1. © G.K.Raju, Ph.D. Confidential FDA Manufacturing Subcommittee Meeting July 20, 2004 G.K. Raju, Ph.D. Executive Director, MIT/PHARMI Massachusetts Institute of Technology PHARMACEUTICAL MANUFACTURING IN THE 21 st CENTURY: A “Science” Perspective

2. © G.K.Raju, Ph.D. Confidential OUTLINE  THE “FRAME”  A VOCABULATORY  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

3. © G.K.Raju, Ph.D. Confidential Pharmaceutical Manufacturing: A Social Capability Regulator Pharmaceutical Industry Patients Academia Government Pharma Mfg Health Care

4. © G.K.Raju, Ph.D. Confidential OUTLINE  INTRODUCTION  A “SCIENCE” PERSPECTIVE  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

5. © G.K.Raju, Ph.D. Confidential “MANUFACTURING SCIENCE” : Mfg. Science LEVEL 1 LEVEL 2 LEVEL 4 LEVEL 5 LEVEL 3 CORRELATIVE KNOWLEDGE What Is Correlated to What? “CAUSAL" KNOWLEDGE What “Causes” What? MECHANISTIC KNOWLEDGE How? First Principles Why? DESCRIPTIVE KNOWLEDGE: What?

6. © G.K.Raju, Ph.D. Confidential A Science Perspective: 1. “SCIENCE” “Science” (noun) A body of knowledge, body of facts or information, body of laws or principles, body of truths, or verities or realities…… “Science” (a process) A means for solving problems…

7. © G.K.Raju, Ph.D. Confidential A “Science” Perspective: 2. MANUFACTURING “SYSTEM” A “manufacturing system” is a set of processes and systems (and people) bound by a common material and information flow. Material Information WEIGH WET GRANULN STEPFB DRY STEP BLEND ENCAPSULATE SIEVE QC 1 QC 3 QC 4 DRY MIX QC 2

8. © G.K.Raju, Ph.D. Confidential A “Science” Perspective: 3. Manufacturing “Capability” Voice of Your Customer Voice Of Your Process Manufacturing Capability = CEOScientistVP OperationsRegulatorPatient

9. © G.K.Raju, Ph.D. Confidential OUTLINE  INTRODUCTION  A “SCIENCE” PERSPECTIVE  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

10. © G.K.Raju, Ph.D. Confidential “MANUFACTURING SCIENCE” : Desired State (“There”) Mfg. Science LEVEL 1 LEVEL 2 LEVEL 4 LEVEL 5 LEVEL 3 CORRELATIVE KNOWLEDGE What Is Correlated to What? “CAUSAL" KNOWLEDGE What “Causes” What? MECHANISTIC KNOWLEDGE How? First Principles Why? DESCRIPTIVE KNOWLEDGE: What?

11. © G.K.Raju, Ph.D. Confidential “PROCESS UNDERSTANDING”: THE DESIRED STATE Process Understanding Time LEVEL1 LEVEL2 LEVEL4 LEVEL5 LEVEL3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”) Launch

12. © G.K.Raju, Ph.D. Confidential OUTLINE  INTRODUCTION  A “SCIENCE” PERSPECTIVE  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

13. © G.K.Raju, Ph.D. Confidential “MANUFACTURING SCIENCE” : Current State (“Here”) Mfg. Science LEVEL 1 LEVEL 2 LEVEL 4 LEVEL 5 LEVEL 3 CORRELATIVE KNOWLEDGE What Is Correlated to What? “CAUSAL" KNOWLEDGE What “Causes” What? MECHANISTIC KNOWLEDGE How? First Principles Why? DESCRIPTIVE KNOWLEDGE: What?

14. © G.K.Raju, Ph.D. Confidential Time LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Process Understanding “PROCESS UNDERSTANDING”: THE CURRENT STATE (“HERE”)

15. © G.K.Raju, Ph.D. Confidential OUTLINE  INTRODUCTION  A “SCIENCE” PERSPECTIVE  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

16. © G.K.Raju, Ph.D. Confidential FROM “HERE” TO “THERE”: STRATEGIC LEVERAGE Time LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Process Understanding What is “development”? Vocabulary? How do you measure? Knowledge to understanding

17. © G.K.Raju, Ph.D. Confidential FROM “HERE” TO “THERE”: TACTICAL LEVERAGE Time LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Process Understanding Investigations True Root Causes Separate Critical From Non-critical

18. © G.K.Raju, Ph.D. Confidential OUTLINE  INTRODUCTION  A “SCIENCE” PERSPECTIVE  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

19. © G.K.Raju, Ph.D. Confidential “SCIENCE” PERSPECTIVE: IMPLICATIONS 1. Finally, A Positive Vision ….. 2. Enabling Vocabulary

20. © G.K.Raju, Ph.D. Confidential “SCIENCE” PERSPECTIVE: IMPLICATIONS 3. Basis For VERY Different Relationship With Regulator Mfg. Science LEVEL 1 LEVEL 2 LEVEL 4 LEVEL 5 LEVEL 3 CORRELATIVE KNOWLEDGE What Is Correlated to What? “CAUSAL" KNOWLEDGE What “Causes” What? MECHANISTIC KNOWLEDGE How? First Principles Why? DESCRIPTIVE KNOWLEDGE: What? Lower Risk Quality By Design More Harmonized Lower Cost High Quality Lower Times

21. © G.K.Raju, Ph.D. Confidential  cGMPS FOR 21 st CENTURY  Science Based  Risk Based  Modern Quality Management Techniques  Harmonization  PAT – A FRAMEWORK FOR INNOVATIVE PHARMACEUTICAL MANUFACTURING AND QUALITY ASSURANCE “SCIENCE” PERSPECTIVE: IMPLICATIONS 4. Connectivity to Current Momentum

22. © G.K.Raju, Ph.D. Confidential “SCIENCE” PERSPECTIVE: IMPLICATIONS 5. A Basis To Collaborate With Your “Competitor” Mfg. Science LEVEL 1 LEVEL 2 LEVEL 4 LEVEL 5 LEVEL 3 CORRELATIVE KNOWLEDGE What Is Correlated to What? “CAUSAL" KNOWLEDGE What “Causes” What? MECHANISTIC KNOWLEDGE How? First Principles Why? DESCRIPTIVE KNOWLEDGE: What?

23. © G.K.Raju, Ph.D. Confidential “SCIENCE” PERSPECTIVE: IMPLICATIONS 6. An Inside-Out View That Enables A Systems View Regulator Pharmaceutical Industry Patients Academia Government Pharma Mfg Health Care

24. © G.K.Raju, Ph.D. Confidential “SCIENCE” PERSPECTIVE: IMPLICATIONS 7. A Foundation To Transform Lives All Over Again.. Time 1978 19882008 1998 201820031983199320132023 Last 25 Years 2028 Next 25 Years 1978 19882008 1998 201820031983199320132023 Last 25 Years 2028 Next 25 Years A New Shared Vision Manufacturing Capability

25. © G.K.Raju, Ph.D. Confidential Time Social Resources Required “Ensure” 1978 19882008 1998 201820031983199320132023 Last 25 Years 2028 Next 25 Years A New Shared Vision Time To Quality 1978 19882008 1998 201820031983199320132023 Last 25 Years 2028 Next 25 Years A New Shared Vision “Science” Perspective: 7. A Foundation To Transform Lives All Over Again

26. © G.K.Raju, Ph.D. Confidential OUTLINE  INTRODUCTION  A “SCIENCE” PERSPECTIVE  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

27. © G.K.Raju, Ph.D. Confidential NEXT STEPS  Broaden Shared Vision  Long Term Social Roadmap  A “Real” Economic Case  “Real” Case Studies  “Pilot” The Future

28. © G.K.Raju, Ph.D. Confidential OUTLINE  INTRODUCTION  A “SCIENCE” PERSPECTIVE  THE DESIRED STATE: “THERE”  THE CURRENT STATE: “HERE”  FROM “HERE” TO “THERE”: LEVERAGES  IMPLICATIONS  NEXT STEPS  ACKNOWLEDGEMENTS

29. © G.K.Raju, Ph.D. Confidential ACKNOWLEDGEMENTS l Consortium For The Advancement Of Manufacturing Of Pharmaceuticals (CAMP) l Charles Cooney (MIT) l Steve Byrn and Kenneth Morris (PURDUE) l Janet Woodcock, Helen Winkle and Ajaz Hussain (FDA)