Key Success Factors for Bioprocess Technology Selection, Scale-up & Engineering of New Facilities

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Hilary Bishop
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1 Key Success Factors for Bioprocess Technology Selection, Scale-up & Engineering of New Facilities by Edi D. Eliezer Principal BioPrizM (856)

2 Key Factors for Bioprocess Technology Selection, Scale-up, Engineering of New Facilities Biocatalyst Raw Materials Process Technologies Products Scale Economics S Economics R E P Biocatalyst Raw Materials Product Technology B T Scale

3 From R&D to Commercial Manufacturing Facility Key Project Phases Operations & Engineering perspectives R&D Time Technology Transfer (Scale-up) Conceptual Design Detailed Engineering Marketing Study Feasibility Study Construction Qualification Masterplan, Commissioning Start-up Cost estimate Decision on project Commercial Mfg.

Cost Impact of Key Engineering Project Phases Cost Impact Ability of a Phase s Decision Work quality Scope Change Impacting CAPEX Conceptual Detailed Construction

4 Cost Impact of Key Engineering Project Phases Cost Impact Ability of a Phase s Decision Work quality Scope Change Impacting CAPEX Conceptual Detailed Construction Project Phases (time) Key Success Factor: Early Integration of Process Development and Engineering Concepts for Successful Commercial Bioprocesses and Facilities.

5 Typical BioProcess Block Flow Diagram Basis for Facility Concept Design Bio / Microbial Labs. Media Prep / Sterilization Solutions Prep/ Storage Warehouse: Raw Materials Product Fermentation or Bioconversion Recovery & Purification Finishing Utilities: Process Water (WFI) Steam (Clean) Cooling Water Chilled Water Compressed Air Electrical HVAC Waste Systems

DO 2, CO 2, Pressure Process Engineering Process type (batch, continuous, fed-batch) Oxygen Transfer Heat Transfer

6 BioProcess Design Basis & Scale-up - Upstream Fermentation & Bioreactor Critical Design Parameters Biological & Chemical Culture type Containment Operating and Optimal ranges for: - ph, Temperature - Foam type & control - Shear, Viscosity - DO 2, CO 2, Pressure Process Engineering Process type (batch, continuous, fed-batch) Oxygen Transfer Heat Transfer Bioreactor type & Scale-up Instrumentation & Controls Sterile/ rdna Design, MOC Media Prep./ Sterilization CIP & Waste systems

7 Typical Bioreactor Designs STRs JLR BC Immobilized Cell BRXs M M M Air Air O2, CO2, ph Microbial Cultures in Submerged Fermentation Systems Microbial & other Cultures in Immobilized / Fixed Bed Systems - Bioconversions

8 Bioreactor Design Selection Industrial Realities Impact of Biocatalyst, Process (KPI) & Scale: Inter-related JLR Industrial-scale Limitations istrs M OURm (mm/l.hr) 500 Maximum Fermentor Size vs. Major KPI: OURmax BC 500 Vm (m3) Microbial Cultures Bacteria Yeast Fungal Biocatalyst Scale Technology

Commercial Fermentation Scale-up Challenges & Options Case study of BC Production Pilot Scale-up Challenges Glucose 500,000 L 1,000 L Mixing effects on metabolism & productivity of: Pressure

9 Commercial Fermentation Scale-up Challenges & Options Case study of BC Production Pilot Scale-up Challenges Glucose 500,000 L 1,000 L Mixing effects on metabolism & productivity of: Pressure Gradients/oscillations-Gas: O 2, CO 2 Grad/oscil- Liq: Glucose, NH3, ph Temperature Control Glu= 100 O2= 5% Glucose Glu= 10 O2= 20% Risk Management & Solutions Scaled-Down Lab/Pilot tests Simulate Micro/biology & Macro/Eng ng. FMEA, 6-Sigma approaches O2= 20% Glu= 10 Air Air

10 Bioprocess & Facility Definition: Risks & Economics Selection of Bioreactor Design, Size & Quantities istr M istr M BC BC Industrial-scale Limitations OURm (mm/l.hr) Maximum Fermentor Size vs. Major KPI: OURmax M Risks (KPI, $) Design & Economic Selection between: Design & Economic Selection between: 0 Vm (m3) 1 X 400 m3. $ 2 x 200 m3. $$ 1 X 600 m3. $ 2 x 300 m3. $$ Scale-up risks, Operations Integration, Costs Technology Risks (BRX)

11 Process & Project Engineering, Economics and Strategy Optimum Industrial Process Selection KPI s Which Key Performance Indicators (KPI s) to select? Maximum Fermentation Titer?. Not Always! Don t disregard industrial limitations (examples) Bioconversion Yields on Raw Materials can be a major factor on Costs, but impact can change with Product, Technology & Scale (examples) Integrate DSP with Upstream performances for overall optimum (examples)

12 Typical Microbial Fermentation Process Kinetics

13 Process & Project Engineering, Economics and Strategy Selecting Industrial Fermentation Process Design Space Economics Technology Scale

14 Product Concentration Product Viscosity Impact Of Raw Materials On Upstream and DSP Raw Material A, B A B Media Prep. Media Pre- Processing Fermentation DSP - Concentration Centrifugation TFF Filtration Media Sterilization A>B B>A Fermentor Production Pf-a P-b V-a [P] P-a V-b Pf-b Fermentation Time DSP Concentration Factor What is Best for Upstream Not Always Best for DSP & Overall Process If KPI is reaching High Fermentor Titer, but this present issues in DSP, then: Develop New Integrated UPS+DSP with optimized overall performance Switch from Batch to Continuous process

Process & Project Engineering, Economics and Strategy BioProcess Modeling is Key for Economic Optimizations Need Experienced Simulation of Real Commercial Process scenarios - with the 6 key

15 Process & Project Engineering, Economics and Strategy BioProcess Modeling is Key for Economic Optimizations Need Experienced Simulation of Real Commercial Process scenarios - with the 6 key factors - for estimation of new Facility CAPEX & OPEX. CAPEX reduced by 60% from $203 to $78 MM Industrial Process Modeling can be a major Guide for R&D and Project Objectives i.e. What to Focus on.

16 Process & Project Engineering, Economics and Strategy COGS vs. Capacity, Media Costs, Titer COGS vs. Capacity at Various Titers & Media Costs COGS vs. Titers at Various Capacities Economic analysis defines Critical or Minimum Capacity or Titer for Optimum COGS

17 Process & Project Engineering, Economics and Strategy Costs vs. Scale. Product impact on COGS Distribution COGS decreases with increased capacity/scale. CAPEX % of COGS changes with Scale, Technology & Product Economics Raw Materials Product Product-type impact Raw Materials cost % of COGS in Industrial Biotech is More than for BioPharma products CAPEX % of COGS in Industrial Biotech is Less than BioPharma products Scale

Conclusions BioProcess Commercialization: Success factors Integrate, early on, R&D, Engineering and Manufacturing Teams Assess each Bioprocess option from an Integrated industrial view Select optimal

18 Conclusions BioProcess Commercialization: Success factors Integrate, early on, R&D, Engineering and Manufacturing Teams Assess each Bioprocess option from an Integrated industrial view Select optimal option based on Scale-up reliability & economics Use Modeling to evaluate each Bioprocess (& 5 key factors) impact on Facility Design, Utilities & Costs Perform a Conceptual Design with preliminary CAPEX and OPEX From Concept to Commercial: DuPont BioPDO

19 THANK YOU! Success through Early Integration of Process Development, Engineering & Economics Economics Biocatalyst Raw Materials Product Technology Scale (856)

26/04/2013 Improving productivities in fermentation processes. Heleen De Wever Köln, April 2013

26/04/2013 Improving productivities in fermentation processes Heleen De Wever Köln, 23 25 April 2013 Bio based production chemicals Aspect Substrate Microorganisms Operation mode Sterilization equipment