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

2. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l MOTIVATION l “MANUFACTURING SCIENCE”: DIMENSIONS l QUALITY BY DESIGN: THE LEVERAGES l QUALITY BY DESIGN: THE COMPONENTS l CONSIDERATIONS

3. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SYSTEM” A “manufacturing system” is 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

4. © G.K.Raju, Ph.D. Manufacturing Science ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE PHARMACEUTICAL MANUFACTURING SYSTEM COST QUALITY TIME SAFETY

5. © G.K.Raju, Ph.D. Manufacturing Science 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

6. © G.K.Raju, Ph.D. Manufacturing Science QUALITY “TESTING” END OF LINE CONSUMES SIGNIFICANT TIME 0 5 10 15 20 25 TIME (Days) ABCDEF Overall Cycle Time Components Process Times QC Testing Times

7. © G.K.Raju, Ph.D. Manufacturing Science QUALITY “TESTING” END OF LINE MAKES IT DIFFICULT TO UNDERSTAND “EXCEPTIONS” 0100200300400500600700800 LOT NUMBER OVERALL CYCLE TIMES Lots without Exceptions Lots with Exceptions

8. © G.K.Raju, Ph.D. Manufacturing Science PHARMA MANUFACTURING CYCLE TIMES (DAYS): HALF A YEAR, LITTLE IMPROVEMENT…. * Derived from COGS numbers

9. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l MOTIVATION l “MANUFACTURING SCIENCE”: DIMENSIONS l QUALITY BY DESIGN: THE LEVERAGES l QUALITY BY DESIGN: THE COMPONENTS l CONSIDERATIONS

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

12. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: The “Time” Dimension THE DESIRED STATE Extent Of Mfg. Science Time “Right First Time” LEVEL 1 LEVEL 2 LEVEL 4 LEVEL 5 LEVEL 3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”)

13. © G.K.Raju, Ph.D. Manufacturing Science “EXTENT OF MANUFACTURING SCIENCE”: COST, QUALITY AND TIME OPPORTUNITY Extent Of Mfg. Science Time “Right First Time” LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”) Cost Quality Time Opportunity Desired Actual

14. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l MOTIVATION l “MANUFACTURING SCIENCE”: DIMENSIONS l QUALITY BY DESIGN: THE LEVERAGES l QUALITY BY DESIGN: THE COMPONENTS l CONSIDERATIONS

15. © G.K.Raju, Ph.D. Manufacturing Science QUALITY BY DESIGN: THE LEVERAGES Extent Of Mfg. Science Or Quality By Design Time “Right First Time” LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”) Strategic Leverage Tactical Leverage

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

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

18. © G.K.Raju, Ph.D. Manufacturing Science WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 1: INITIAL WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 2: REPEATABLE WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 4: MANAGED LEVEL 5: OPTIMIZING WEIGHINGBLEND FILM COATING COMPRESS BOTTLE PACKAGING WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 3: DEFINED QUALITY BY DESIGN: A PROCESS ROADMAP

19. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l MOTIVATION l “MANUFACTURING SCIENCE”: DIMENSIONS l QUALITY BY DESIGN: THE LEVERAGES l QUALITY BY DESIGN: THE COMPONENTS l CONSIDERATIONS

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

21. © G.K.Raju, Ph.D. Manufacturing Science lHow Much Was Known About This Product & Process Before? u API u Excipients u Etc. lWhat Kind of “A-Priori Knowledge” Exists? u First Principle Knowledge u Mechanistic Knowledge u Causal Knowledge u Correlative Knowledge u Descriptive Knowledge COMPONENTS OF “QUALITY BY DESIGN: A-PRIORI KNOWLEDGE

22. © G.K.Raju, Ph.D. Manufacturing Science Current ApproachProposed Approach 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 xx x x xxx 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 xx x x xxx x x x x x x x x Process Development Commercial Production 1a 1b 2a 2b COMPONENTS OF “QUALITY BY DESIGN: INFORMATION EXCHANGE: EXTENT AND TYPE WHAT IS THE QUALITY AND QUANTITY OF DATA USED

23. © G.K.Raju, Ph.D. Manufacturing Science ON-LINE TECHNOLOGY IMPACTS DOMINANT CYCLE TIMES On-line LIF, NIR, Pattern Recognition, etc.

24. © G.K.Raju, Ph.D. Manufacturing Science CURRENT STATE WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 1: INITIAL WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 2: REPEATABLE WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 4: MANAGED LEVEL 5: OPTIMIZING WEIGHINGBLEND FILM COATING COMPRESS BOTTLE PACKAGING WEIGHING GRANULATION FB DRY MILLING BLEND FILM COATING COMPRESS BOTTLE PACKAGING LEVEL 3: DEFINED Minimum Requirement “MANUFACTURING SYSTEM” ROADMAP: CURRENT Relative To DESIRED State

25. © G.K.Raju, Ph.D. Manufacturing Science l Safety and Efficacy l Process Capability Associated With Critical- To-Quality (CTQ) Variables l Variability of Critical-To-Quality Variables l Predictive Ability Of Performance COMPONENTS OF “QUALITY BY DESIGN: PERFORMANCE MEASUREMENT

26. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: DESIRED RELATIVE TO CURRENT STATE (Personal Opinion) Extent Of Mfg. Science Time “Right First Time” LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”)

27. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l MOTIVATION l “MANUFACTURING SCIENCE”: DIMENSIONS l QUALITY BY DESIGN: THE LEVERAGES l QUALITY BY DESIGN: THE COMPONENTS l CONSIDERATIONS

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

29. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : IMPLICATIONS Extent Of Mfg. Science Or Quality By Design LEVEL1 LEVEL2 LEVEL4 LEVEL 5 LEVEL3 PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, … LEVEL5 Lower Risk Higher Process Understanding Lower Variability Lower Costs

30. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : IMPLICATIONS Extent Of Mfg. Science Or Quality By Design LEVEL1 LEVEL2 LEVEL4 LEVEL3 PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, … LEVEL5 FDA