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FEL-2 Feasibility Study: GreenGene
SMITH GROUP – Hayoung Lee, Soo Lee, Iyore Olaye, Sang Yoo
School of Chemical and Biomolecular EngineeringCornell UniversityIthaca, NY 14853
May 8, 2016
Table of Contents
I. Project StatementII. Market AnalysisIII. Process UnitsIV. Plant Location and Plant LayoutV. ConstructabilityVI. Economic AnalysisVII. Recommendation for FEL-3
2SMITHGroup GreenGene May 9, 2016
Project Statement
q Client: NanoBio Pharmaceuticals• New product : GreenGene (anti-hypertensive drug)• Modeled using Penicillin G production process
q Objective • Capture 20% of the North American market after 5 years• Produce 120% of the estimated year five demand• Assumed dosage: 100mg/day
q Determine• Capital and operating costs for the facility• Ex-plant price of GreenGene proxy
3SMITHGroup GreenGene May 9, 2016
GreenGene Feasibility Study
4SMITHGroup GreenGene
Process is financially robust based on Penicillin G studyProceed to FEL-3 Stage
May 9, 2016
Location?Fairfax, Iowa
Economic Analysis?
Price per dose at 18% DCFROR: $0.008/doseBased on Penicillin G production processAverage Competitive price per dose of hypertension API: $0.03/dose
Total Project Cost: $110 MMOperating Cost: $21 MM
Environmental Concerns?No significant environmental or safety concerns
5SMITHGroup GreenGene May 9, 2016
Market Analysis
Market Analysis
6SMITHGroup GreenGene May 9, 2016
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
0 1 2 3 4 5 6 7 8 9 10
Amou
nt o
f Ant
i-hyp
erte
nsiv
e Dr
ug (T
g)
YearsofProduction2019
q Target Market :
North Americans with Hypertension
q 100 mg dose per day
q Economic Goals for GreenGene:
• Capture 20 % of total market
• Supply 120% of demand by year 5
Supply estimate served as a basis for equipment sizing and economic analysis throughout FEL-2 study
Annual demand
Annual supply
High Blood Pressure Facts." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 19 Feb. 2015. Web. 09 May 2016.
7SMITHGroup GreenGene May 9, 2016
Process Units
Process Overview
8SMITHGroup GreenGene May 9, 2016
Media Preparation
9SMITHGroup GreenGene May 9, 2016
See PFD: Process Sheet 1
Objective: Mix raw materials and sterilize the media without degrading nutrients
Media Preparation
10SMITHGroup GreenGene May 9, 2016
Fermentation
11SMITHGroup GreenGene May 9, 2016
See PFD: Process Sheet 2
Objective: Purify air to meet pharmaceutical standards / Achieve desired concentration of titer through controlled reaction kinetics
Fermentation
12SMITHGroup GreenGene May 9, 2016
Reaction Basics
13SMITH GROUP GreenGene
Main Reaction :Cell + Glucose + O2 + PAA + (NH4)2SO4
à More Cells + Penicillin G + CO2 + H2O + Heat
Penicillin G
Penillic Acid
Penicilloic Acid
Degradation of Penicillin G (Side Reactions) :
May 9, 2016
Birol, Gülnur, Cenk Ündey, and Ali Çinar. "A Modular Simulation Package for Fed-batch Fermentation: Penicillin Production." Computers & Chemical Engineering 26.11 (2002): 1553-565. Web.
0
50
100
150
200
250
300
350
400
450
500
0 50 100 150 200
Con
cent
ratio
n (g
/L)
Time (hr)
14SMITHGROUP GreenGene
[Glucose]
[Cell]
[PenicillinG]
Chemical Reaction Kinetics
• Based on Bajpai & Reuss
kinetic model
• [Cell]max = [Glucose]min
• [Cell]min = [Glucose]max
• Stress fermenter 4
May 9, 2016
After 200 total hours, 50 g/L
of [Penicillin G] is achieved
15SMITHGROUP GreenGene
Chemical Reaction Kinetics-Penicillin G
• 18th Hour [Substrate] = 0 growth is constant at a
maximum
• Batch Mode = 7 hours
• Stress = 50 hours
0
10
20
30
40
50
60
0 20 40 60 80 100 120 140
Con
cent
ratio
n (g
/ L)
Time (hr)
Batch
Stress
May 9, 2016
What about the production goal?
Penicillin G Degradation Rate
• Penicillin degradation is a first order reaction
• After 50 hours of stressing, 40g/L remains
• After 90 hours of stressing, 40g/L remains due to higher degradation rate
A. Kheirolomoom et al., The combined effects of pH and temperature on penicillin G decomposition and its stability modeling Process Biochemistry.. 35: 205-211, 1999
16SMITH GROUP GreenGene
Shorter time still yields the same amount of Penicillin G
v
ç pH 6.8
!" !!! = −!"!
!"#!! = [!"#!!]!!!!.!!"#!! !
May 9, 2016
0
10
20
30
40
50
60
0 2 4 6 8 10 12 14
Peni
cillin
G (g
/L)
pH
Sensitivity Analysis on pH
• [Penicillin G]max at pH 7
• Optimal operating range: 6.5-7.5• pH 7 ± 2 yields only 80% [Penicillin G]max
• VERY SENSITIVE!!!!
17SMITH GROUP GreenGene
Optimal pH during stressing is 6.5 – 7.5Variation in pH has a significant impact
May 9, 2016
A. Kheirolomoom et al., The combined effects of pH and temperature on penicillin G decomposition and its stability modeling Process Biochemistry.. 35: 205-211, 1999
Example of Process Control
18SMITHGroup GreenGene
q Process Control Objective• Provide oxygen to keep cells alive• Maintain constant pH at 6.5
q Process Control Strategy• Monitor the concentration of air and
pH level• Implement a feed forward control loop
based on the kinetic model
May 9, 2016
Fermentation Campaign Diagram
19SMITH GROUP GreenGene
Train 1
Train 2
Train 3
Train 4
123412343434
q Number of Reactor Trains : 4• Train 1,2 : fermenter 1, 2, 3, 4 • Train 3,4 : fermenter 3, 4
May 9, 2016
Achieved optimal operation schedule with reduced cost
Extraction
20SMITHGroup GreenGene May 9, 2016
See PFD: Process Sheet 3
Objective: Obtain a product with maximum percent yield
Extraction
21SMITHGroup GreenGene May 9, 2016
Water-rich MIBK Recovery
22SMITHGroup GreenGene May 9, 2016
See PFD: Process Sheet 4
Objective: Maintain economically and environmentally optimal recovery of extraction solvent
Water-rich MIBK Recovery
23SMITHGroup GreenGene May 9, 2016
Optimization: Water-rich MIBK Recovery
24SMITHGroup GreenGene
0
200
400
600
800
1000
1200
0 10 20 30 40 50 60 70
mol
e M
IBK
tran
sfer
red
(mol
e)
Time elapsed (min)
Optimal utilities cost achieved at 82% recovery
May 9, 2016
0
20,000
40,000
60,000
80,000
100,000
120,000
0 20 40 60 80 100 120C
ost (
$)Percent Recovery (%)
"MIBK Markets and Analysis." Web. 09 May 2016.
MIBK-rich Solvent Recovery
25SMITHGroup GreenGene May 9, 2016
See PFD: Process Sheet 5
Objective: Maintain economically and environmentally optimal recovery of extraction solvent
MIBK-rich Solvent Recovery
26SMITHGroup GreenGene May 9, 2016
IPA Solvent Recovery
27SMITHGroup GreenGene May 9, 2016
See PFD: Process Sheet 6
Objective: Maintain economically and environmentally optimal recovery of extraction solvent
IPA Solvent Recovery
28SMITHGroup GreenGene May 9, 2016
Water and Biowaste Treatment
29SMITHGroup GreenGene May 9, 2016
See PFD: Utilities Sheet 1,2
Objective: Purify water to meet pharmaceutical standards / Treat any waste produced by the plant to meet the EPA regulations
Water Treatment
30SMITHGroup GreenGene May 9, 2016
Biowaste Treatment
31SMITHGroup GreenGene May 9, 2016
Environmental and Health Issues
32SMITHGroup GreenGene
q Environmental Design Considerations
q Health Issues
May 9, 2016
Boiler • Burn off-gas from fermenters and biodigestors• Prevent toxic gas release to atmosphere
Biodigestors • Treat biowaste properly
EPA regulations • Clean Air Act• Waste effluent limitation
Protection of Plant Personnel
• Personal protective equipment: eyewear, gloves, etc.• Hazard communication trainings
Accident Prevention/Emergency Response
• Toxicity detectors to indicate exposure• In case of leakage
- Have the necessary clean up materials ready- Have trained personnel to clean up the area
"US Environmental Protection Agency." US Environmental Protection Agency. Web. 09 May 2016.
Safety Issues
33SMITHGroup GreenGene
q General Considerations• Fire prevention• Fire suppression• Dust explosion prevention
q Greatest risk: Tornado• Build underground shelter• Emergency response plan
May 9, 2016
No significant safety concerns
A. Kheirolomoom et al., The combined effects of pH and temperature on penicillin G decomposition and its stability modeling Process Biochemistry.. 35: 205-211, 1999
34SMITHGroup GreenGene May 9, 2016
Plant Location& Plant Layout
35SMITHGroup GreenGene May 9, 2016
Plant Location Considerations
• Proximity to major raw materials– Corn steep liquor
• Ease of transportation for materials/ equipment/ product– Railroad, highway
• Weather conditions– Tornado
Location: Fairfax, Iowa
Plant Layout Philosophy
36SMITHGroup GreenGene
q Safetyq Sufficient roadway
• Easy and efficient access to different unitsq Strategic placement of unit operationsq Wind Direction
May 9, 2016
Plot Plan
37SMITHGroup GreenGene May 9, 2016
OSBL
38SMITHGroup GreenGene
Fire HouseWarehouseControl RoomLaboratoryMaintenance/equipment roomAdministration BuildingMain Process Building Motor Control CenterEmergency GeneratorUninterrupted Power SupplySwitch BoardFuel Gas Supply DrumInstrument Air CompressionBackup Instrument Air Compression Guard House
May 9, 2016
39SMITHGroup GREENGENE May 9, 2016
Constructability
Project Organization
40SMITHGroup GreenGene April 27, 2016
Project Manager
Construction Manager
Plumbing Civil Electrical
ProjectAccountant
Engineering Manager
Controls Manager
Utilities Manager
ProcessSectionManagers
Fermenters Managers
DownstreamManager
SolventRecoveryManager
CommissioningManager SafetyManager
QualityInspectors
Constructability
41SMITHGroup GreenGene
Total time from planning to startup: 34 months
May 9, 2016
Labor Requirements
42SMITHGroup GreenGene
5 8 1225
40
98
165180
155
55
Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10
# of
Lar
bore
rs
Quarter of Project TImeline
May 9, 2016
Maximum number of laborers = 200Will not impact the surrounding city; labor need can be fulfilled
Startup and Shut Down Procedure
43SMITHGroup GreenGene April 27, 2016
Startup1. Activate electrical system 2. Activate fire and water systems 3. Activate natural gas/
instrument 4. Fill Cooling-water system and
circulate 5. Activate air and steam systems6. Turn on boiler7. Start air compressors8. Start feed to the biodigestor9. Sterilize media using steam10. Start up one fermenter train at
a time
Shut Down1. Remove hazardous process
materials2. Reroute streams to
designated area3. Turn heat and coolant off4. De-pressure the systems 5. Isolate the systems from other
processes 6. If shut down prolongs, protect
the equipment from deteriorating
No significant deviation from the standard procedure
44SMITHGroup GREENGENE May 9, 2016
Economic Analysis
ICARUS Summary Costs
45SMITHGroup GreenGene
Item Cost (MM$)
Equipment 9.0
Equipment Setting 0.34
Piping 5.4
Civil(Building & Construction)
16
Steel 0.54
Instrumentation(Model Base Controls)
7.0
Electrical 3.8
Insulation 0.44
Paint 0.45
Other 38
G and A Overheads 3.0
Owner’s Costs 6.6
Total Project Cost: $110 MM with 25 % contingency
May 9, 2016
Economic Analysis Breakdown
Item Cost ($MM)
Annual Amount of Product Sold 10,500 (MM of Doses)
Total Sales Revenue(at .008 cent/dose) 84
Raw Material Cost 4.0
Variable Costs 4.0
Fixed Costs 6.5
Gross Margin 74
46SMITHGroup GreenGene
Operating ramp-up:Initial Start Up: 50 % Capacity Ramp up linearly to 100 % in year 5
Determining product price:DCFROR: 18% (NPV: 0) in year 10 at 100% capacity
May 9, 2016
Economic Analysis Results
47SMITHGroup GreenGene
-120
-80
-40
0
40
80
120
-4 -2 0 2 4 6 8 10
Cas
h Fl
ow (M
M $
)
Year of Production
Pay Back Period: 3.7 Years
Cash Flow
Discounted Cash Flow
May 9, 2016
Assumptions:Depreciation = 10%Tax Rate = 38%
DCFROR = 18%Cost/dose = $0.008/dose
Sensitivity Analysis - Controllable
48SMITHGroup GreenGene
0 0.002 0.004 0.006 0.008 0.01 0.012 0.014 0.016
Years until Full Capacity
Total Invested Capital
No. of Batches
Labor Cost
Cost per Dose ($)
Attention should be given to the number of failed batches to ensure product price consistency
2 years7 years
± 30%
- 5%
± 30%
May 9, 2016
Varia
ble
Fact
ors
Sensitivity Analysis - Uncontrollable
49SMITHGroup GreenGene
0.0064 0.0069 0.0074 0.0079 0.0084 0.0089 0.0094
± 30%
± 10%
Attention should be given to the amount sold to ensureproduct price consistency.
Cost per Dose ($)
Amount Sold
Fixed Cost
Raw Material Cost
± 30%
May 9, 2016
Varia
ble
Fact
ors
Economic Analysis
50SMITHGroup GreenGene May 9, 2016
Total Project Cost: $110 MM• Working Capital: $21.0 MMCost Summary
Price/dose at 18% DCFROR: $0.008• Based on Penicillin G production
processPricing Strategy
No significant deviationInsensitive overall, thus financially robust
Sensitivity Analysis
Recommendations for FEL-3
51SMITHGroup GreenGene May 9, 2016
Recommendation for FEL-3
52SMITHGroup GreenGene
• Kinetic modeling based on GreenGene• Revisit optimization and control strategy for solvent
recovery systems• Products and in-process quality control sampling
May 9, 2016
Revalidate and modify the process based on GreenGene
Thank you
53SMITHGroup GreenGene May 9, 2016
Questions?
54SMITHGroup GreenGene May 9, 2016