CONTINUOUS QUALITY VERIFICATION (CQV) G. K. Raju, Ph. D 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 1

MIT Pharmaceutical Manufacturing Initiative Objective: To Describe the Opportunity to Improve Pharmaceutical Manufacturing Performance Research Development Marketing Manufacturing

Pharmaceutical Manufacturing Research Development Manufacturing Marketing Inbound Logistics Bulk Active Bulk Formulation Filling & Finish Outbound Logistics Packaging

STUDYING PHARMACEUTICAL MFG: VERTICAL VS. HORIZONTAL APPROACH Plant A Plant A Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing Plant B Plant B Bulk Active Formulation Filling/ Tableting Packaging/ Finishing Bulk Active Bulk Formulation Filling/ Tableting Packaging/ Finishing

PHARMACEUTICAL MANUFACTURING THE HORIZONTAL APPROACH Company A Filling/ Tableting/ etc. Packaging/ Finishing Bulk Active Bulk Formulation Company B Bulk Active Filling/ Tableting/ etc. Packaging/ Finishing Bulk Formulation Company C Bulk Active Formulation Filling/ Tableting/ etc. Packaging/ Finishing

DESCRIBING THE OPPORTUNITY IN ROUTINE MANUFACTURING CONTINUOUS QUALITY VERIFICATION (CQV) DESCRIBING THE OPPORTUNITY IN ROUTINE MANUFACTURING 1

In Process Development In Routine Manufacturing PROCESS CYCLE TIMES WHICH PROCESSES? 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

PROCESS A WITH QC TESTS QC1 QC2 QC3 QC4 API MICRO LOD Particle Size BLEND DRY MIX STEP FB DRY WEIGHING WET GRANULATION STEP SIEVE ENCAPSULATE QC1 QC2 QC3 QC4 API MICRO LOD Particle Size Description ID Assay CU Impurity Dissolution MICRO

PROCESS A WITH CYCLE TIMES < 3 DAYS BLEND DRY MIX Processing FB DRY SIEVE WEIGH WET GRANULN STEP ENCAPSULATE 7 DAYS QC2 QC3 13 DAYS QC1 QC4 LOD Particle Size API MICRO Description ID Assay CU Impurity Dissolution MICRO

PROCESS B WITH QC TESTS QC1 QC2 API OVI Description ID Assay CU CHEMICAL WEIGHING BLEND FILL CAPSULES BOTTLE PACKAGING QC1 QC2 API OVI Description ID Assay CU Impurity Dissolution

PROCESS B WITH CYCLE TIMES 17 DAYS CHEMICAL WEIGHING BLEND FILL CAPSULES BOTTLE PACKAGING 14 DAYS 7 DAYS QC1 QC2 API OVI Description ID Assay CU Impurity Dissolution

PROCESS C WITH QC TESTS QC1 QC2 QC2 API Particle Size LOD Description FILM COATING BOTTLE PACKAGING COMPRESS GRANULATION STEP WEIGHING FB DRY BLEND QC1 QC2 QC2 API Particle Size LOD Description ID Assay CU Impurity Dissolution

PROCESS C WITH CYCLE TIMES 21 DAYS BOTTLE PACKAGING GRANULATION STEP COMPRESS WEIGHING FB DRY BLEND FILM COATING 14 DAYS 6 DAYS QC1 QC2 API Description ID Assay CU Impurity Dissolution

PROCESS D WITH QC TESTS QC1 QC2 QC3 API Particle Size LOD Description FILM COATING GRANULATION STEP CHEMICAL WEIGHING Processing BLEND 1: BLEND 2: PRE- BLEND FINAL BLEND COMPRESS BOTTLE PACKAGING QC1 QC2 QC3 API Particle Size LOD Description ID Assay CU Impurity Dissolution

PROCESS D WITH CYCLE TIMES 20 DAYS 15 DAYS BLEND 2: PRE-BLEND FILM COATING BOTTLE PACKAGING GRANULATION STEP CHEMICAL WEIGHING PROCESSING BLEND 1: FINAL BLEND COMPRESS 10 DAYS 15 DAYS QC1 QC2 QC3 API Particle Size LOD Description ID Assay CU Impurity Dissolution 60 DAYS

PROCESS D WITH QC TESTS: Cycle Times including BULK ACTIVE 20 DAYS 15 DAYS BLEND 2: PRE-BLEND FILM COATING BOTTLE PACKAGING GRANULATION STEP CHEMICAL WEIGHING BLEND 1: FINAL BLEND COMPRESS PROCESSING 10 DAYS 15 DAYS QC1 QC3 QC2 21-90 DAYS 60 DAYS

PROCESS D WITH QC TESTS Cycle Times 5 10 15 20 QC1 PFD QC3 Release Actual Target Potential QC1 BLEND 2: PRE-BLEND CHEMICAL WEIGHING GRANULATION PROCESSING STEP BLEND 1: FINAL BLEND COMPRESS FILM COATING BOTTLE PACKAGING QC2 QC3 15 DAYS 10 DAYS 20 DAYS 60 DAYS

WHAT DRIVES THE QC TESTING TIMES? 5 10 15 20 QC1 PFD QC3 Release Actual Target Potential 2% Sampling Batching Other Products Waiting Coordinating TEST Other Products Other Paperwork Waiting Coordinating

In Process Development In Routine Manufacturing PROCESS CYCLE TIMES WHICH PROCESSES? 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

PROCESS E WITH QC TEST POINTS ACTIVE INITIAL GRANULATION STAGE LOD MILL QC1 WEIGH DRY MIX WET GRANULN WET GRANULN FL BED DRY MILL SECOND GRANULATION STAGE COATING STAGE LOD LOD COAT MILL MILL QC4 QC2 QC3 WET GRAN DRY SIFT STORE MIX MIX DRY STORE SIFT&BLEND STAGE BLEND&FILL STAGE STORE SIFT BLEND BLEND BLEND BLEND STORE BOTTLE FILL LOD MIX MIX GRANUL DRY MILL EXCEPIENT PREPARATION STAGE

PROCESS E WITH QC TEST TIMES 7 days 3 days 7 days 7 days QC1 QC2 QC3 QC4 ACTIVE < 1 day < 1 day 1-2 days < 1 day < 1 day < 1 day FIRST GRAN SECOND GRAN SIFT& BLEND BLEND FILL COAT

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

PROCESS F: LIQUID LINE ENVIRO. MONITORING WFI TESTING Endotoxin TOC QC Check WASH AUTOCLAVE WFI STOPPERS WEIGH QC Check QC Check WASH DEPYROGEN SEALS BUFFER VIALS WEIGH TERMINAL STERILIZATION ID pH ADJ COMPOUND FILL STOPPER CAP WEIGH FILTER LABEL/PKG ID pH BIOBURDEN Wt Check Visual Check Appearance ID Assay Impurity Fill Vol, Osmolarity, Partic. Endotoxin STERILITY TESTING

PROCESS F: LIQUID LINE WITH CYCLE TIMES ENVIRONMENTAL MONITORING 7 days 10 days WFI TESTING 3-4 days 3-4 months STERILITY TESTING 17-20 days 7 days BIOBURDEN TESTING

PERCEIVED PROCESS CYCLE TIMES: SUMMARY

CYCLE TIME COMPONENTS

ON-LINE TECHNOLOGY IMPACTS DOMINANT CYCLE TIMES On-line LIF, NIR, Pattern Recognition, etc.

Quality Monitoring is Discontinuous CQV OPPORTUNITY IN ROUTINE MANUFACTURING SUMMARY Quality Monitoring is Discontinuous QC testing times are approximately = 1 month Factor of 20-25 opportunity in cycle time: Process Factor of 20-25 opportunity in cycle time: QC QC Cycle Times >= Process Cycle Times Time is driven by off-line nature of test Exception is MICRO test 1

DESCRIBING THE OPPORTUNITY IN PROCESS DEVELOPMENT CONTINUOUS QUALITY VERIFICATION (CQV) DESCRIBING THE OPPORTUNITY IN PROCESS DEVELOPMENT 1

THE VERTICAL APPROACH Blending Drying Granulation Flow Tableting Bulk Active Formulation Filling & Finish Packaging Company A Company B Company C Blending Drying Granulation Flow Tableting Transport Rapid Microbial Detection Fermentation

BLENDING UNIT OPERATION VERTICAL ANALYSIS I: BLENDING UNIT OPERATION Company A Bulk Active Bulk Formulation Filling & Finish Packaging Company B Bulk Active Bulk Formulation Filling & Finish Packaging Company C Bulk Active Bulk Formulation Filling & Finish Packaging Eg. Blending

In Process Development In Routine Manufacturing PROCESS CYCLE TIMES WHICH PROCESSES? 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

MIT Pharmaceutical Manufacturing Initiative FOCUS Explore the Potential Impact of On-line Monitoring Technology on Blending Process Development

Results & Decision Making Blending Operation Model Undermixed mix-longer Active ingredient Excipients Raw material load 8 8 Sampling 8 Mixing Blender cleaning Homogeneous Next batch Discarded Next batch Transporting Analysis Homogeneity test OK? Results & Decision Making

LIGHT INDUCED FLUORESCENCE SYSTEM FOR THE DETERMINATION OF THE PHARMACEUTICAL MANUFACTURING: LIF FOR ON-LINE MONITORING OF BLENDING LIGHT INDUCED FLUORESCENCE SYSTEM FOR THE DETERMINATION OF THE HOMOGENEITY OF DRY POWDER BLENDING

LIF VERIFICATION STUDIES Established a correlation between LIF assessment of homogeneity and thief-sampling with off-line analysis

PROCESS D: BLENDING PROCESS DEVELOPMENT FILM COATING GRANULATION STEP CHEMICAL WEIGHING Processing BLEND 1: BLEND 2: PRE- BLEND FINAL BLEND COMPRESS BOTTLE PACKAGING OFF LINE QC TEST ON LINE SENSOR

Blending Operation: Two Technologies, Two Approaches Process Development, Validation and Manufacturing 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 OFF LINE On-line Information Feedback Well Blended Discarded Analysis & Decision making Blending Raw Materials ON LINE

Blending Data Collected from CAMP Companies Operation Characteristics Low Medium High Cleaning time (min) 20 10 6 250 35 18 480 60 30 90 120 2 25 48 Loading time (min) Discharge time (min) Sampling time (min) Transport time (min) QC Testing time (min) QC Holding time (min)

Process Development and Validation 6% no wait between blends Results Blending Performance Process Development and Validation 6% no wait between blends 1 Blend 2 Blends 3 Blends Best 2.32 0.36 4.96 0.68 8.45 1.07 Time (days) Med. 13.19 1.31 23.45 1.93 30.65 2.41 Worst 25.82 2.57 43.40 3.56 56.17 4.46

Process Development and Validation Blending Performance Process Development and Validation

APPROACH TO LEARNING: Consequences on Process Development & Commercial Production Current Approach Proposed Approach x Process Development Commercial Production 1a 1b 2a 2b

Process development can be on the critical path CQV Opportunity in Process Development SUMMARY Process development can be on the critical path Factor of 10-15 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 1

WHAT ARE THE IMPLICATIONS? CONTINUOUS QUALITY VERIFICATION (CQV) WHAT ARE THE IMPLICATIONS? 1

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

PROCESS A WITH CURRENT QC TESTS AND NEW POSSIBILITIES BLEND DRY MIX STEP FB DRY WEIGHING WET GRANULATION STEP SIEVE ENCAPSULATE QC1 QC2 QC3 QC4 API MICRO LOD Particle Size Description ID Assay CU Impurity Dissolution MICRO

Need to Focus on Both Material Flow and Information Flow

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

HORIZONTAL AND VERTICAL APPROACHES Company A High Vol Bulk Active Bulk Formulation Filling & Finish Packaging Company B Variable Bulk Active Bulk Formulation Filling & Finish Packaging Company C Bulk Active Bulk Formulation Filling & Finish Liquids Packaging Blending Drying Granulation Flow Tableting Transport Rapid Microbial Detection Fermentation

Data Mining of Process Data Data -> Information -> Knowledge 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. …

Learning Curve: Cycle Times Accelerated Learning Curve Facilitated By Continuous Quality Verification

On-line sensors doing the same thing will have only incremental impact 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. 1

PRODUCT LIFE CYCLE: OPPORTUNITIES Reduction of time-to-market manufacturing cost

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!

Professor Charles Cooney (MIT) Professor Stephen Byrn (Purdue) CAMP ACKNOWLEDGEMENTS Professor Charles Cooney (MIT) Professor Stephen Byrn (Purdue) CAMP

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