Sept 17th 2003

1. QUALITY BY DESIGN: The Means To Fundamental Manufacturing Science G.K.Raju, Ph.D. Sept 17th 2003

2. OUTLINE • MOTIVATION • “MANUFACTURING SCIENCE”: DIMENSIONS • QUALITY BY DESIGN: THE LEVERAGES • QUALITY BY DESIGN: THE COMPONENTS • CONSIDERATIONS

3. QC2 QC3 QC1 QC4 BLEND DRY MIX STEP FB DRY SIEVE WET GRANULN STEP WEIGH ENCAPSULATE “MANUFACTURING SYSTEM” A “manufacturing system” is set of processes and systems (and people) bound by a common material and information flow. Information Information Material Material

4. PHARMACEUTICAL MANUFACTURING SYSTEM SPACE RESEARCH QUALITY ACTIVE FORMULN FILL PACK DEVELOPMENT TIME ACTIVE FORMULN FILL PACK COST MANUFACTURING ACTIVE FORMULN FILL PACK SAFETY TIME

5. 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

6. QUALITY “TESTING” END OF LINECONSUMES SIGNIFICANT TIME Overall Cycle Time Components 25 20 15 TIME (Days) Process Times 10 QC Testing Times 5 0 A B C D E F

7. QUALITY “TESTING” END OF LINE MAKES IT DIFFICULT TO UNDERSTAND “EXCEPTIONS” Lots with Exceptions Lots without Exceptions OVERALL CYCLE TIMES 0 100 200 300 400 500 600 700 800 LOT NUMBER

8. PHARMA MANUFACTURING CYCLE TIMES (DAYS):HALF A YEAR, LITTLE IMPROVEMENT…. * Derived from COGS numbers

9. OUTLINE • MOTIVATION • “MANUFACTURING SCIENCE”: DIMENSIONS • QUALITY BY DESIGN: THE LEVERAGES • QUALITY BY DESIGN: THE COMPONENTS • CONSIDERATIONS

10. “MANUFACTURING SCIENCE”:DIMENSIONS Body of Knowledge, Laws, Principles Involved In The Transformation of Materials and Information into Goods for the Satisfaction of Human Needs Extent Of Mfg. Science

11. “MANUFACTURING SCIENCE” :Levels of Knowledge LEVEL 5 First Principles Extent Of Mfg. Science Or Quality By Design MECHANISTIC KNOWLEDGE LEVEL 4 LEVEL 3 CAUSAL KNOWLEDGE Why? PROCESS KNOWLEDGE How, Correlative .. LEVEL 2 DESCRIPTIVE KNOWLEDGE: What, Etc, … LEVEL 1

12. “MANUFACTURING SCIENCE”:The “Time” DimensionTHE DESIRED STATE “Right First Time” LEVEL 5 Design/Development Centric Approach Manufacturing Science (“learning before doing”) Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) LEVEL 4 Extent Of Mfg. Science LEVEL 3 LEVEL 2 FDA Minimum Requirement LEVEL 1 Time

13. “EXTENT OF MANUFACTURING SCIENCE”:COST, QUALITY AND TIME OPPORTUNITY “Right First Time” Desired LEVEL 5 Cost Quality Time Opportunity Design/Development Centric Approach Manufacturing Science (“learning before doing”) LEVEL 4 Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Extent Of Mfg. Science LEVEL 3 Actual LEVEL 2 FDA Minimum Requirement LEVEL 1 Time

14. OUTLINE • MOTIVATION • “MANUFACTURING SCIENCE”: DIMENSIONS • QUALITY BY DESIGN: THE LEVERAGES • QUALITY BY DESIGN: THE COMPONENTS • CONSIDERATIONS

15. QUALITY BY DESIGN:THE LEVERAGES “Right First Time” LEVEL 5 Extent Of Mfg. Science Or Quality By Design Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) LEVEL 4 Strategic Leverage Tactical Leverage LEVEL 3 Design/Development Centric Approach Manufacturing Science (“learning before doing”) LEVEL 2 FDA Minimum Requirement LEVEL 1 Time

16. QUALITY BY DESIGN:STRATEGIC LEVERAGE: “Learning Before Doing” • Significantly Enhanced Level of Product & Process Understanding BEFORE Commercial Manufacturing • Enables Mechanistic Basis for Setting Product and Process Quality Specifications • Impact Over Whole Lifecycle • Easier to Make Fundamental Process Design Changes (Fewer Regulatory Barriers)

17. QUALITY BY DESIGN:STRATEGIC LEVERAGE: “Learning By Doing” • Enhanced Level of Product & Process Understanding DURING Commercial Manufacturing • Potential To Leverage Large Amounts of Production Data • Investigation/Exceptions Provide Opportunity To Learn • Difficult to Make Significant Product & Process Changes • Rarely an environment to develop mechanistic understanding

18. FILM COATING FILM COATING BOTTLE PACKAGING BOTTLE PACKAGING GRANULATION GRANULATION MILLING MILLING COMPRESS COMPRESS WEIGHING WEIGHING FB DRY FB DRY BLEND BLEND FILM COATING BOTTLE PACKAGING GRANULATION MILLING COMPRESS WEIGHING FB DRY BLEND QUALITY BY DESIGN:A PROCESS ROADMAP LEVEL 5: OPTIMIZING FILM COATING BOTTLE PACKAGING COMPRESS WEIGHING BLEND LEVEL 4: MANAGED LEVEL 3: DEFINED FILM COATING BOTTLE PACKAGING GRANULATION MILLING COMPRESS WEIGHING FB DRY BLEND LEVEL 2: REPEATABLE LEVEL 1: INITIAL

19. OUTLINE • MOTIVATION • “MANUFACTURING SCIENCE”: DIMENSIONS • QUALITY BY DESIGN: THE LEVERAGES • QUALITY BY DESIGN: THE COMPONENTS • CONSIDERATIONS

20. Performance Measurement Information Exchange A-priori knowledge QUALITY BY DESIGN:COMPONENTS Extent Of Manufacturing Science Or Quality By Design PROCESS & PRODUCT Y = F(X)

21. COMPONENTS OF “QUALITY BY DESIGN:A-PRIORI KNOWLEDGE • How Much Was Known About This Product & Process Before? • API • Excipients • Etc. • What Kind of “A-Priori Knowledge” Exists? • First Principle Knowledge • Mechanistic Knowledge • Causal Knowledge • Correlative Knowledge • Descriptive Knowledge

22. 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 COMPONENTS OF “QUALITY BY DESIGN:INFORMATION EXCHANGE: EXTENT AND TYPE WHAT IS THE QUALITY AND QUANTITY OF DATA USED

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

24. FILM COATING FILM COATING BOTTLE PACKAGING BOTTLE PACKAGING GRANULATION GRANULATION MILLING MILLING COMPRESS COMPRESS WEIGHING WEIGHING FB DRY FB DRY BLEND BLEND FILM COATING BOTTLE PACKAGING GRANULATION MILLING COMPRESS WEIGHING FB DRY BLEND “MANUFACTURING SYSTEM” ROADMAP:CURRENTRelative To DESIRED State LEVEL 5: OPTIMIZING FILM COATING BOTTLE PACKAGING COMPRESS WEIGHING BLEND LEVEL 4: MANAGED LEVEL 3: DEFINED FILM COATING BOTTLE PACKAGING GRANULATION MILLING COMPRESS WEIGHING FB DRY BLEND CURRENT STATE LEVEL 2: REPEATABLE Minimum Requirement LEVEL 1: INITIAL

25. COMPONENTS OF “QUALITY BY DESIGN:PERFORMANCE MEASUREMENT • Safety and Efficacy • Process Capability Associated With Critical-To-Quality (CTQ) Variables • Variability of Critical-To-Quality Variables • Predictive Ability Of Performance

26. “MANUFACTURING SCIENCE”: DESIRED RELATIVE TO CURRENT STATE(Personal Opinion) “Right First Time” LEVEL 5 Design/Development Centric Approach Manufacturing Science (“learning before doing”) Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) LEVEL 4 Extent Of Mfg. Science LEVEL 3 LEVEL 2 FDA Minimum Requirement LEVEL 1 Time

27. OUTLINE • MOTIVATION • “MANUFACTURING SCIENCE”: DIMENSIONS • QUALITY BY DESIGN: THE LEVERAGES • QUALITY BY DESIGN: THE COMPONENTS • CONSIDERATIONS

28. QUALITY BY DESIGN:IS THE EXTENT OF “RIGHT FIRST TIME” CONSENT DECREE WARNING LETTER Time (& cost) Associated With Addressing Cause For Not Being “Right” External Failure Common Focus FDA 483 RECALLS COMPLAINTS Internal Failure REJECTS QA APPROVAL Appraisal FINAL QC TESTING IN-PROCESS TESTING DEVELOPMENT Prevention Where “Right” is Measured

29. “MANUFACTURING SCIENCE” :IMPLICATIONS LEVEL 5 LEVEL 5 First Principles • Lower Risk • Higher • Process • Understanding • Lower • Variability • Lower • Costs Extent Of Mfg. Science Or Quality By Design LEVEL 4 MECHANISTIC KNOWLEDGE LEVEL 3 CAUSAL KNOWLEDGE Why? PROCESS KNOWLEDGE How, Correlative .. LEVEL 2 DESCRIPTIVE KNOWLEDGE: What, Etc, … LEVEL 1

30. “MANUFACTURING SCIENCE” :IMPLICATIONS LEVEL 5 First Principles LEVEL 4 Extent Of Mfg. Science Or Quality By Design MECHANISTIC KNOWLEDGE LEVEL 3 CAUSAL KNOWLEDGE Why? FDA PROCESS KNOWLEDGE How, Correlative .. LEVEL 2 DESCRIPTIVE KNOWLEDGE: What, Etc, … LEVEL 1