BIOREACTOR SYSTEM DESIGN CELL CULTURE SYSTEM DESIGN & SCALE-UP. INDUSTRY TRENDS FOR IMPROVED RELIABILITY AND PERFORMANCE EQUIVALENCE. By: Ted DeLoggio BIOPROCESS CONSULTANTS The Institute for International Research BIOREACTOR SYSTEMS Philadelphia, April 20, 1998
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BIOREACTOR SYSTEM DESIGN
CELL CULTURE SYSTEM DESIGN & SCALE-UP.INDUSTRY TRENDS FOR IMPROVED RELIABILITY AND
PERFORMANCE EQUIVALENCE.
By: Ted DeLoggio
BIOPROCESS CONSULTANTS
The Institute for International Research
BIOREACTOR SYSTEMS
Philadelphia, April 20, 1998
CURRENT DESIGN TRENDS
MAJOR TOPICS
• PROCESS DESIGN & SCALE-UP• BIOREACTOR• PIPING• BIOREACTOR SYSTEM
INTEGRATION• BIOPROCESS SYSTEMS
INTEGRATION
PROCESS DESIGN & SCALE-UP
COMMON CELL CULTURE SCALE-UP PROBLEMS“OBSTACLE OR OPPORTUNITY”
• [CO2] TOXICITY
• HYDRODYNAMIC SHEAR STRESS
• INTERFACIAL SHEAR
• BLEND TIME
• OTR REQUIREMENTS
• METABOLIC EQUIVELENCE
[CO2] TOXICITY
DESCRIPTION OF PROBLEM[CO2] sensitivity begins at 75-100 mmHg
Gas exchange occursas bubbles rise. Sizeand composition ofbubbles change.
BALANCE
•OTR•CTR
Gas exchange at surface.
Cells consume O2and produce CO2.CO2 reacts with water to form HCO3
-
CO2O2
CO2O2
HCO3-
+H+
CO2O2
CO2O2
[CO2]74 ppm
OUROTR
CO2O2
CTRCER
CO2O2
air overlay ~0.05 VVM
[CO2] TOXICITYSCALE-UP IMPACT OF “OUR” ON [CO2]
025
5075
100
125
150
0 2000 4000 6000 8000 10000 12000
Bioreactor Volume, liters
[CO
2], m
mH
g
0.5 OUR 1.0 OUR 2.0 OUR (mmol/L/hr)
[CO2] TOXICITY
Design and Operating Actions to Reduce the Riskof [CO2] Toxic Effects
• PREVENTIVE ACTIONS– USE DRILLED HOLE SPARGERS (>3000l)– MAXIMIZE P/V, REDUCE SUPPLIMENTAL O2– IMPELLER TYPE, CONSIDER (K/Np) RATIO ↓– CONSIDER STRIPPING SPARGER IF SINTERED
ELEMENTS ARE USED
• REMEDIAL ACTIONS– EVALUATE BUFFER SALT COMPOSITION– CONTROLLED CARBON SOURCE ADDITION– CONSIDER USE OF STRIPPING GAS– OPTIMIZE pH CONTROL LOOP TUNING
MIXING SCALE-UP PROCEDURES IN BIOTECHNOLOGY
All Procedures Require Geometric Similarity in Scale Up
CRITERIA PROCEDURE PROCESS EXAMPLE
Equal Mass Transfer Coefficients
(P/V)2 ≅ 1 (P/V)1
Microbial FermentationCell Culture
Equal Physical Shear to particles
(σ)2 ≅ 1 (σ)1
Cell culture
Equal Blend time or Vessel Turnover
(N)2 ≅ 1 (N)1
Rapid Kinetic Reactions
DESIGN SENSITIVITY PRESERVING VESSEL GEOMETRY IN SCALE -UP
• PROCESS DESIGN & SCALE-UP• BIOREACTOR• PIPING• BIOREACTOR SYSTEM
INTEGRATION• BIOPROCESS SYSTEMS
INTEGRATION
BIOREACTOR DESIGN METHODOLOGY
GOAL:
Reproduce the metabolic and physical environment achieved at the current scale of operation to produce product at the new scale with equivalent quality and quantity. To assure safety, consistency, robustness, and validatability of the process per the customers
established product & process requirements.
PROCESS OBJECTIVES
• Define mixing, mass transfer, heat transfer needs
• NOZZLES– ORIENT TOP ASSEMBLY FOR SPRAYBALL COVERAGE.– USE “SHOP” WELDED VALVE ASSEMBLIES.– SLOPE TO DRAIN, AVOID DEADLEGS.– USE FLUSH MOUNTED SAMPLE AND HARVEST VALVES.
• USE DIMPLED OR HALF-PIPE JACKET DESIGN– CONSIDER TWO SIDE WALL ZONES.– CONSIDER ONE BOTTOM ZONE
• DOUBLE MECHANICAL SEAL vs MAGNETIC– MAGNETIC OPTIONS IMPOSE SCALABILITY ISSUES.
SUITABLE FOR PROCESS VESSEL NOT BIOREACTOR– USE PRESSURIZED BARRIER FLUID– SELECT “BEST” SEAL NOT BIOREACTOR VENDOR
• PROVIDE “ALARM & RECOVERY METHOD FOR SEAL FAILURE
• USE DIRECT SPEED PICK-UP FOR ACCURACY
AGITATION CONSIDERATIONS
• IMPELLER TYPE, DIAMETER, AND NUMBER
• VESSEL, AGITATION, AND SPARGE DECISIONS ARE INTERDEPENDANT.
• CONSIDER ACCESS FOR MAINTENANCE
• SHAFT DESIGN & DEFLECTION CALCULATIONS.– Design for the worst case scenario and future impeller needs
• GEAR BOX FOR LOW SPEED OPERATIONS
BIOREACTOR SYSTEM INTEGRATION
• VESSEL ADDITIONS
• GAS MANAGEMENT AND CONTROL
• TEMPERATURE CONTROL
• EXHAUST
• AGITATION
• PROCESS CONTROL AND SENSORS
“BUILDING BLOCKS”
CURRENT DESIGN TRENDS
MAJOR TOPICS
• PROCESS DESIGN & SCALE-UP• BIOREACTOR• PIPING• BIOREACTOR SYSTEM
INTEGRATION• BIOPROCESS SYSTEMS
INTEGRATION
PROCESS PIPING
• SKID v. D&B v. GRAY SPACE OPTIONS• DESIGN AND SIZE FOR PROCESS, CIP & SIP• LOCATE CRITICAL COMPONENTS FOR
ACCESSIBILITY• REDUCE FIELD HAND WELDS• SLOPE AND DRAIN LOW POINTS• CONSIDER 3-D MODELING FOR INTERFERENCE• INTEGRATE DRAWINGS WITH “BOM” AND “PM”• CONSIDER 3rd PARTY FOR INSPECTION
– USE PHYSICAL WELD SAMPLES– AGREE ON SPECIFICATIONS AND INSPECTION
PROCESS PIPINGCIP DESIGN CONSIDERATIONS
• DEVELOP CIP SCENARIOS ALONG WITH PROCESS
• USE PARALLEL FLOW PATHS
• CONSIDER CIP SUPPLY AND RETURN FLOW REQUIREMENTS FOR LINE SIZING
• DEFINE STRATEGY TO VERIFY SECONDARY CLEANING PATH
• MODULARIZE AUTOMATION TO OPTIMIZE CLEANING CYCLES
PROCESS PIPINGSIP DESIGN CONSIDERATIONS
• USE AUTOMATIC TEMP. MEASUREMENT AND STER. VERIFICATION