greengene fel-2 feasibility test

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


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


Market Analysis

Market Analysis


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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.


Process Units

Process Overview


Media Preparation


See PFD: Process Sheet 1

Objective: Mix raw materials and sterilize the media without degrading nutrients

Media Preparation


Fermentation



Objective: Purify air to meet pharmaceutical standards / Achieve desired concentration of titer through controlled reaction kinetics

Fermentation


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.

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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

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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


Shorter time still yields the same amount of Penicillin G

v

ç pH 6.8

!" !!! = −!"!

!"#!! = [!"#!!]!!!!.!!"#!! !

May 9, 2016

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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!!!!


Optimal pH during stressing is 6.5 – 7.5Variation in pH has a significant impact

May 9, 2016


Example of Process Control


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


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



Objective: Obtain a product with maximum percent yield

Extraction


Water-rich MIBK Recovery



Objective: Maintain economically and environmentally optimal recovery of extraction solvent

Water-rich MIBK Recovery


Optimization: Water-rich MIBK Recovery


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Optimal utilities cost achieved at 82% recovery

May 9, 2016

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"MIBK Markets and Analysis." Web. 09 May 2016.

MIBK-rich Solvent Recovery




IPA Solvent Recovery




Water and Biowaste Treatment


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


Biowaste Treatment


Environmental and Health Issues


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


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



Plant Location& Plant Layout


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


q Safetyq Sufficient roadway

• Easy and efficient access to different unitsq Strategic placement of unit operationsq Wind Direction

May 9, 2016

Plot Plan


OSBL


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


Total time from planning to startup: 34 months

May 9, 2016

Labor Requirements


5 8 1225

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98

165180

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55

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# of

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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


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


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


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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


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


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


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


Recommendation for FEL-3


• 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


Questions?


greengene fel-2 feasibility test

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