Bio Process Simulation
Bio Process Simulation
CHARLES L. COONEY
DOWNSTREAM PROCESSING
COURSE
MIT, CAMBRIDGE, MA
PROCESS SYNTHESIS &
PROCESS ANALYSIS
Where do you begin Process Design?
Information on
Products, raw
materials, etc.
M&E balances,
sizing, costing,
economic
evaluation
YOUR GOAL
1. Product definition
• Product specifications
• Defines analytical needs
• Market size
2. Select the synthetic technology
3. Create process flow diagram (PFD)
4. Material & energy balances to calculate costs
• Materials (reagents and consumables)
• Equipment
• Utilities
• Labor
5. Assess assumptions and uncertainty
6. Identify economic and quality hot spots
7. Assess profitability and risk
8. Create the R/D agenda
WHAT DO I WANT & NEED TO KNOW FOR
PROCESS MODELING AND SIMULATION
• What is the cost of goods?
• What are the cost sensitive operating parameters?
• What are the assumptions and where is the
uncertainty?
• Where are the economic hot spots?
• Where should one focus R&D?
• What is the impact of process change on cost and
quality?
• Are there alternative processes?
• Where are the process bottlenecks?
• How can I increase throughput & profitability?
PROFIT = VF M (S P S A − C M )
WHEN SELECTING UNIT OPERATIONS THERE ARE CHOICES
AND DECISIONS MUST BE MADE
Bioreactor
Intracellular Extracellular
Products Products
Concentration
1. Ultrafiltration
Denatured Products
2. Evaporation
Renaturation 3. Reverse Osmosis
1. Solubilization 4. Precipitation
2. Reoxidation 5. Crystallization
6. Extraction
6. Adsorption
7. Distillation
Volume/Mass Equipment
Raw Materials of Product prices
Utilities
Purchase Equipment
Labor Cost
Consumables Multipliers
•Flowsheet formulation
•Material and energy balances
•Equipment size estimation
•Estimation of capital costs
•Estimation of operating cost
•Profitability
•Assay for the process
Monoclonal Antibodies
Penicillin V O
H H
S
N CH3
H
N CH3
O
CH3
• Hydrophobic β-lactam
• Produced by Penicillium chrysogenum
• Penicillin G and V main penicillins of commerce
• Used a human medicine and in animal health
• Further processed to semi-synthetic penicillins
• Annual production penicillin: 65,000 tons
• Price penicillin V: $11/BU, or $17-18/kg
1. Estimation of Capital
Investment
Types of Cost Estimates
Order-of-Magnitude estimate
(> +/- 30%)
Development
Accuracy
Study estimate (+/- 30%)
Stage of
Bioengineering
Purchase Equipment
Cost
Fermenter Size/
Amount of Product
Plant size can be derived from:
• Volume and number of fermenters
• Annual amount of product to produce
S-102
P-8 / AF-102
S-103 S-116
Air Filtration
S-104 S-106
P-1 / V-101
S-150 S-151
Blending / Storage Medium S-111 P-4 / ST-101 S-112
P-3 / MX-101 Heat Sterilization
Mixing
S-107 S-109
S-110
S-118 S-152
S-119 P-20 / RVF-101
P-21 / HX-101
S-108 Removal Biomass
Cooling
P-7 / V-103
S-115 P-9 / V-106 S-153
P-2 / V-102 Fermentation
Storage
Blending / Storage Glucose
Peters, M., Timmerhaus, K. and West, R.: Plant design and economics for chemical
engineers; McGraw Hill: Boston, 2003.
Price Indices
Start up/Validation
0.05 DFC = 8.3
cost
Working Capital: = 0.7
30 days*
• Six-Tenth Factor:
Derived from statistical/empirical data
K2 = K1 (P2/P1)0.6
• Example: MAb:
• 381 kg MAb per year, $175 Million investment cost
• Estimated investment cost for a 500 kg plant:
K2 = 175 (500/381)0.6 = $206 Million
Penicillin:
Equipment Purchase Costs
Purchase costs Cost ($ million)
Basket Centrifuge
Crystallization Unit
Compressors
Air Filters
Fermenters
Heat Sterilizer
Blending Tanks
Rest
Final Filtration
$ million
HIC
Protein A Chr.
Primary Recovery
Bioreaction
Inoculum Preparation
Consumables Consumables
Raw
Materials Downstream Final
Bioreaction
Utilities Processing Product
Labor
Waste Waste
Raw Material Costs
*Peters, M., Timmerhaus, K. and West, R.: Plant design and economics for chemical
engineers; McGraw Hill: Boston, 2003.
Energy Consumption
• Typical energy consumptions:
– Process heating & cooling
– HVAC
– Evaporation/distillation
– Bioreactor aeration, agitation
– Centrifugation, cell disruption, etc.
• Utility costs:
– Electricity: 4.5 ct/kWh
– Steam: 4.40 $/ton
– Cooling water: 8 ct/m3
Labor Cost
• Amount of labor:
– Calculated from demand for each process step
– Defines the number of people per shift/number of
shifts
• Hourly cost
– Internal company average value
– Literature, e.g. Peters et al. (2003):
skilled labor: 34 $/h
– Bureau of Labor Statistics (www.bls.gov)
Depreciation
Consumables 8.2
Utilities 0.024
Uncertainty Analysis
Technical
parameters
e.g. product Environmental
concentration
S-10
S-10
S-10
S-11
Indices
P-8 / AF-1
S-10 S-11
Air Filtratio
S-10 S-10
P-1 / V-1
S-11 P-4 / ST-1S-11 S-15 S-15
Blending / Storage Me
P-3 / MX-1 Heat Sterilizat
Mixing
S-10 S-10
S-11
S-11 S-15
S-11 P-20 / RVF-
P-21 / HX-1
S-10 Removal Biom
Coolin
P-7 / V-1
S-11 P-9 / V-1 S-15
P-2 / V-1 Fermentati
Storag
Supply chain
Blending / Storage Glu
S-11 S-11
P-6 / AF-1
Air Filtratio S-16 Unit Production
parameters Monte Carlo simulations
P-5 / G-1
Gas Compres S-16
S-16
S-15
S-15
P-22 / MX-1
Acidificatio S-15
Cost
e.g. media price
P-23 / CX-1
S-16
S-17 S-16 S-16 Centrifugal Extrac
S-17 P-24 / MX-1
Neutralizati S-15 S-15
S-16 P-25 / V-1 S-16
Re-ectraction + Crystall
S-17
P-26 / BCF- S-15
P-31 / FBDR- S-16 S-17
Basket Centrifuga
S-17 Fluid Bed Dry
S-17 P-29 / MX-1
Adding Fresh Butyl Ac
0.0200
Final product concentration:
0.0100
Normal distribution, Std.-Dev.: 10%
0.0000
44.6 52.3 60.0 67.6 75.3
0.0200
0.0150 Agitator power:
0.0100
0.0050 Normal distribution, Std.-Dev.: 20%,
0.0000 min: 1.5 kW/m3, max: 3.5 kW/m3
1.5 1.9 2.3 2.7 3.1
0.0250
0.0200 Price glucose:
0.0150
0.0100 Beta distribution, α = 3.49; β = 1.2,
0.0050
0.0000
Distribution type fits best actual data
2.1 7.6 13.0 18.4 23.8
Probability Distribution UPC:
Technical Parameters
3500
3000
2500
Frequency
2000
1500
1000
500
0
12.1 14.5 16.9 19.3 21.7
UPC ($/kg)
Probability Distribution UPC Unit
Cost
0.14
Supply chain/market par.
0.12 all parameters
0.1 pen concentration only
Tech. Par. without pen conc.
probability
0.08
0.06
0.04
0.02
0
10.0 12.5 15.0 17.5 20.0 22.5 25.0
UPC [$/kg]
Production of Alkaline Protease for
Detergent Use
Rotary Vacuum
Filtration
pH or salt
adjustment
Crystallization
Average Flowrate
20000
15000
(kg/hr)
10000
5000
0
T102 VF201 UF202 SD401 SW502
1.2
Product Yield
0.8
0.4
0.0
T102 VF201 UF202 SD401 SW502
40
(solids wet basis)
30
Specific Activity
20
10
0
T102 VF201 UF202 SD401 SW502
Figure by MIT OCW.
Improving Titer
1000
800
Product cost ($/kg)
600
400
200
0
1 2 3 4 5 6 7
Initial enzyme concentration (g/l)
•INEFFICIENT LEARNING