1. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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

2. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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 (PHARMI) Objective: To Describe and Capture the Opportunity to Improve Pharmaceutical Manufacturing Performance MIT Pharmaceutical Manufacturing Initiative Research Development Manufacturing Marketing

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

5. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL/FINISH PACKAGE ACTIVE FORMULNFILL/FINISHPACKAGE ACTIVE FORMULNFILL/FINISHPACKAGE RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing

6. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance COST QUALITY TIME SAFETY

7. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance Blending

9. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Blending Operation Model Blender cleaning 8 Mixing Active ingredient Excipients Raw material load 8 8 Sampling Transporting Homogeneity test OK? Results & Decision Making Undermixed mix-longer Homogeneous Next batch Discarded Next batch Analysis

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

11. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) LIF VERIFICATION STUDIES Established a correlation between LIF assessment of homogeneity and thief-sampling with off-line analysis

12. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS D: BLENDING PROCESS DEVELOPMENT CHEMICAL WEIGHING GRANULATION Processing STEP BLEND 1: BLEND 2: PRE- BLEND FINAL BLEND FILM COATING COMPRESS BOTTLE PACKAGING OFF LINE QC TEST ON LINE SENSOR

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

15. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Blending Performance Process Development and Validation

16. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) On-Line Blend Uniformity Opportunity in Process Development 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 SUMMARY

17. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance Which Products? High Volume Complex Liquid

19. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS A WITH QC TESTS WEIGHING WET GRANULATION STEPFB DRY STEP BLEND ENCAPSULATESIEVE API MICRO Particle Size Description ID Assay CU Impurity Dissolution MICRO QC 1 QC 3 QC 4 DRY MIX QC 2 LOD

20. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS A WITH CYCLE TIMES WEIGH WET GRANULN ProcessingFB DRY STEP BLEND ENCAPSULATE SIEVE API MICRO Particle Size Description ID Assay CU Impurity Dissolution MICRO QC 1 QC 3 QC 4 DRY MIX QC 2 LOD 7 DAYS 13 DAYS < 3 DAYS

21. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS D WITH QC TESTS CHEMICAL WEIGHING GRANULATION Processing STEP BLEND 1: BLEND 2: PRE- BLEND FINAL BLEND FILM COATING COMPRESS BOTTLE PACKAGING API Particle Size LOD Description ID Assay CU Impurity Dissolution QC 1 QC 2 QC 3

22. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS D WITH CYCLE TIMES QC 1 BLEND 2: PRE-BLEND CHEMICAL WEIGHING GRANULATION PROCESSING STEP BLEND 1: FINAL BLEND COMPRESS FILM COATING BOTTLE PACKAGING QC 2 QC 3 15 DAYS 10 DAYS 20 DAYS 15 DAYS 60 DAYS Description ID Assay CU Impurity Dissolution Particle Size LOD API

23. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS D WITH QC TESTS: Cycle Times including BULK ACTIVE QC 1 BLEND 2: PRE-BLEND CHEMICAL WEIGHING GRANULATIONSTEP BLEND 1: FINAL BLEND COMPRESS FILM COATING BOTTLE PACKAGING QC 2 QC 3 15 DAYS 10 DAYS 20 DAYS15 DAYS 60 DAYS 21-90 DAYS PROCESSING

24. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance Which Products? High Volume Complex Liquid

25. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS E WITH QC TEST TIMES ACTIVE FIRST GRAN SECOND GRAN QC 1 7 days COAT SIFT& BLEND QC 4 QC 3 QC 2 FILL 7 days 3 days < 1 day < 1 day 1-2 days < 1 day < 1 day < 1 day

26. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance Which Products? High Volume Complex Liquid

27. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS F: LIQUID LINE WITH CYCLE TIMES 10 days 7 days ENVIRONMENTAL MONITORING BIOBURDEN TESTING 17-20 days 7 days 3-4 days STERILITY TESTING WFI TESTING 3-4 months

28. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) OVERALL CYCLE TIMES: QC TESTING TIMES ARE SIGNIFICANT

29. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CYCLE TIME COMPONENTS

30. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ON-LINE TECHNOLOGY IMPACTS DOMINANT CYCLE TIMES On-line LIF, NIR, Data Analysis, etc.

31. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) WHAT DRIVES THE QC TESTING TIMES? 0 5 10 15 20 QC1PFDQC3Release Actual Target Potential Sampling Batching Other Products Waiting Coordinating Other Products Other Paperwork Waiting Coordinating 2% TEST

32. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance COST QUALITY TIME SAFETY

35. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PHARMACEUTICAL MANUFACTURING: LOOKING BEYOND THE “AVERAGE” 0100200300400500600700800 LOT NUMBER OVERALL CYCLE TIMES Lots without Exceptions Lots with Exceptions NEED FOR FUNDAMENTAL TECHNOLOGY

36. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) OVERALL CYCLE TIMES: QC TESTING TIMES ARE SIGNIFICANT

38. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Average Cycle time 95 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 Pharmaceutical Manufacturing: Impact of Exceptions (Detailed Analysis of 2 Products) NEED FOR FUNDAMENTAL TECHNOLOGY

39. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance Which Products? High Volume Complex Liquid Blending Drying Granulation Flow Tableting Transport Assay Fermentation Rapid Microbial Detection

41. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Pharmaceutial Manufacturing Performance Which Products? High Volume Complex Liquid Blending Drying Granulation Flow Tableting Transport Assay Fermentation Rapid Microbial Detection 10% 5% 1% 0.5% 0.1%

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

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

45. MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) 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