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QBA AND ELEMENTS OF QBD

QBA AND ELEMENTS OF QBD. Girish MALHOTRA, PE EPCOT International Quality By Design International Pharmaceutical Academy October 19-20, 2009 Somerset, New Jersey. My Commercialization Perspective. MY DEFINITION OF API:. IT IS A “SPECIALTY CHEMICAL” THAT HAS A DISEASE CURING VALUE. GOAL.

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QBA AND ELEMENTS OF QBD

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  1. QBA AND ELEMENTS OF QBD Girish MALHOTRA, PE EPCOT International Quality By Design International Pharmaceutical Academy October 19-20, 2009 Somerset, New Jersey EPCOT International

  2. My CommercializationPerspective EPCOT International

  3. MY DEFINITION OF API: IT IS A “SPECIALTY CHEMICAL” THAT HAS A DISEASE CURING VALUE. EPCOT International

  4. GOAL REPEATABLE QUALITY AND HIGH PROFITABILITY EPCOT International

  5. Quality and Profitability Good Process High on-stream-time (high equipment utilization) Green and Safe Quality first and all the time Easier Regulatory compliance Better “Total Business Process” EPCOT International

  6. EXPECTATION: QUALITY PRODUCTS PROCESS INNOVATION LOWER COST EPCOT International

  7. API MANUFACTURING: • RELY ON QBA. • WHY? EPCOT International

  8. API MANUFACTURING: • COMPETITIVE PRESSURE (TIME) FIRST TO MARKET • REGULATIONSTOO EXPENSIVE TO COMPLY • PRICE ABLE TO ACHIEVE DESIRED MARGINS EPCOT International

  9. API LAB DEVELOPMENT PROVE CHEMISTRY CONCEPT PROVE FEASIBILITY OF CHEMISTRY DEFINES PROCESS CONCEPTS EPCOT International

  10. API LAB DEVELOPMENT LAB EQUIPMENT AND SYNTHESIS BASED ON OUR LEARNING AT UNIVERSITIES. HAND ME DOWN METHODS. THEY WORK. EPCOT International

  11. API LAB DEVELOPMENT LABORATORY PROCESSES NOT OPTIMIZED. REGULATORY PROCESS AND SPEED TO MARKET PREVENT OPTIMIZATION. FEAR OF PROCESS CHANGE AND REGULATORY RE-APPROVAL INVESTMENT. EPCOT International

  12. Pharmaceutical Processes Quality by analysis CHOKEDINNOVATION Current status Manufacturing EPCOT International

  13. LOW PROCESS CAPABILITY(Source: Doug Dean, PricewaterhouseCoopers. FDA Science Board Meeting November 16, 2001) Utilization levels – 15% or less (low levels masked). Scrap and rework – we plan for 5-10% Cost of quality – in excess of 20% (that’s the way it is). EPCOT International

  14. CURRENT STATE SOME IMPROVEMENT SINCE 2001 RECENT SURVEY 70% FEEL “NOT ENOUGH” EPCOT International

  15. CURRENT STATE INADEQUATE TO MEET FUTURE NEEDS EPCOT International

  16. CURRENT STATE MANUFACTURING DIFFICULTIESDUE TO LACK OF PROCESS UNDERSTANDING EPCOT International

  17. “QUALITY BY ANALYSIS (QBA)” QBA OFF SPECPRODUCT  QUALITY PRODUCT QBA IS “ANALYSIS PARALYSIS.” WASTED $, €, £ , ¥, , INFLUENCES “THE WHOLE BUSINESS PROCESS.” EPCOT International

  18. “QUALITY BY ANALYSIS (QBA)” “CURRENT ANALYTICAL METHODS TELL US: WE ARE “OFF-COURSE” THEY DO NOT TELL US WHY. THEY DO NOT FIX THE PROBLEM. EPCOT International

  19. CMC, PAT, DS, CQA, FDA, ICH etc. GENERAL BELIEF WILL SOLVE ALL OF THE PROBLEMS. DELIVER: QUALITY BY DESIGN (QBD) NOT TRUE. EPCOT International

  20. TLAs CONFUSE THAN SOLVE VARIED INTERPRETATION. EPCOT International

  21. WE ARE MORE WORRIED ABOUT THE DIRECTIVES AND GUIDELINES. WE NEED TO DO THE RIGHT THING. EPCOT International

  22. Process knowledge should be such that: We can duplicate our mistakes. Can’t be done! Perfection is possible! Improves profitability. Reduces overall investment. Simplifies the business process. EPCOT International

  23. CURRENT DEVELOPMENT STATUS It is notdue to lack of our desire. It is due to market pressures. It is due to tradition (Chemistry-Centric). It is due to gap between translate EPCOT International

  24. API DEVELOPMENT : NEED TO CHANGE Thinking Strategy Execution Scale-up Commercialization EPCOT International

  25. API PROCESS DEVELOPMENT Is like finessing cards in Poker. Need to finesse PHYSICAL PROPERTIES to have a winning process. EPCOT International

  26. Yield OPPORTUNITIES Solvent use Intermediate Isolation Phase Separation Unit Processes and Operations Reaction Kinetics Physical Properties Mass and Heat Balance EPCOT International

  27. ? EPCOT International

  28. NEED TO UNDERSTAND: • FUNDAMENTALS TAUGHT @ UNDERGRADUATE LEVEL • NEED TO UNDERSATND THEIR VALUE. EPCOT International

  29. NEED TO UNDERSTAND: • PHYSICAL PROPETIRES • CHEMISTRY AND REACTION MECHANISM • ABILITY TO APPLY WILL GIVE QUALITY EPCOT International

  30. RAW MATERIALS, INTERMEDIATES • AND • FINISHED PRODUCTS • ARE • PURE CHEMICALS DISTINCT PHYSICAL PROPERTIES i.e. SPECIFICATIONS CQA: CRITICAL QUALITY ATTRIBUTES EPCOT International

  31. CHEMISTRY REACTION MECHANISM DEFINE: • CRITICAL OPERATING PARAMETERS • i.e. DESIGN SPACE EPCOT International

  32. AT TIMES WE ARE MORE WORRIED ABOUT TLA’S RATHER THAN WHAT THEY MEAN. BUZZ WORDS FOR FUNDAMENTALS. ALPHABET SOUP EPCOT International

  33. FUNDAMENTALS: SHOW METHODS AND WAYS TO MANIPULATE SIMPLIFY PROCESS EPCOT International

  34. UNDERSTAND PHYSICAL PROPERTIES EPCOT International

  35. UNDERSTAND REACTION CHEMISTRY AND MECHANISM EPCOT International

  36. RIGHT PERSPECTIVE:A QBDPROCESS. OTHER “TLA” SECOND NATURE EPCOT International

  37. OUR OBJECTIVE GOOD PROCESS HIGH ON-STREAM-TIME (HIGH EQUIPMENT UTILIZATION) GREEN AND SAFE QUALITY FIRST AND ALL THE TIME (QBD) EASIER REGULATORY COMPLIANCE BETTER “TOTAL BUSINESS PROCESS” EPCOT International

  38. WE CAN DELIVER QBD PROCESS:IF WE UNDERSTAND PHYSICAL PROPERTIES &CHEMICAL INTERACTION. EPCOT International

  39. PHYSICAL PROPERTIES: • PHYSICAL STATE • BOILING POINT/ MELTING POINT • AZEOTROPE • VISCOSITY • DENSITY • THERMODYNAMIC PROPERTIES • SOLUBILITY EPCOT International

  40. PHYSICAL PROPERTIES: • EACH CHEMICAL HAS ITS UNIQUE STRUCTURE. • FIXED MOLECULAR WEIGHT. • DEFINED SPECIFICATIONS. EPCOT International

  41. OUR GOALS ARE DEFINED • ANY DEVIATION IS DUE TO AN IMPURITY. • PERFORMANCE IS DEFINED. • DEVELOP A PROCESS TO DELIVER. EPCOT International

  42. PHYSICAL PROPERTIES: PHYSICAL STATE • VALUE IN PROCESSING • SIMPLIFICATION EPCOT International

  43. PHYSICAL PROPERTIES: • PHYSICAL STATE • LIQUID: IDEAL • SOLID: MELT OR DISSOLVED • GAS: LIQUID FEED EPCOT International

  44. PHYSICAL PROPERTIES: • BOILING POINT/ AZEOTROPE POINT • CAN BE USED TO MANIPULATE/ CONTROL REACTION RATE • PROCESS OPERATING CONDITIONS EPCOT International

  45. PHYSICAL PROPERTIES: • VISCOSITY • VISCOSITIES < 10 cp FACILITATE MIXING EPCOT International

  46. PHYSICAL PROPERTIES: • DENSITY • DENSITY DIFFERENCE OF VALUE EPCOT International

  47. PHYSICAL PROPERTIES: • THERMODYNAMIC PROPERTIES • HEAT OF REACTION CONTROLS RX RATE • PROCESS OPERATING CONDITIONS EPCOT International

  48. PHYSICAL PROPERTIES: • SOLUBILITY • CAN BE USED TO MANIPULATE/ CONTROL REACTION RATE • PROCESS OPERATING CONDITIONS • CRYSTALLIZATION • YIELD LOSS @ ISOLATION EPCOT International

  49. SOLVENT USE • CRITICAL ASPECT OF PROCESS • INFLUENCES PRODUCTIVITY EPCOT International

  50. OPPORTUNITIES: SOLVENTS LAB:MULTIPLE SOLVENTS. OK FOR EXPLORATION AND UNDERSTANDING EPCOT International

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