL MANUFACTURING:NEW TECHNOLOGY OPPORTUNITIES..G.K.Raju, Ph.D.Executive Director,Pharmaceutical Manufacturing Initiative (PHARMI),MIT Program on the Pharmaceutical Industry,Massachusetts Institute of Technology November 16th 2001

  2. OUTLINE • MIT Pharmaceutical Manufacturing Initiative • Process Development • Blending: On-line blend uniformity • So what? • Routine Manufacturing • Where is the time spent “on average”? • Looking beyond the “average” • So what? • Pharmaceutical Manufacturing: • The New Technology Opportunity

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

  4. Pharmaceutical Manufacturing: Context of Experiences.. MIT: MIT Pharma Mfg Initiative (PHARMI) CAMP FDA Food & Drug Administration Consortium For The Advancement Of Manufacturing For Pharmaceuticals G.K. Raju, Ph.D. Purdue Univ: Dept of Industrial & Physical Pharmacy

  5. ACTIVE FORMULN FILL/FINISH PACKAGE ACTIVE FORMULN FILL/FINISH PACKAGE ACTIVE FORMULN FILL/FINISH PACKAGE Pharmaceutial Manufacturing SPACE RESEARCH DEVELOPMENT MANUFACTURING TIME

  6. Pharmaceutial Manufacturing Performance SPACE RESEARCH COST ACTIVE FORMULN FILL PACK QUALITY DEVELOPMENT ACTIVE FORMULN FILL PACK TIME MANUFACTURING ACTIVE FORMULN FILL PACK SAFETY TIME

  7. OUTLINE • MIT Pharmaceutical Manufacturing Initiative • Process Development • Blending: On-line blend uniformity • So what? • Routine Manufacturing • Where is the time spent “on average”? • Looking beyond the “average” • So what? • Pharmaceutical Manufacturing: • The New Technology Opportunity

  8. Pharmaceutial Manufacturing Performance SPACE RESEARCH ACTIVE FORMULN FILL PACK DEVELOPMENT ACTIVE FORMULN FILL PACK MANUFACTURING ACTIVE FORMULN FILL PACK TIME Blending

  9. 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

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

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

  12. OUTLINE • MIT Pharmaceutical Manufacturing Initiative • Process Development • Blending: On-line blend uniformity • So what? • Routine Manufacturing • Where is the time spent “on average”? • Looking beyond the “average” • So what? • Pharmaceutical Manufacturing: • The New Technology Opportunity

  13. 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

  14. 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

  15. Blending Performance Process Development and Validation

  16. On-Line Blend Uniformity Opportunity in Process Development SUMMARY • Large (Factor of 10-15) reduction in cycle time • in blend process development • Large variability reduction in blend • process development time • Independence of organization/product • -> predictability

  17. OUTLINE • MIT Pharmaceutical Manufacturing Initiative • Process Development • Blending: On-line blend uniformity • So what? • Routine Manufacturing • Where is the time spent “on average”? • Looking beyond the “average” • So what? • Pharmaceutical Manufacturing: • The New Technology Opportunity

  18. Pharmaceutial Manufacturing Performance SPACE RESEARCH ACTIVE FORMULN FILL PACK DEVELOPMENT ACTIVE FORMULN FILL PACK MANUFACTURING ACTIVE FORMULN FILL PACK Which Products?High VolumeComplexLiquid TIME

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

  20. 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

  21. 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

  22. 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

  23. 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

  24. Pharmaceutial Manufacturing Performance SPACE RESEARCH ACTIVE FORMULN FILL PACK DEVELOPMENT ACTIVE FORMULN FILL PACK MANUFACTURING ACTIVE FORMULN FILL PACK Which Products?High VolumeComplexLiquid TIME

  25. 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

  26. Pharmaceutial Manufacturing Performance SPACE RESEARCH ACTIVE FORMULN FILL PACK DEVELOPMENT ACTIVE FORMULN FILL PACK MANUFACTURING ACTIVE FORMULN FILL PACK Which Products?High VolumeComplexLiquid TIME

  27. 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

  28. OVERALL CYCLE TIMES:QC TESTING TIMES ARE SIGNIFICANT

  29. CYCLE TIME COMPONENTS

  30. ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES On-line LIF, NIR, Data Analysis, etc.

  31. 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

  32. CONTINUOUS QUALITY VERIFICATION IN ROUTINE MANUFACTURING • Quality testing is Discontinuous • QC testing times are large • QC Cycle Times > Process Cycle Times • OFF-LINE NATURE of test drive time ON-LINE QC TESTING CAN GREATLY IMPACT OVERALL CYCLE TIMES

  33. OUTLINE • MIT Pharmaceutical Manufacturing Initiative • Process Development • Blending: On-line blend uniformity • So what? • Routine Manufacturing • Where is the time spent “on average”? • Looking beyond the “average” • So what? • Pharmaceutical Manufacturing: • The New Technology Opportunity

  34. Pharmaceutial Manufacturing Performance SPACE RESEARCH COST ACTIVE FORMULN FILL PACK QUALITY DEVELOPMENT ACTIVE FORMULN FILL PACK TIME MANUFACTURING ACTIVE FORMULN FILL PACK SAFETY TIME

  35. PHARMACEUTICAL MANUFACTURING:LOOKING BEYOND THE “AVERAGE” Lots with Exceptions Lots without Exceptions OVERALL CYCLE TIMES 0 100 200 300 400 500 600 700 800 LOT NUMBER NEED FOR FUNDAMENTAL TECHNOLOGY

  36. OUTLINE • MIT Pharmaceutical Manufacturing Initiative • Process Development • Blending: On-line blend uniformity • So what? • Routine Manufacturing • Where is the time spent “on average”? • Looking beyond the “average” • So what? • Pharmaceutical Manufacturing: • The New Technology Opportunity

  37. OVERALL CYCLE TIMES:QC TESTING TIMES ARE SIGNIFICANT

  38. Pharmaceutical Manufacturing:Impact of Exceptions (Detailed Analysis of 2 Products) • Average Cycle time95 days • Std dev(Cycle time)>100 days • Exceptions increase cycle time by>50 % • Exceptions increase variability by >100% • Capacity Utilization of “System” LOW PERFORMANCE MEASURE VALUE NEED FOR FUNDAMENTAL TECHNOLOGY

  39. OUTLINE • MIT Pharmaceutical Manufacturing Initiative • Process Development • Blending: On-line blend uniformity • So what? • Routine Manufacturing • Where is the time spent “on average”? • Looking beyond the “average” • So what? • Pharmaceutical Manufacturing: • The New Technology Opportunity..

  40. Pharmaceutial Manufacturing Performance SPACE RESEARCH ACTIVE FORMULN FILL PACK DEVELOPMENT ACTIVE FORMULN FILL PACK MANUFACTURING Which Products?High VolumeComplexLiquid ACTIVE FORMULN FILL PACK TIME Assay Fermentation Blending Drying Granulation Flow Tableting Transport Rapid Microbial Detection

  41. 10% 5% 1% 0.5% 0.1% Pharmaceutial Manufacturing Performance SPACE RESEARCH ACTIVE FORMULN FILL PACK DEVELOPMENT ACTIVE FORMULN FILL PACK MANUFACTURING Which Products?High VolumeComplexLiquid ACTIVE FORMULN FILL PACK TIME Assay Fermentation Blending Drying Granulation Flow Tableting Transport Rapid Microbial Detection

  42. PHARMACEUTICAL MANUFACTURING:The New Technology Opportunity.. • New Technology Can Be A Huge Win For: • INDUSTRY • FDA • SOCIETY • But We Can Only Capture Its Potential If We Work Together In a “Win-Win” Mode • If We Don’t We All Lose.. • Lets Find A Way To All Win..

  43. Pharmaceutical Manufacturing: Context of Experiences.. MIT: MIT Pharma Mfg Initiative (PHARMI) CAMP FDA Food & Drug Administration Consortium For The Advancement Of Manufacturing For Pharmaceuticals G.K. Raju, Ph.D. Purdue Univ: Dept of Industrial & Physical Pharmacy

  44. ACKNOWLEDGEMENTS • Consortium for the Advancement of Manufacturing of Pharmaceuticals (CAMP) • Professor Charles Cooney (MIT) • Professor Stephen Byrn (Purdue)

  45. NOTE ON CONTEXT • This presentation represents personal opinion does not necessarily represent the views of MIT, Purdue or CAMP • Some data have been disguised for reasons of sensitivity and confidentiality

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