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MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CONTINUOUS QUALITY VERIFICATION (CQV) G.K.Raju, Ph.D. Pharmaceutical Manufacturing Initiative (PHARMI),

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Presentation on theme: "MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CONTINUOUS QUALITY VERIFICATION (CQV) G.K.Raju, Ph.D. Pharmaceutical Manufacturing Initiative (PHARMI),"— Presentation transcript:

1 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CONTINUOUS QUALITY VERIFICATION (CQV) G.K.Raju, Ph.D. Pharmaceutical Manufacturing Initiative (PHARMI), MIT Program on the Pharmaceutical Industry, Massachusetts Institute of Technology July 2001

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

3 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Pharmaceutical Manufacturing Research Development Manufacturing Marketing Bulk Active Bulk Formulation Filling & Finish Packaging Inbound Logistics Outbound Logistics

4 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) HORIZONTAL APPROACH STUDYING PHARMACEUTICAL MFG: VERTICAL VS. HORIZONTAL APPROACH Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Plant A Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Plant B Plant A Plant B VERTICAL APPROACH

5 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Bulk Active Bulk Formulation Filling/ Tableting/ etc. Packaging/ Finishing Bulk Active Bulk Formulation Filling/ Tableting/ etc. Packaging/ Finishing Company A Company B Company C Bulk Active Bulk Formulation Filling/ Tableting/ etc. Packaging/ Finishing THE HORIZONTAL APPROACH PHARMACEUTICAL MANUFACTURING

6 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) DESCRIBING THE OPPORTUNITY IN ROUTINE MANUFACTURING CONTINUOUS QUALITY VERIFICATION (CQV)

7 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) WHICH PROCESSES? PROCESS CYCLE TIMES In Process Development In Routine Manufacturing Biggest Impact Here? Time-to-market Enabling Potent Products Place for Validation? Potent Products Difficult Processes High Volume Products Products with Tough QC Tests Generic Competition

8 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

9 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

10 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS B WITH QC TESTS CHEMICAL WEIGHING BLEND FILL CAPSULES BOTTLE PACKAGING API OVI Description ID Assay CU Impurity Dissolution QC 1 QC 2

11 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS B WITH CYCLE TIMES CHEMICAL WEIGHING BLEND FILL CAPSULES BOTTLE PACKAGING API OVI Description ID Assay CU Impurity Dissolution QC 1 QC 2 7 DAYS14 DAYS 17 DAYS

12 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS C WITH QC TESTS WEIGHING GRANULATION FB DRY STEP BLEND FILM COATING COMPRESS BOTTLE PACKAGING API Particle Size LOD Description ID Assay CU Impurity Dissolution QC 1 QC 2

13 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS C WITH CYCLE TIMES WEIGHING GRANULATION FB DRY STEP BLEND FILM COATING COMPRESS BOTTLE PACKAGING API Description ID Assay CU Impurity Dissolution QC 1 QC 2 21 DAYS 6 DAYS 14 DAYS

14 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

15 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

16 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 DAYS PROCESSING

17 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS D WITH QC TESTS 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 QC1PFDQC3Release Actual Target Potential

18 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) WHAT DRIVES THE QC TESTING TIMES? QC1PFDQC3Release Actual Target Potential Sampling Batching Other Products Waiting Coordinating Other Products Other Paperwork Waiting Coordinating 2% TEST

19 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) WHICH PROCESSES? PROCESS CYCLE TIMES In Process Development In Routine Manufacturing Biggest Impact Here? Time-to-market Enabling Potent Products Place for Validation? Potent Products Difficult Processes High Volume Products Products with Tough QC Tests Generic Competition

20 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS E WITH QC TEST POINTS WEIGH DRY MIX WET GRANULN WET GRANULNFL BED DRYMILL STOREDRY SIFT WET GRANMIX COAT STORE MILL SIFT STORE BLEND STOREBOTTLE FILL DRY MIX GRANULDRYMILL ACTIVE INITIAL GRANULATION STAGE SECOND GRANULATION STAGECOATING STAGE EXCEPIENT PREPARATION STAGE SIFT&BLEND STAGEBLEND&FILL STAGE QC 4 QC 3 QC 2 QC 1 LOD

21 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

22 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) WHICH PROCESSES? TOWARDS PARAMETRIC RELEASE In Process Development In Routine Manufacturing Biggest Impact Here? Time-to-market Enabling Potent Products Place for Validation? Potent Products Difficult Processes High Volume Products Products with Tough QC Tests Generic Competition

23 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS F: LIQUID LINE WEIGH pH ADJCOMPOUND FILTER FILL STOPPERCAP LABEL/PKG TERMINAL STERILIZATION WEIGH VIALS STOPPERS WFI BUFFER WASH AUTOCLAVE DEPYROGEN SEALS Appearance ID Assay Impurity Fill Vol, Osmolarity, Partic. Endotoxin STERILITY TESTING ENVIRO. MONITORING BIOBURDEN WFI TESTING Endotoxin TOC ID pH Visual Check Wt Check QC Check

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

25 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PERCEIVED PROCESS CYCLE TIMES: SUMMARY

26 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CYCLE TIME COMPONENTS

27 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ON-LINE TECHNOLOGY IMPACTS DOMINANT CYCLE TIMES On-line LIF, NIR, Pattern Recognition, etc.

28 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CQV OPPORTUNITY IN ROUTINE MANUFACTURING Quality Monitoring is Discontinuous QC testing times are approximately = 1 month Factor of opportunity in cycle time: Process Factor of opportunity in cycle time: QC QC Cycle Times >= Process Cycle Times Time is driven by off-line nature of test Exception is MICRO test SUMMARY

29 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) DESCRIBING THE OPPORTUNITY IN PROCESS DEVELOPMENT CONTINUOUS QUALITY VERIFICATION (CQV)

30 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Bulk Active Bulk Formulation Filling & Finish Packaging Bulk Active Bulk Formulation Filling & Finish Packaging Bulk Active Bulk Formulation Filling & Finish Packaging Company A Company B Company C THE VERTICAL APPROACH Blending Drying Granulation Fermentation Rapid Microbial Detection Flow Tableting Transport

31 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Bulk Active Bulk Formulation Filling & Finish Packaging Bulk Active Bulk Formulation Filling & Finish Packaging Bulk Active Bulk Formulation Filling & Finish Packaging Company A Company B Company C VERTICAL ANALYSIS I: BLENDING UNIT OPERATION Eg. Blending

32 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) WHICH PROCESSES? PROCESS CYCLE TIMES In Process Development In Routine Manufacturing Biggest Impact Here? Time-to-market Enabling Potent Products Place for Validation? Potent Products Difficult Processes High Volume Products Products with Tough QC Tests Generic Competition

33 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) FOCUS Explore the Potential Impact of On-line Monitoring Technology on Blending Process Development MIT Pharmaceutical Manufacturing Initiative

34 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

35 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

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

37 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

38 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

39 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Blending Data Collected from CAMP Companies Operation Characteristics LowMediumHigh Cleaning time (min) Loading time (min) Discharge time (min) Sampling time (min) Transport time (min) QC Testing time (min) QC Holding time (min)

40 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Results Blending Performance Process Development and Validation 6% no wait between blends 1 Blend2 Blends3 Blends Best Med. Worst Time (days)

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

42 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) APPROACH TO LEARNING: 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 Consequences on Process Development & Commercial Production

43 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CQV Opportunity in Process Development Process development can be on the critical path Factor of reduction in cycle time in blend process development (maybe more..) Variability reduction in blend process dev. time independence of organization/product -> predictability… Benefits not restricted to use of new on-line sensors improvement data analysis of existing sensor data use of this for experimental design SUMMARY

44 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) WHAT ARE THE IMPLICATIONS? CONTINUOUS QUALITY VERIFICATION (CQV)

45 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) FDA Pharmaceutical Companies CAMP Purdue MIT Abbott Aventis Bristol-Myers Squibb Johnson & Johnson Hoffmann-La Roche Glaxo SmithKline Wyeth-Ayerst Consortium for the Advancement of Manufacturing in Pharmaceuticals (CAMP) Vendors

46 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PROCESS A WITH CURRENT QC TESTS AND NEW POSSIBILITIES 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

47 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Need to Focus on Both Material Flow and Information Flow INFORMATION FLOW MATERIAL FLOW

48 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Manufacturing Information Management: Has Hardware and Software Components 10% 5% 1% 0.5% 0.1% Fast Response On-Line Real-Time Accurate Robust Rapid Rate of Learning Short Cycle Times Benchmarking Modeling Continuous Problem Solving

49 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Bulk Active Bulk Formulation Filling & Finish Packaging Bulk Active Bulk Formulation Filling & Finish Packaging Bulk Active Bulk Formulation Filling & Finish Packaging Company A Company B Company C HORIZONTAL AND VERTICAL APPROACHES Blending Drying Granulation Fermentation Rapid Microbial Detection Flow Tableting Transport High Vol Variable Liquids

50 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CQV: BENEFITS Data Mining of Process Data Data -> Information -> Knowledge Rationale for New Sensors Variable Categorization: PCCPs, etc. Basis for Specifications, Batch Record Design Basis for Experimental Design, Etc. …

51 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Learning Curve: Cycle Times Accelerated Learning Curve Facilitated By Continuous Quality Verification

52 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CQV: SO WHAT? On-line sensors doing the same thing will have only incremental impact This impact will still be only incremental even if there is an MES/EBR system Data Warehousing focused on exceptions can have a large impact On-line sensors + EBR + Data Warehousing can fundamentally change pharma. mfg.

53 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PRODUCT LIFE CYCLE: OPPORTUNITIES Reduction of time-to-market Reduction of manufacturing cost

54 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Pharmaceutical Manufacturing: Opportunity Areas Manufacturing: Cost --> Profit Organizational focus: Functional --> Process Optimization: Local --> Supply chain Inventory Management: JIC --> JIT Cost of Quality: Inspection --> Prevention KEY TECHNOLOGY OPPORTUNITY: On-line Sensors+EBR+Data Warehousing!

55 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) ACKNOWLEDGEMENTS Professor Charles Cooney (MIT) Professor Stephen Byrn (Purdue) CAMP

56 MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) NOTE ON CONTEXT This presentation does not necessarily represent the views of MIT, Purdue or CAMP Some data have been disguised for reasons of sensitivity and confidentiality


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