Facility Intensification and Cost Reduction using an Integrated Buffer Delivery Platform
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The document discusses the Biocontinuum™ platform by Merck KGaA, aimed at enhancing buffer preparation and management in bioprocessing to achieve significant cost reductions and efficiency improvements. Key innovations include reduced facility build times, increased flexibility in buffer usage, and a strong focus on outsourcing buffer preparation to mitigate common challenges. It emphasizes the importance of buffer concentrates and the necessity for accurate, streamlined processes to support next-generation biomanufacturing.
Facility Intensification and Cost Reduction using an Integrated Buffer Delivery Platform
- 1. Integrated Buffer Delivery and Management for Facility Intensification and Cost Reduction The BioContinuum™ Platform 1 Shannon J. Ryan, Ph.D. 2 May 2019
- 2. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.
- 3. Speed Reduce new facility build times by 70%. Compress production lead time by 80%. Quality 10X robustness. 90% reduction in cost of poor quality. Flexibility Reduce product change-over time by 90%. Cost 90% reduction in cost to manufacture and CAPEX. Business Drivers Market Growth Uncertainty New Product Classes Cost Pressure Market Trends Market Trends, Business Drivers and Key Enablers to Drive Next Generation BioProcessing: Process Intensification Process Analytics Software & Automation Key Enablers Single Use 3
- 4. Next Generation Processing: Evolutionary Journey in mAb Manufacturing End state Today Near-term Mid-term Process Batch Intensified Connected Continuous Format Stainless Hybrid Single Use SU/Closed 4 Our Mission Developing technologies, applications and expertise which enable biotherapeutic manufacturers to confidently enter the era of next generation processing.
- 5. Topics 1 Buffer Preparation Overview 2 Preparation cost Models 3 Integrated Delivery & Management 4 Summary 5
- 6. Buffer preparation is an essential function but does not add value 1 Buffer Prep Is a Core Operation Drives plant schedule and capacity 2 Critical, But not Value-Added Imbalance between resources & footprint required and simplicity of buffer prep On-site buffer Preparation Dilution of Buffer Concentrates Buffer Conditioning or blending Ready-t0-use buffers Requirements: 5-10 L buffer per L bioreactor 15 Unique buffers Critical attributes for process performance 6
- 7. 7 Challenges in Buffer Preparation require new approaches Problem Statement: How do we provide the right buffer at the right time and specifications while minimizing our labor and footprint? On-site buffer Preparation Buffer Conditioning or blending Ready-t0-use buffers Traditional Buffer Preparation Pain Points : 1. Large amount of classified floor space 2. Significant Labor Requirements 3. Buffer volumes that grow linearly with Bioreactor Titer 4. Quality Control testing 5. Excess Capacity to account for preparation error Dilution of Buffer Concentrates
- 8. 8 Significant Desire to Move toward Outsourced Buffer Preparation 87 44 28 19 6 9 100100 Today 3 4 5 years from now MEAN adoption Ready to use buffers Automated buffer conditioning system Dilution of buffer concentrates Standard mix vessel 70 34 43 20 30 29 28 18 10 8 10 100 0 100 Clinical (n=8) Commercial (n=15) Preclinical (n=4) 100 5 years expectation breakdown by manufacturing scale Intensified buffer preparation will increase from 7% to 47% by 2023
- 9. Topics 1 Buffer Preparation Overview 2 Preparation cost Models 3 Integrated Delivery & Management 4 Summary 9
- 10. 10 Made In House (MIH) • Buffer chemicals hydrated in mix tanks, filtered, and QC-released prior to use • Single Use mixers and hold vessels used up to 2,000 L; SS vessels at > 2,000L Ready to Use (RTU) • Buffers shipped to site at ready to use concentration. • Transported in single use vessels up to 1,000 L • QC-released prior to use Buffer Concentrates (CONC) • Buffer concentrates (10x for cost models) shipped to site • QC-released prior to use • Concentrates diluted into hold vessels using automated system 3 Buffer Preparation Methods for Cost Models
- 11. 11 MAb Facility Considerations for Buffer Preparation Scenarios Design Variables Values Modeled Facility Scale 200 L, 2000 L, & 5 X 2000 L Fed-batch Bioreactors MAb Titer 1 g/L, 5 g/L, and 10 g/L Run Rate 12 & 20 batches/year
- 12. 12 Impact of Buffer Preparation Method on Facility Design 18% Reduction in Cleanroom Area Utilizing Buffer Concentrates On-Site Buffer Preparation 970 m2 manufacturing cleanroom Ready to Use Buffers 914 m2 manufacturing cleanroom 6% cleanroom footprint Buffer Concentrates 791 m2 manufacturing cleanroom 18% cleanroom footprint 2,000 L bioreactor 3,730 m2 facility Buffer concentrates shrink new facility footprint or increase capacity of existing facilities
- 13. $315 $180 $208 $81 $63 $55 $45 $40 $33 $- $50 $100 $150 $200 $250 $300 $350 MIH RTU CONC MIH RTU CONC MIH RTU CONC buffercost($/L) 13 200 L Bioreactor Facility, 12 Runs per Year Ready to Use Buffers Reduce Costs up to 43% over Made-in-House Buffers Ready to use buffers save 10 to 43% over made in house buffers Buffer concentrates are the lowest cost option for 5 & 10 g/L scenarios 1 g/L 5 g/L 10 g/L
- 14. $11 $13 $11 $- $2 $4 $6 $8 $10 $12 $14 MIH RTU CONC buffercost($/L) 14 2,000 L Bioreactor Facility, 12 Runs per Year Buffer Concentrates Reduce Costs up to 16% over Made-in-House Buffers Concentrates save 16% at 1 g/L titer and have similar cost to MIH at 5 & 10 g/L titer Concentrates lower labor by 20% and CAPEX by 42% at 10 g/L 10 g/L 32,3% 20,3% 18,3% 2,1% 10,5% 5,2% 4,0% 7,3% Cost Contribution for MIH 2000L 10 g/L Annual Consumable Cost Annual Raw Material Cost Annual Labor Cost Annual Warehousing Cost Annual Incoming QC Cost Annual Facility Expense (depreciated) 30yrs Annual CAPEX Expense (depreciated) 10yrs Annual Shipping Cost 4,9% 71,2% 14,0% 0,6% 0,7% 4,0% 2,3% 2,3% Cost Contribution for CONC 2000L 10 g/L Annual Consumable Cost Annual Raw Material Cost Annual Labor Cost Annual Warehousing Cost Annual Incoming QC Cost Annual Facility Expense (depreciated) 30yrs Annual CAPEX Expense (depreciated) 10yrs Annual Shipping Cost
- 15. 15 5 X 2,000 L Bioreactor Facility, 12 Runs per Year Buffer Concentrates Reduce Labor and CAPEX by ≥50% Buffers Concentrates and Made in House buffers similar cost up to 2.4 million L/yr Concentrates reduce labor by 50% and CAPEX by 53% while increasing operator safety 33,3% 20,7% 21,2% 2,4% 6,3% 4,4% 3,6% 8,2% Cost Contribution for MIH 5 X 2000L 5g/L Annual Consumable Cost Annual Raw Material Cost Annual Labor Cost Annual Warehousing Cost Annual Incoming QC Cost Annual Facility Expense (depreciated) 30yrs Annual CAPEX Expense (depreciated) 10yrs 6,3% 74,7% 10,6% 0,7% 0,3% 3,6% 1,5% 2,3% Cost Contribution for CONC 5 X 2000L 5g/L Annual Consumable Cost Annual Raw Material Cost Annual Labor Cost Annual Warehousing Cost Annual Incoming QC Cost Annual Facility Expense (depreciated) 30yrs Annual CAPEX Expense (depreciated) 10yrs $9 $10 $9 $- $2 $4 $6 $8 $10 $12 MIH RTU CONC buffercost($/L) 5 g/L
- 16. 16 All Facility Scales, 20 Runs per Year Buffer Concentrates Cost Competitive at Consumption Rate of 4 million L/yr $8 $10 $8 $- $2 $4 $6 $8 $10 $12 MIH RTU CONC buffercost($/L) Buffer Cost at 5 X 2,000L Bioreactor Scale $13 $16 $13 $- $2 $4 $6 $8 $10 $12 $14 $16 $18 MIH RTU CONC buffercost($/L) Buffer Cost at 2,000L Bioreactor Scale $64 $50 $42 $- $10 $20 $30 $40 $50 $60 $70 MIH RTU CONC buffercost($/L) Buffer Costs at 200L Bioreactor Scale 5 g/L 5 g/L 5 g/L Conclusions Buffer Concentrates are cost competitive with made in house buffers and: • Reduce labor costs • Reduce facility CAPEX and overhead • Increase operator safety Cost models can be customized to individual process and facility
- 17. Topics 1 Buffer Preparation Overview 2 Preparation cost Models 3 Integrated Delivery & Management 4 Summary 17
- 18. BioContinuum™ Buffer Delivery Platform Delivering Certainty in Buffer Preparation and Management in < 16 weeks Buffer Concentrates Buffer Dilution System Services & Training Mobius® Select Assemblies 18
- 19. 19 Facility Floor View BioContinuum™ Buffer Delivery Platform Process-Specific Buffer Concentrates Buffer Dilution SYSTEM Single Use assemblies and Containers
- 20. Sterile Buffer Concentrates Liquid production sites Irvine St. Louis Singapore Nantong (Opening soon) 20 Production Facility imMEDIAte ADVANTAGE™ HTST
- 21. Sterile Buffer Concentrates Our Sterile Liquid Capabilities at a glance 50 – 1,000 L batch size Production according to ISO 9001:2008 and GMP conditions Separate areas NAO / AO Non-hazardous and hazardous materials Configurable packaging 21
- 22. 22 Customer-recommended concentrates • Defined 19 most commonly used buffers in Mab Processes • Chromatography, TFF, dilution buffers Maximum solubility (typically 10-30x) and stability in Mobius assemblies characterized Define design space in which buffers can be made, stored, and delivered Sterile, concentrated stock solutions will be configurable and user-defined. Buffers Available as Concentrates 0.1M Acetate + 0.5 M NaCl, pH 5.5 0.1M Citrate, pH 5.4, pH 5.5 1.0 M Tris, pH 8.4, pH 8.5 0.1M Acetic Acid 0.05M Tris, 0.5M Arginine, pH 8.4, pH 8.5 0.1M Acetic Acid, pH 5.0 1- 2 M Citric Acid 1-2 M Phosphoric Acid 20% Ethanol 50-100 mM acetic acid, pH 3.2 50-100 mM citric acid, pH 3.2 50-100 mM glycine, pH 3.2 50mM Bis-Tris, pH 7 50mM MES, pH 6-7 50mM Phosphate pH 7.4 Sterile Buffer Concentrates BPOG Buffer Workstream defined Design Space for Configurable Concentrates
- 23. 23 Control Strategies pH control Sensor Accuracy, ≥ 1% In addition: o Tendency to drift o Memory effect often observed o Frequent calibration required Conductivity control Sensor Accuracy, ≥ 1% In addition: o Frequent calibration required Highest accuracy in buffer dilution with Millipore/YMC buffer dilution systems Volumetric flow control delivers accuracy and precision for consistent buffer preparation
- 24. 24 Control Strategies pH control Sensor Accuracy, ≥ 1% In addition: o Tendency to drift o Memory effect often observed o Frequent calibration required Conductivity control Sensor Accuracy, ≥ 1% In addition: o Frequent calibration required Volumetric Flow Control Flow meters and pumps are more accurate and stable than pH or conductivity detectors 17 and 33 LPM systems Lewa Ecodos® pump with Intellidrive® − Volume Flow Control Accuracy <1.0% − Highest accuracy in dilution at 20:1 ratio or greater Highest accuracy in buffer dilution with MilliporeSigma/YMC buffer dilution systems Volumetric flow control delivers accuracy and precision for consistent buffer preparation Accurate buffer concentrate preparation and dilution negates need for pH or conductivity conditioning
- 25. Mobius® Select Assemblies Configurable Assemblies Provide Flexibility and Delivery in 8 weeks Enhanced supply transparency and security Quality and supply agreements Monitored safety stock levels with continuous replenishment Less materials of construction and raw material changes Reduces consumable management burden and costs Drives standardization and harmonization of part numbers Reduces change notifications Eliminates need for extractable testing - savings of $125K+ Faster implementation Assembly drawing in < 24hrs Prototype in ≤ 4wks Documentation available via Emprove® Dossiers Assembly in ≤ 6wks Flexibility Unlimited configurable designs with 400 pre-qualified components Enhanced quality Prequalified library of components Automated manufacture 25 Mobius® Select
- 26. Topics 1 Buffer Preparation Overview 2 Preparation cost Models 3 Integrated Delivery & Management 4 Summary 26
- 27. Summary Buffer concentrates offer significant footprint and cost reduction Volumetric control for dilution is the most accurate preparation method BioContinuum™ Buffer Delivery Platform executes preparation and management with certainty 2727 1 2 3
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- 29. shannon.ryan@milliporesigma.com Shannon Ryan 29 The vibrant M, BioContinuum, imMEDIAte ADVANTAGE, Mobius, are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. © 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.