1

Suggested Design Projects 2013-2014

1. Basic Chemicals from Natural Gas: Oxidative Coupling
(recommended by Gary Sawyer, Consultant formerly ARCO, Lyondell-Basell)

Background
The recent development of US natural gas reserves has provided an historic opportunity for
natural gas as a source of basic chemicals. The opportunity to transition from oil to
natural gas as the foundation of our daily livesechoes the wood-to-coal transition in the
19th century, and coal-to-oil in the 20th. (Dr. Alex Tkachenko) Oxidative coupling of
methane (OCM) is a very active area for research and venture capital working to achieve
this transition.

The basic chemistry is:

CH
4
+ O
2
C
2
H
4
+ H
2
O

However, the partial or total oxidation to CO or CO
2
is thermodynamically favored; thus a
catalyst is needed to control the reaction kinetically such that reasonable yields to ethylene
are obtained. Ethylene is the most important building block in the petrochemical industry.
Over 50 billion lb/yr are produced in the US alone by steam cracking of various
hydrocarbon feedstocks. (Dan Lippe, 2013).

A number of catalysts have been researched under various operating conditions, as per the
references below. A simplified schematic of the process with important design parameters
is given in Figure 1 below.

Recycles?
Methane Ethane/EthyleneProduct
Oxygen Methane
Oxygen
Lower Typical Upper CO Wastewater
Bound Value Bound CO2
FeedConditions Ethane
CH4:O2molratio 4 Ethylene
ReactionConditions Water
Temperature,C 700
Pressure,atm 1
Spacetimeyield,kgmol/hr/kgcat 10
ReactionResults
%MethaneConverted 20%
SelectivitytoEthane+Ethylene 60%
Ethane/Ethyleneratio 1
SelectivitytoCO+CO2 40%
CO/CO2molratio 0.25
OCM Reactor Separations
UnconvertedGases(to
thermaloxidizer?)


Figure 1, Oxidative Combination of Methane Schematic and Reaction Assumptions

2
Deliverables and Scope of Work
Your firm, Process Evaluation, Inc., has been contracted by a major ethylene producer to
develop a process model and economics that will guide their research on OCM catalyst. At
each step below, review your findings with your stakeholders (in your case, faculty and
industrial consultants).
1) Review literature and set ranges on model inputs. Determine a suitable range of
parameters for the table in Figure 1 based on your review of the references below.
Also, select a set of conditions that you believe are achievable targets and use these as a
base case in your economic analysis. However, do not over-constrain the material
balance calculations (for example, the CH
4
:O
2
ratio must be at no more than 5/1 for the
reaction results in the typical column of the table in Figure 1, or else there is
insufficient oxygen.
2) Create a simplified model. Develop one or more block flow diagrams in Excel with
material balances that update with changing assumptions. Determine viable separation
techniques for the reaction products (that is, expand on the simple separations block
above). Assess which streams can be recycled, or how they are disposed of. The final
product will be a mixture of ethane and ethylene, free of moisture, which is sold to an
ethylene producer who will produce on-spec ethylene in their existing distillation train.
Perform an economic analysis and summarize your results. At this stage, we are only
considering the raw material costs. Energy, fixed costs, and investment will come
later.
3) Develop a flowsheet. Choose a design from step 2 to develop into a more detailed
flowsheet. In this flowsheet, you will:
a. Prepare a Process Flow Diagram showing major equipment such as vessels, heat
exchangers, and pumps.
b. Select operating pressures for key unit operations
c. Show heating and cooling duties, and offer opportunities for heat integration.
d. Calculate compressor horsepower if gas streams are being compressed.
You may use either ASPEN PLUS or Excel to calculate heat and material balances, but
the model should be able to handle reasonable changes to the Target assumptions.
Again, perform an economic analysis which now includes energy and raw materials.
This is essentially the variable cost of production.
4) Determine capital cost and final economics. Size the equipment, estimate the installed
capital cost, and complete a cash flow analysis for your selected flowsheet.
Your analysis will consider:
What economic environment makes the achievable targets an attractive process?
What process parameters are needed to have an attractive process given the economic
data below?
3
Additional Comments and Guidelines
Plant Scale. Size for 1 billion lb/yr of total ethylene plus ethane. This is roughly a 2%
increase in US capacity.
Reactor Design and Modeling. At this stage, the reactions do not need to be modeled
kinetically; instead, use a stoichiometric model with conversions and yields. Be
mindful of the flammable limits of methane, and that these limits widen with increased
pressure. Although the reactor design is eventually very important, we are looking for
the big picture, here. You can consider isothermal reactors such as packed tube-in-shell
designs, or packed adiabatic reactors or fluidized beds with cooling between stages. In
the latter case, assume an allowable adiabatic temperature rise of 50C.
Possible separation techniques. The list below is not meant to be comprehensive, and
may not even be appropriate, but it can provide some insight for fitting pieces together.
If using cryogenic separation techniques, be mindful that any moisture will freeze and
plug equipment.
o Simple compression and condensation, to remove most water and possibly some
ethylene/ethane.
o Selective absorption to remove ethylene/ethane from the bulk gas stream, with a
solvent such as dimethylformamide. (Linde has a process to recover acetylene from
ethylene with this solvent)
o Selective absorption to remove CO
2
, such as with the Benfield process.
o Molecular sieve adsorption beds to remove water from gas streams.
o Catalytic oxidation to convert CO to CO
2
.
Battery Limit Conditions
o Although natural gas contains some ethane and other impurities, assume pure
methane as your feedstock, available at 50 psig and ambient temperature.
o Oxygen is available at 100 psig and ambient temperature. It contains 0.5 wt%
argon.
o An Ethane/Ethylene mixture must be supplied at 450 psig to the olefins unit with
less than 100 ppm water and 50 ppm CO+CO
2

Recycles. How much of the unconverted gas gets recycled is a significant design
choice you have. The tradeoff is that more recycle increases energy and equipment
cost. You may consider recycling CO
2
as a diluents to limit adiabatic temperature rise
and somewhat shrink the flammable envelope.
Economic Data
Your analysis will include sensitivity to pricing assumptions. Typical recent prices are:
Ethylene: 45 cent/lb (Dan Lippe, 2013)
Ethylene Ethane price spread: 20 cent/lb (Young)
Include a conversion cost of 1 c/lb mixed ethane/ethylene feed to the olefins plant that
separates these components.
Natural Gas: $3.50/MMBTU (InfoMine)
4
Oxygen: use 2 cent/lb
Electricity: use 7 cent /kW-hr

References
Dan Lippe, P. C. (2013, 3 14). 2012 ethylene production bounces back; turnarounds in
early 2013 to curb output. Retrieved Aug. 1, 2013, from Oil and Gas Journal:
http://www.ogj.com/articles/print/volume-111/issue-3/processing/2012-ethylene-
production-bounces-back-turnarounds.html
Dr. A. Tkachenko, P.-E. (n.d.). Retrieved Aug. 1, 2013, from Siluria Technologies
Management: http://siluria.com/About/Management
InfoMine. (n.d.). Natural Gas Prices. Retrieved Aug. 2, 2013, from
http://www.infomine.com/investment/metal-prices/natural-gas/1-year/
Young, W. R. (n.d.). Ethylene Profitability Outlook Positive. Retrieved August 2, 2013,
from:
http://www.mergers-
alliance.com/uploads/opinion/3b5dfebf42239ec21e52957875fce209.pdf
Additional References
Scheffler, Robert Schlgl, & Reinhard Schomcker (2011): A Critical Assessment of Li/
MgO-Based Catalysts for the Oxidative Coupling of Methane, Catalysis Reviews, 53:4,
424-514.
http://th.fhi-berlin.mpg.de/site/uploads/Publications/CatRev-53-424-2011.pdf

US Patent Application 20130178680, Catalyst for Oxidative Coupling of Methane,
Method for Preparing the Same, and Method for Oxidative Coupling Reaction of Methane
using the Same, Ha et al., 7/11/2013
US Patent 8,450,546, Process for the Oxidative Coupling of Methane, Chinta et al.,
5/28/2013
US Patent 7,291,321B2, Preparation of Catalyst and Use for High Yield Conversion of
Methane to Ethylene, Bagherzadeh et al., 11/6/2007
US Patent 7,250,543 Preparation of Catalyst and Use for High Yield Conversion of
Methane to Ethylene, Bagherzadeh et al., 7/31/2007
For flammable envelopes of methane in enriched air, see:
http://en.wikipedia.org/wiki/Flammability_diagram
Bureau of Mines bulletin 627, Flammability Characteristics of Combustible Gases and
Vapors, M. Zabetakis, 1965
5
2. Acrylic Acid from Ethylene
(recommended by John A. Wismer, Arkema)

The global market for acrylic acid (AA) exceeds 10 billion pounds/year. In developed
countries, demand is growing faster than GDP thanks to a healthy growth in acrylic resins
and superabsorbent polymers. Most of the worlds production capacity uses propylene as a
precursor with acrolein being the key intermediate. However, AA can also be made from
ethylene. Historically, propylene has sold at a slight discount to ethylene due to its ready
availability as a by-product of refinery cracking operations. In recent years, the market
dynamics in the US have started to shift in response to two trends that are projected to
continue in the coming years. The first is near-zero growth in US refinery production in
the face of competition from foreign megarefineries and a hostile regulatory
environment. This is taking place in spite of an increase in domestic oil production. The
second trend is the increasing availability of ethane from shale gas as a feedstock to
ethylene crackers. As the new ethane crackers force the shutdown of the higher cost
naphtha units, lower ethylene prices should follow.

Your client is interested in knowing whether ethylene derived acrylic acid will be a threat
to its propylene based manufacturing platform. The proposed route to acrylic acid from
ethylene proceeds in three steps.



The first step is a direct oxidation of ethylene to ethylene oxide. Purveyors of relatively
new microchannel reactor technologies have made EO a target process
1.2.3
. Microchannel
reactor technology enables the process to operate safely in the flammable region and
controls reactor temperatures within a narrow range to improve selectivity. Evaluate this
technology and use on the first step if appropriate. Design details for microchannel
reactors can be found in previous senior design project reports
10
.

The second step is a carbonylation of ethylene oxide to beta-propriolactone. This is
typically a liquid phase catalyzed reaction. The carbon monoxide reactant is available by
pipeline on the Gulf Coast. This reaction can proceed in a number of solvents, but there
are obvious advantages to high-boiling solvents such as sulfolane. The catalyst is
presumably homogeneous. It typically is comprised of carbonyl cobaltate and a metal
centered Lewis acid. All patent examples are based on batch reactors
6
. Part of the design
challenge is to extract kinetic data from the batch results so that CSTR-based
6
configurations can be evaluated. The major non-selective is succinic anhydride- a result of
the carbonylation of the lactone. There are indications that succinic anhydride can be
greatly reduced or eliminated by reactor design and/or manipulation of process
conditions.
7,8

The final step is an acid catalyzed rearrangement of beta-lactone to acrylic acid. This
reaction is highly selective as long as an inhibitor is used to prevent polymerization of the
acrylic acid
9
. There are suggestions of process intensification by close coupling the
carbonylation and rearrangement reactions to avoid propriolactone isolation. The toxicity
of propriolactone and its susceptibly to decomposition at its normal boiling-point provide
strong incentives for avoiding its isolation.

The acrylic acid project should produce 300 million pounds/year. Ethylene pricing should
be cost plus based on quoted prices for ethane. This should give significantly lower
prices than the current market price of ethylene, which will hold up as long as naphtha
based crackers supply a significant portion of domestic ethylene.

References

1) Kestenbaum, H., et al., Silver-Catalyzed Oxidation of Ethylene to Ethylene Oxide in a
Microreaction System, Ind. Eng. Chem. Res., 2002, 41, 710-719

2) Maurer et al., US2009/0270640 A1, Method for Production of Ethylene Oxide in a
Microchannel Reactor, October 29, 2009

3) Mazanec et al., US2006/036106 A1, Process for Converting Ethylene to Ethylene
Oxide Using Microchannel Process Technology, Feb 16, 2006

4) Patel, Jignesh Patel, Absorber Optimization: Employing Process Simulation
Software, Chem. Eng., Aug., 2013, Vol 120, No. 8, pps 46-48 (EO separation train)

5) Dever, JP, et al. Ethylene Oxide, Kirk-Othmer Encyc. of Chem. Technology, 2004.

6) Allen, S. et al, US2012/0123137 Process for Beta-Lactone Prod. May 17, 2012

7) Porcelli, R., et al., WO2013/063191 Process for Production of Acrylates from
Epoxides, May 2, 2013

8) Rowley, J. M, Catalytic Double Carbonylation of Epoxides to Succinic Anhydrides:
Cat. Discovery, Reaction Scope, and Mech.. J. Am, Chem. Soc, 2007, 129, 4948-4960

9) Schnulzer, A., US3,176,042 Treating Propriolactone with Heated Phosphoric Acid to
Produce Acrylic Acid

10) Hammond, J., et al.,Alaskan Natural Gas To Liquids (GTL) Using Microchannel
Reactors 4-14-09, CBE 459 Design Project
7
3. Sunlight to Convert Carbon Dioxide into Transportation Fuels
(recommended by Matthew Targett, LP Amina)

Overview
Investigate the science and economics of a sunlight to fuels technology. Design the
process and facility using engineering and financial projections, including best, base and
worst case scenarios. Take a systems approach in producing your business model.

Background on Technology
Reversing combustion, though theoretically possible, has long been considered
technologically and economically impractical, but a prototype at the Sandia National
Laboratories is challenging conventional wisdom by recycling carbon dioxide into fuels.
Developed by Rich Diver, the Counter Rotating Ring Receiver Reactor Recuperator (CR5)
uses heat from concentrated solar power to drive highly endothermic reactions involving
metal oxides, CO
2
splitting and water splitting in rotating loops. You will combine the CO
and H
2
(produced directly or indirectly) from the CR5 in a Fischer-Tropsch reactor to
produce transport fuels and chemicals.

The technology involves concentrated solar energy, in which mirrors focus and reflect
sunlight onto the CR5 to produce temperatures higher than 2000
o
C. In the CR5 dish
modules, the concentrated solar energy heats loops of metal oxides to reduce them to their
base metals by removing oxygen. The reduced metals are rotated into a lower temperature
chamber with carbon dioxide and, being highly reactive, the metals strip oxygen atoms
from the gases, producing carbon monoxide and metal oxide. The loops continue rotating
between the concentrated solar-heated chamber and the cooler, carbon dioxide chamber for
continuous production of carbon monoxide. Water can be used in place of carbon dioxide
to produce hydrogen; otherwise, part of the carbon monoxide produced by the CR5 can be
used to strip oxygen from water molecules in a separate reactor that you will design. The
products, carbon monoxide and hydrogen, will then be feedstocks in your Fischer-Tropsch
process to produce transport fuels.

The reactions in the CR5 dish modules (reduce metal oxides to produce CO from CO
2
):
Fe
3
O
4
3FeO+1/2O
2

3 FeO + CO
2
Fe
3
O
4
+CO
--------------------------------------
CO
2
1/2O
2
+CO

If you decide it is more practical to do so, you can design a portion of your CR5 modules to
use water instead of CO
2
to gain the hydrogen needed for the Fischer-Tropsch process. If
not, you can design another reactor to produce H
2
by the water-gas shift of CO from the
CR5 process, e.g.:
CO + H
2
OCO
2
+H
2

The CO and H
2
you produce will be fed into a Fischer Tropsch process and produce a
transport fuel based on your analyses. An example of a reaction is below:
8 CO + 17 H
2
C
8
H
18
+ 8 H
2
O
8

Tips on Commercialization Portion
In your economic assessments and facility cost predictions, some aspects you may want to
consider are:
fixed and variable costs (e.g., cost of facility and labor)
return on investment
location of facility
price projections of each raw material
feedstock for the carbon dioxide
useful by-products
price projections of the final product (your fuel of choice)

In judging the competitiveness of each scenario, you may want to take into account the
political and economic landscape of the energy industry and climate change challenge.
This includes other technological developments in transport fuels that might influence spot
prices, such as new pipelines or Bakken crude that influence WTI crude, which is the US
benchmark. Also take into account the changing nature of energy policy, such as
incentives for renewable fuels and regulations that may give you an upper hand.

Some companies working on Concentrated Solar Power include: Abengoa, Bright Source,
Torresol Energy. Some facilities researching high temperature redox other than Sandia
include DLR German Aerospace Center, Paul Scherrer Institute and ETH Zurich, and the
Weizmann Institute in Israel.

References
Sunshine to Petro: Solar Recycling of Carbon Dioxide into Hydrocarbon Fuels. Sandia
National Laboratories.
<http://energy.sandia.gov/wp/wp-content/gallery/uploads/S2P_SAND2009-5796P.pdf>
Diver, RB. Innovative Solar Thermochemical Water Splitting. 2008.
Diver, RB. Solar Driven H
2
O/CO
2
Splitting via Thermochemical Cycles. 2010.
Sandias Sunshine to Petrol Project Seeks Fuel from Thin Air. Sandia National
Laboratories. 5 Dec. 2007.
<https://share.sandia.gov/news/resources/releases/2007/sunshine.html>
Chen, K. Three-Dimensional Modeling of Solar Thermochemical Splitting of CO
2
in a
CR5. 2011.
Mayer, LJ. Thermal Recuperation Modeling of a Solar Thermochemical Reactor. 2011.
Steinfeld A. Design Aspects of Solar Thermochemical Engineering. 1999.
T-Raissi, A. Analysis of Solar Thermochemical Water-Splitting Cycles for Hydrogen
Production. 2003.
Steinfeld, A. Solar Thermochemical Production of HydrogenA Review. 2004.
Rennels, R. Solar Thermochemical Hydrogen Production Project Progress Toward
Industrial Scale Water Splitting. 2008.

Note: The creator of this project is not based in Philadelphia. Many or all interactions will
be through SKYPE, phone and/or email.
9
4. High-Efficiency Compressed Air Energy Storage (CAES)
(recommended by Adam Brostow, Air Products and Chemicals)

Background
With the development of intermittent renewable energy sources such as solar and wind it is
becoming increasingly important to economically and efficiently store excess energy to
provide uninterrupted power supply. Energy storage is also important for time-of-day
energy management and peak shaving.

Figure 1 shows the general concept of CAES: compressed air energy storage. Air is
compressed in a compressor CMP (that can be driven by electric motor EM) and stored in a
tank. It can then be expanded in expander EXP to generate energy. Compression may be
isothermal or adiabatic. Expansion may be with or without the reheat. Compressor and
expander may be the same unit or different units.


EXP
TANK
CMP AIR
EM

Figure 1

CAES was known for a long time and considered not very efficient. Recently, a startup
company, LightSail, led by 25-year old Danielle Fong, claims to achieve 70% efficiency
(energy in vs. energy out).

Figure 2 shows the system proposed by LightSail and called RAES (regenerative air energy
storage). Air is compressed (and later expanded) in a reciprocating (positive displacement)
compressor-expander CMP/EXP. Water mist is injected to remove the heat of compression
(or later to add heat to the expansion). Air and water is separated in phase separator PS.
Compressed air is stored in a tank. Water is recirculated. Heat is rejected (or, in expansion
step, extracted from) a heat sink such as the atmosphere or a pond. The process is shown
on Figure 6 of US Patent 8,247,915 and described in columns 10-11 of said patent.




10
heat sink
H2O
CMP / EXP
PS
TANK


Figure 2

Related Ideas

Figure 3 shows the use of a DCAC (direct contact aftercooler). A spay nozzle is replaced
with packing for improved gas-liquid heat and mass exchange. Can it be used for the
process shown on Figure 3? Would the process benefit from evaporative cooling of
circulating water (a cooling tower)?


H2O
heat si nk
DCAC
AIR
CMP


Figure 3

Also explore AHAT (Advanced Humid Air Turbine) and water injection in a gas turbine.

Problem Statement

An intermittent energy source (such as solar or wind) produces 1 MW of energy. The
assignment is to design a CAES or RAES system (process and apparatus) that will store
this energy for three hours with an efficiency of at least 70%. What can be done to
improve this efficiency? Whats the maximum efficiency that can be achieved? How does
the cost compare to other means of energy storage, such as batteries (or, in the case of
RAES, conventional CAES)? What will be the effect on cost/efficiency if the energy was
to be stored for six hours? Is the solution the same for wind power (the wind blows
11
intermittently 24 hours a day) and solar power (only available during the day, affected by
cloud cover)?

References

US Patent 8,247,915
US Patent 8,240,142
US Patent 8,037,677

Links

Danielle Fong (read A Brief Note on Thermodynamics):
http://daniellefong.com/

LightSail (see the diagram):
http://lightsail.com/

Technology Review article on LightSail:
http://www.technologyreview.com/tr35/profile.aspx?TRID=1302

Wired article on LightSail:
http://www.wired.com/wiredenterprise/2012/07/danielle-fong/

12
5. Export of Marcellus Shale LNG
(recommended by Ann Hewitt, Steven Lee, Ryan Marschang, and Tyler Moeller,
CBE 459 students)

Overview

The Marcellus Shale natural gas field that spans from West Virginia to New York is
leading the recent surge in domestic energy production, with the United States government
predicting that the U.S. will be a liquefied natural gas (LNG) exporter by 2016.
1
This
development has prompted the need for more LNG export facilities in the U.S. An inactive
LNG import facility, Dominion Cove Point LNG in Maryland has the necessary
infrastructure to transport natural gas from the Marcellus Shale and could be retrofitted to
export LNG to locations around the world.
2

Description

The Marcellus Shale field contains an estimated 177 trillion cubic feet of natural gas
according to conservative estimates, with the actual total likely much higher. Companies
continue to look for efficient, cost-effective ways of transferring this fuel to profitable
locations, extending across the country and beyond. The most feasible option for
transporting natural gas farther than 1,500 km is as LNG, which is created through a series
of processes involving removal of water and contaminants, liquefaction, refrigeration, and
storage before eventual transportation.
3

The project involves designing an LNG facility to convert Marcellus Shale natural gas for
export to global markets. Existing pipeline infrastructure is in place for a facility on the
East Coast. Using materials and knowledge gained from the chemical engineering
curriculum, the team will design a liquefaction process consisting of multiple stages,
including pre-feed processing, liquefaction (refrigeration cycle), storage, product loading,
and transportation. An efficient method of liquefaction to be considered is the Cascade
process.
4

A comparison of feasible LNG plant designs will be necessary. Floating LNG facilities are
one alternative to traditional onshore plants. Another option is the retrofitting of the
Dominion Cove Point LNG plant, which is currently set up to import but could be
converted to an export facility. This project envisions an extensive analysis of the
conversion from import to export, which will be considered along with an appropriate
process design of gas liquefaction.

In addition to a strong technical foundation and design, this project will also investigate the
economics of the various plant possibilities. Determining the costs to produce, liquefy, and
transport the LNG will elucidate whether the cost to retrofit the Cove Point facility is
feasible from a financial standpoint, beyond its technical merits. The economic advantage
of converting the Cove Point facility is that the LNG tankage, port, and other infrastructure
is already in place, likely resulting in a lower capital investment compared to building a
new LNG export facility from scratch.
13

Furthermore, this project will inspect the economics of exporting Marcellus Shale gas.
With the recent closure of the vast majority of nuclear power plants in Japan, the nation is
more reliant now than ever before on imported natural gas to satisfy its energy needs. In
2012, United States natural gas (NG) prices were at 2.76 $/MMBtu and Japan LNG prices
were at 16.75 $/ MMBtu in 2012, presenting a large U.S. economic opportunity for
successful LNG production and export.
5
This project will present an economic analysis of
a chemical process involving the costs of constructing and operating an LNG facility and
distribution to a market where LNG is in high demand. The LNG markets in other
countries are often locked into long-term contracts, unlike the natural gas market in the
U.S., and this project will allow for the exploration of the current LNG financial landscape.

Key Points of Proposal

Design and construction of an LNG export plant based on a retrofit of an existing
import facility with infrastructure to use Marcellus Shale gas as the feed.

Evaluation of different LNG processes/technologies with consideration for possible
improvements and explanation of why converting an import facility into an export
facility is cheaper than starting from scratch.

Evaluation of the economics involved in the decision to build an LNG plant.

References

1. Annual Energy Outlook 2012 Early Release Overview. U.S. Energy Information
Administration. http://www.eia.gov/forecasts/aeo/er/pdf/0383er%282012%29.pdf

2. Phillips, S., Marcellus Shale Exports Could Transform the Global LNG Market.
State Impact. July 25, 2013.
http://stateimpact.npr.org/pennsylvania/2013/07/25/marcellus-shale-exports-could-
transform-global-lng-market/

3. Choi, M. S., LNG for Petroleum Engineers. SPE Projects, Facilities & Construction,
Volume 6, Number 4. December 2011.
http://www.onepetro.org/mslib/app/Preview.do?paperNumber=SPE-133722-
PA&societyCode=SPE

4. U.S. Patent 2000/6016665 A, Jan. 25, 2000, Cascade Refrigeration Process for
Liquefaction of Natural Gas, Bowen, R. R. and Cole, E. T.

5. BP. "Natural Gas Prices." Natural Gas Prices.
http://www.bp.com/en/global/corporate/about-bp/statistical-review-of-world-energy-
2013/review-by-energy-type/natural-gas/natural-gas-prices.html

14
Additional Resources

1. Gervois, G., et al, Floating LNG A Look at Export and Import Terminals. Offshore
Technology Conference. May 2005.
http://www.onepetro.org/mslib/app/Preview.do?paperNumber=OTC-17547-
MS&societyCode=OTC

2. Talib, J. H. and Price, B. C., LNG Barges: The Offshore Solution for Export of US
Pipeline Gas. Offshore Technology Conference. May 2013.
http://www.onepetro.org/mslib/app/Preview.do?paperNumber=OTC-23939-
MS&societyCode=OTC

3. Uhl, A.E., et al., Elements of LNG Export-Import Systems. Society of Petroleum
Engineers. 1972.
http://www.onepetro.org/mslib/app/Preview.do?paperNumber=00003824&societyCode
=SPE

4. Verghese, J. and Ballout, N., Development Options for North American LNG Export:
The Merits of Inshore Deployed FLNG for Liquefaction of Onshore Shale Gas and
Examination of Principal Technology Drivers. Offshore Technology Conference.
2013.
http://www.onepetro.org/mslib/app/Preview.do?paperNumber=OTC-24091-
MS&societyCode=OTC
15
6. Methanol to Benzene
(recommended by Bruce M. Vrana, DuPont)

Inexpensive natural gas in the U.S. from fracking is leading to the resurgence of the U.S.
chemical industry and a wide array of new possibilities. World-scale methanol plants,
which had left North America two decades ago, are now being announced and built to
capitalize on this inexpensive gas. Until now, however, there has been no economical
means to convert natural gas to aromatics. Benzene, toluene and xylene (BTX) are
conventionally produced by reforming naphtha in an oil refinery or by extracting them
from naphtha-fed ethylene crackers. Both sources of BTX are tied to expensive crude oil.
Your main interest is in p-xylene (PX), used in the PET value chain, among others. But all
components of BTX are valuable to your company.

Your company has developed a catalyst to convert methanol to BTX, with a large fraction
of xylenes. The proposed process uses a proprietary Zeolite catalyst impregnated with
lanthanum, molybdenum, and zinc to form aromatics. Co-feeding ethylene and propylene
increases the selectivity to BTX significantly.

Your team has been assembled to develop the most economic process to make benzene
and/or BTX and capitalize on world-scale methanol plants. Management desires a plant to
produce 1MMM lb/yr of total BTX from methanol at your U.S. Gulf Coast site. They also
desire a plant that uses this new catalyst in the most economical way. But management did
not specify whether you should separate the BTX produced into one or more pure products
(benzene, toluene, PX, etc.) as well as a mixed BTX stream as a coproduct, or whether you
should just produce mixed BTX. They also did not specify whether ethylene and
propylene should be used. They only want to maximize the NPV of the venture, and leave
the selection of the feeds and products up to you.

You will need to focus on the process to make BTX, not the process to make the catalyst,
which you can assume will be produced for you by a catalyst vendor.

Methanol is available at your plant site for $1.00/gal. If desired, you may purchase a
mixed ethylene/propylene stream for $0.30/lb from your on-site ethylene plant. Benzene
can be sold for $3.50/gal. Toluene can be sold for $3.75/gal. PX can be sold for $0.75/lb.
Other xylenes, if any, and any mixed BTX streams can be sold for $3.00/gal. All prices are
forecasts by your marketing organization for long term average prices, expressed in 2014
dollars for the quantities needed delivered to your site or sold from your site.

You will need to make many assumptions to complete your design, since the data you have
are far from complete. State them explicitly in your report, so that management may
understand the uncertainty in your design and economic projections before approving an
expensive pilot plant to provide the scale-up data you need to complete the design. Test
your economics to reasonable ranges of your assumptions. If there are any possible show-
stoppers (i.e., possible fatal flaws, if one assumption is incorrect that would make the
design either technically infeasible or uneconomical), these need to be clearly
communicated and understood before proceeding.
16

The plant design should be as environmentally friendly as possible, at a minimum meeting
Federal and state emissions regulations. Recover and recycle process materials to the
maximum economic extent. Also, energy consumption should be minimized, to the extent
economically justified. The plant design must also be controllable and safe to operate.
Remember that, if the plant is approved, you will be there for the plant start-up and will
have to live with whatever design decisions you have made.

Reference

U.S. Patent 8,450,548, May 28, 2013, assigned to Saudi Basic Industries Corporation
(SABIC)



17
7. Propylene Oxide from Propylene
(recommended by Bruce M. Vrana, DuPont)

Propylene oxide (PO) is an important intermediate in the manufacture of propylene glycol
(PG), polyether polyols and many other products. PG is in turn used to make unsaturated
polyester resins, cosmetics, environmentally-friendly antifreezes, etc. The conventional
PO processes have many drawbacks. The chlorohydrin process produces chlorinated
byproducts, both organic compounds and inorganic salts, which must be disposed of.
Other processes generally produce a co-product, such as styrene, which can adversely
affect the economics of producing PO. These drawbacks have prevented your company
from expanding production of PO.

Several companies have researched using hydrogen peroxide to make PO. But these efforts
have been limited by the high cost of H
2
O
2
. Your companys chemists have developed a
catalyst that uses H
2
and O
2
directly to produce PO, rather than making peroxide.

Your team has been assembled to develop a plant design to put this new catalyst into
operation on the U.S. Gulf Coast. Your team will be the first to think about a commercial
process concept to use the catalyst. You will need to focus on the process to make PO, not
the process to make the catalyst, which you can assume will be produced for you by a
catalyst vendor. Management desires a plant to produce 200MM lb/yr of PO.

Propylene is available by pipeline at your plant site for $0.40/lb. Propylene oxide can be
sold for $0.70/lb. Hydrogen costs $0.50/lb from the nearby pipeline. Oxygen can be
purchased from the nearby air separation plant for $0.03/lb. All prices are forecasts by
your marketing organization for long term average prices, expressed in 2014 dollars for the
quantities needed delivered to your site or sold from your site.

You will need to make many assumptions to complete your design, since the data you have
are far from complete. State them explicitly in your report, so that management may
understand the uncertainty in your design and economic projections before approving an
expensive pilot plant to provide the scale-up data you need to complete the design. Test
your economics to reasonable ranges of your assumptions. If there are any possible show-
stoppers (i.e., possible fatal flaws, if one assumption is incorrect that would make the
design either technically infeasible or uneconomical), these need to be clearly
communicated and understood before proceeding.

The plant design should be as environmentally-friendly as possible, at a minimum meeting
Federal and state emissions regulations. Recover and recycle process materials to the
maximum economic extent. Also, energy consumption should be minimized, to the extent
economically justified. The plant design must also be controllable and safe to operate.
Remember that, if the plant is approved, you will be there for the plant start-up and will
have to live with whatever design decisions you have made.

Reference
U.S. Patent 8,273,907, September 25, 2012, assigned to Sumitomo Chemical Company
18
8. Ethanol to Butanol
(recommended by Bruce M. Vrana, DuPont)

Prior to the advent of the petrochemical industry, which made the process uneconomic,
acetone, butanol and ethanol were produced together by fermentation, using one of several
Clostridia strains. With the growth in interest of biofuels and the increase in price of
petrochemicals, renewable routes to butanol are being revisited by several parties. Butanol
is an excellent biofuel, with many advantages over the incumbent biofuel, ethanol. It has
higher fuel value, meaning more miles per gallon. It can be blended to higher levels
without requiring engine modifications. It has lower vapor pressure than ethanol and
comparable octane number. But direct fermentation routes to butanol are challenging, and
your company is a newcomer in looking at butanol, so it would be futile to attempt to
compete with the companies in various stages of commercializing fermentation routes to
butanol.

Your company has instead developed a traditional catalyst to convert ethanol to n-butanol
with good selectivity. This so-called Guerbet reaction is enhanced with your catalyst by
the addition of hydrogen. Increasing hydrogen pressure improves the selectivity to as high
as 95%, but of course increases the capital cost of the plant. You will want to find the
optimum pressure, balancing the capital and operating costs of the plant.

The United States and Brazil produce most of the worlds ethanol by fermentation of local
agricultural feedstocks. The U.S. industry is almost entirely based on corn, while Brazil
uses sugar cane. Process efficiencies in both countries have improved significantly in
recent years, with increasing ethanol production for use in transportation fuels; thus, do not
use process or cost data that are more than 2-3 years old.

Your team has been assembled to develop the most economic process to make n-butanol
from ethanol. Management desires to use the entire capacity of the adjoining 100MM
gal/yr ethanol plant to make n-butanol. Coincidentally, your company has plants with the
same annual capacity in the U.S. and Brazil. Thus, you may locate your plant in either
country, using appropriate construction costs for your location, and local ethanol prices and
specs.

You will need to focus on the process to make butanol, not the process to make the
catalyst, which you can assume will be produced for you by a catalyst vendor.

If you decide to locate in Brazil, one important factor to consider in your economics is that
ethanol price increases dramatically during the inter-harvest period, typically 3-4 months of
the year when sugar cane cannot be harvested and local ethanol plants shut down. In recent
years, Brazil has imported ethanol from the U.S. during this part of the year. Corn ethanol
in the U.S. has no such restriction, as corn can be stored year-round.

You may locate your site either in an agricultural region of the U.S. (Iowa) or Brazil (So
Paolo state), or in an industrial area, such as the U.S. Gulf Coast or coastal areas of So
Paolo. If the plant is built in an agricultural region, hydrogen will be more expensive, and
19
you will need to ship your product to the end use fuel market. Hydrogen would require an
onsite production facility and you would purchase hydrogen for $0.75/lb. Freight for
butanol would be $0.05/gal, while the freight for the ethanol would be negligible.

If the plant is built in an industrial area, hydrogen will be less expensive and you will need
to ship your feedstock to your site. Hydrogen would be available by pipeline for $0.50/lb
in the U.S., $0.60/lb in industrial regions of Brazil. Freight for ethanol to the site would be
$0.05/gal, while the freight for the product would be negligible.

Hydrogen pressure from either the pipeline or an onsite plant is 200 psig. If you desire
higher pressure, you will need to install a compressor and pay for the energy to compress
it.

All prices are forecasts by your marketing organization for long-term average prices,
expressed in 2014 dollars for the quantities needed delivered to your site or sold from your
site.

Based on your market research, the price per gallon of butanol is 1.3 to 1.5 times the price
per gallon of ethanol, both in the U.S. and Brazil. Obviously, you will want to test how
sensitive your economics are to this price range.

You will need to make many assumptions to complete your design, since the data you have
are far from complete. State them explicitly in your report, so that management may
understand the uncertainty in your design and economic projections before approving an
expensive pilot plant to provide the scale-up data you need to complete the design. Test
your economics to reasonable ranges of your assumptions. If there are any possible show-
stoppers (i.e., possible fatal flaws, if one assumption is incorrect that would make the
design either technically infeasible or uneconomical), these need to be clearly
communicated and understood before proceeding.

The plant design should be as environmentally-friendly as possible, at a minimum meeting
Federal and state emissions regulations. Recover and recycle process materials to the
maximum economic extent. Also, energy consumption should be minimized, to the extent
economically justified. The plant design must also be controllable and safe to operate.
Remember that, if the plant is approved, you will be there for the plant start-up and will
have to live with whatever design decisions you have made.

Reference

U.S. Patent 8,318,990, November 27, 2012, assigned to Mitsubishi Chemical Corporation

20
9. Cell Therapy for Spinal Cord Injuries: Manufacturing Facility
(recommended by Tiffany D. Rau, Eli Lilly)

Overview
Design a manufacturing facility for the production of a stem cell treatment for spinal cord
injuries. The manufacturing facility will also produce the material in custom-designed
vessels that the team will design for the culturing of the stem cells.

Description

You are part of a small to midsize biotechnology company that focuses on cell therapies for
a number of indications. Your company has one launched product, but it is not in the cell
therapy area.

Your company is currently developing a spinal-cord injury, regeneration therapy that will
allow patients to recover from their injuries and be able to move again. There is currently
an unmet need in the market for the treatment of spinal cord injuries yielding significant
functional improvements. Spinal cord injuries are diverse and are typically permanent
leaving a patient with a lower quality of life. There are approximately 250,000 people in
the US with spinal cord injuries, with an additional 12,000 people/year are added in the US
alone (Californias Institute for Regenerative Medicine).

A research team has been pursuing two different cell therapy systems. One uses human
embryonic stem cells (hESC) and the other uses adult stem cells. Both are at the same
stage of development. As part of the commercialization team, you will need to decide
whether to progress the hESC or adult stem cell therapy to market resources are limited
and time is of the essence.

Once your team decides on the platform, you will design a new manufacturing facility/suite
needs to be constructed. hESC and adult stem cells are very delicate cells and are typically
attached cell lines so it is difficult to grow them in traditional bioreactors/fermenters which
are normally designed for suspension cultures. Also note that the therapy is the cell itself
so you need to ensure that the cells are not damaged in the production process. It is
suggested that you design a new-type of low-shear bioreactor system that controls pH,
dissolved oxygen, and temperature. There are systems on the market for growing attached
cell lines as well as stem cells, but your company wants a custom scale-up solution for its
cell-therapy division. Your company would like you to review what is on the market and
then create/optimize a bioreactor system to produce the spinal-cord injury treatment under
GMP conditions.

Your manufacturing process will include everything from vial thaw to purification, but
final formulation and packaging will take place offsite and should only be mentioned in
your report. On completion of this project, you will have designed the process, the new
bioreactor to grow the cells in, and the production facility to make the life-improving cell
therapy for spinal cord injuries. A diverse team of engineers, scientists, regulatory experts,
21
as well as business leaders has been established to help you deliver on your project. Your
project is on the critical path and your patients are waiting.

Important information. Please Read Before Selecting Problem

The creator of this project is not based in Philadelphia so many if not all interactions with
the students will be by SKYPE, phone and email. Also the meetings will be at mutual
agreeable times, but may not necessarily be between the times of 9 am and 5 pm EST.
When selecting this problem, please take this into consideration as interactions will be
remote. Please note that in todays world it is not unusual for interactions to be remote.
The creator has delivered projects around the world while not being at the location.

Helpful/Interesting Information
Examples of cell therapy companies: Biotime, Cellular Dynamics, Celgene, Geron,
Mesoblast, Lonza, and many more.

You may find that the Biopharmaceutical SUPERPRO Designer example on Intelligens
website www.intelligen.com helpful as you create your design project. Please note that the
model works using their evaluation version which is downloadable on their website. The
evaluation version of the software does not allow the user to print or save files.

The FDA has given suggested guidelines for the internal layout of a biopharmaceutical
facility/vaccine facility so you may wish to refer to their website for guidance.
www.fda.gov

Industrial trade publications: BioPharm International, BioProcess International,
Pharmaceutical Manufacturing, Genetic and Engineering News (GEN), and many more.

References
Blanch, H. W., D. S. Clark, BioChemical Engineering, Florida: CRC Press, 1997.

California Institute of Regenerative Medicine.: www.cirm.ca.gov

C. Mason, J. Mason, E. J. Culme-Seymour, G. A. Bonfiglio, B. C. Reeve, Cell Therapy
Companies Make Strong Progress from October 2012 to March 2013 Amid Mixed Stock
Market Sentiment, Cell Stem Cell, Volume 12, Issue 6, 6 June 2013, Pages 644-647, ISSN
1934-5909, http://dx.doi.org/10.1016/j.stem.2013.05.017.
(http://www.sciencedirect.com/science/article/pii/S1934590913002105)

Dos Santos F.F., Andrade P.Z., et al. Bioreactor Design for Clinical Grade Expansion of
Stem Cells. Biotechnology Journal, 8(6) June 2013, pp 644-654.

Gerson, D. F., Paradigm Change in BioManufacturing: Technology is Transforming
Manufacturing Options, Contract Pharma, May 2008.

22
Hambor, J. E. Manufacturing Stem Cells at Scale. Bioprocessing International, Vol 10,
No 6, June 2012, pp 22-23.

King, M. A. Selection Criteria for WFI Production Equipment," Controlled Environments
Magazine, September 2005,
http://www.cemag.us/Article_Print.asp?pid=546, Obtained 28 June 2009.

Lakshmikanthan, J., Outsourcing: Biologics Manufacturing: The CMO Advantage, 14
BioPharm International, February 2007.

Lubiniecki, A. S., Presentation: Global Industrial Perspective of Novel Biologicals
Development, Centocor R&D/Johnson and Johnson,
http://www.pmda.go.jp/english/past/pdf/7A.LubinieckiPMDA10207.pdf, Obtained 25
September 2008.

Ozturk, S., and WeiShou Hu, Cell Culture Technology for Pharmaceutical and CallBased
Therapies (Biotechnology and Bioprocessing Series), Florida: CRC Press 2005.

Pall Corporation, www.pall.com Helpful for both upstream and downstream information

Seider, W.D, J.D. Seader, D.R Lewin, and S. Widagdo. Product and Process Design
Principles: Synthesis, Analysis and Evaluation, Wiley, 2009.

Shukla, A. A., M. R. Etzel, S. Gadam, Process Scale Bioseparations for the
Biopharmaceutical Industry. Florida: CRC Press, 2007.

Stewart, J.M, Seiberling, D., The Secrets Out: Clean in Place, Chemical Engineering,
1996.

23
10. Monoclonal Antibodies via Fluidized Bed Immobilized Cell Culture
(recommended by Lydia Atangcho and Shenali Parikh, CBE 459 students)

Overview
Create a manufacturing process for the monoclonal antibody, Humira (Adalimumab), using
a fluidized-bed bioreactor to make 200 kg per year.

Description
Monoclonal antibodies (mAbs) are biologically identical antibodies created by
homogenous immune cells that originate from the same parent cell. The ability of mAbs to
target only a specific epitope has been used as a scientific tool in detecting and isolating
molecules of interest. This unique characteristic has also made them a key tool in the
biopharmaceutical industry.

Humira (Adalimumab), Remicade (Infliximab) and Rituxan (Rituximab), are just a few of
the top selling prescription drugs on the market that are monoclonal antibodies. However,
mAbs targeting a variety of epitopes continue to be produced through research for targeted
cancer treatments (U.S. Pharmaceutical Sales).

Since the introduction of mAbs to the field of therapeutic medicine, factories have adapted
their designs to produce pure, high-quality mAbs. The FDA supports a quality-by-design
approach in which process design is emphasized as the key aspect to producing healthy,
quality drugs with consistent batches (Dutton, 2010). However, because mAbs require
strict purification processes and a moderately long production process, plants are generally
over-capacity. MAb growth is dependent significantly on the cell culture conditions,
which most commonly include growing cells in suspension. However, increasing batch
sizes will not necessarily solve the problem. With larger batches, larger-scale purification
is necessary, but cannot be accommodated by current plant designs (Kelley, 2009).

We propose to introduce a different cell culture technique for application in large-scale
mAb production one that will provide several useful advantages over traditional
suspension culture techniques. Suspension culture is widely used because it presents the
simplest way of achieving a high cell density for a maximum product yield. One such
technique, animal-cell-perfusion, high-density cell culture, is frequently used in industry
and has been shown to enhance productivity of hybridoma cells (Yamaguchi et al., 1997).
In this culture method, cells growing in suspension are retained in the bioreactor (while
spent media is removed) to achieve a high cell density, therefore increasing cell
productivity (Ohashi et al., 2001) However, research has shown that mAb production can
be enhanced more than double by immobilizing cells on surfaces (Yamaguchi et al., 1997).
Many mammalian cell lines, including those most commonly used for mAb production,
grow most natively on surfaces with close contact to other cells. However, growing cells
on a surface instead of in suspension limits the amount of cells that can be grown at a time,
which subsequently limits the amount of product obtainable. By utilizing microcarriers, or
small porous particles capable of remaining in suspension, cells can grow in pseudo-
suspension by adhering on or inside these particles. This provides a much greater increase
in cell density and cell productivity as these culture conditions are more conducive to the
24
growth of anchorage-dependent cells (Rodrigues et al., 2009). Furthermore, in more native
growth conditions, cell adaptation time is significantly lowered in comparison to
suspension cultures.

Additionally, immobilizing cells results in cell retention, allowing for simpler downstream
purification to achieve a cell-free product. Stemming from previous studies on the
aforementioned cell culture capabilities, the goal is to optimize large-scale production of
monoclonal antibodies specifically by designing a fluidized bed bioreactor for high-
density, immobilized cell culture. Furthermore, it is expected that by enhancing the cell
culture conditions for more efficient cell growth, mAb production will compound,
therefore eradicating the need for increasing batch sizes.

While most mAbs are made on a small to medium scale for laboratory use, successful mAb
drugs used for medicinal treatment are responsible for a multibillion-dollar industry with
each mAb responsible for at least $1 million in sales for its respective companies (U.S.
Pharmaceutical Sales, National Research Council).

In particular, the plant will be designed to optimize the production of Humira
(Adalimumab), currently the number three drug on the market based on 2012 sales. Its
sales in 2012 reached $9.3 billion (U.S. Pharmaceutical Sales). The most recent quarter
saw a 10% increase since the first quarter and 2013 sales are projected to surpass $11
billion (King, 2013). Actual sales may surpass this estimate because the drug continues to
be approved for more diseases and expands into markets such as Japan and the European
Union. In 2010, the combined world market for rheumatoid arthritis, Crohns Disease, and
psoriasis totaled $22.2 billion. $6.55 billion were sales of Humira, accounting for 29%
market share (Nussbaum, 2011).

Based on 2012 sales of over 2.5 million packages sold, with each package including two
doses of 40mg of drug in 0.8mL solution, a fair estimate would be an estimated production
of approximately 200kg of drug in 2013 (FDA) for this plant.

In general, most purification processes for drugs involve multiple steps:

1. Filtration
2. Protein Chromatography
3. Viral Inactivation
4. Additional Chromatography
5. Viral Filtration
6. Ultrafiltration

Two different techniques can be tested for the purification method:

1. Use a traditional setup, outlined above, with permanent separators and vessels which
will require shutdown and a lengthy cleaning process. This method is currently used,
but is liable to interrupt batch production.

25
2. Consider disposable purification methods such as the disposable WAVE bioreactor
which can purify the product using a membrane with tangential flow. However, this
method has not been tested in conjunction with a fluidized bed production technique.
Also, repeatedly purchasing the disposable bioreactor may not necessarily be more cost
effective than using a traditional set up, depending on how frequently the bioreactor
would have to be replaced (WAVE).

After designing the manufacturing process, an economic analysis should be conducted to
determine the cost of the process and profit at the current selling price of Humira. This
economic analysis should also take into consideration the minimum market share needed
for the plant to be profitable and how profits will vary over time and in competition with
new drugs entering the market. In order to make an accurate analysis, it is also important to
consider the time needed to make each batch of drug, how often the plant has to be shut
down for cleaning (including maintenance and sterilization of all units), and the cost for
maintaining the equipment so that each batch is as consistent as possible.

A plant designed for drug optimization will rely upon accurate sizing of all units to
accommodate the type of cell culture used, expected production rate, and the extent of
purity required for the final drug. The plant will have to take into consideration the number
of units used as well, which will be determined for the targeted mass of drug required and
on current industry practices. Batch process may also require holding tanks, pumps, and
pipes which will have to be appropriately sized. The bioreactor will have to be heated and
cooled continuously to maintain a constant temperature.

The manufacturing facilities will include the process steps starting with the cell line and
medium developed by the research lab to produce the monoclonal antibody up to the final
purified product. Final formulation and packaging will take place offsite and are not
included in this design.

Regardless of changes made to current plant designs, all changes must adhere to the FDAs
stringent regulations and GMP in order to create a product that is safe, pure, and consistent.

References
Dutton, G. "Trends in Monoclonal Antibody Production." Genetic Engineering &
Biotechnology News. 15 Feb 2010
<http://www.genengnews.com/gen-articles/trends-in-monoclonal-antibody-
production/3193/>.

FDA. "Humira Docket." Dosage and Administration. Jan. 2003.
<http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_02_B-Abbott-
Humira%20Prescribing%20Info.pdf>.

Kelley, B.. "Industrialization of mAb production technology." Landes Bioscience. 1, 5
(2009): 443-452.
<http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759494/pdf/mabs0105_0443.pdf>.

26


King, S.. "The Best Selling Drugs of All Time; Humira Joins The Elite." Forbes, 28 Jan.
2013.
<http://www.forbes.com/sites/simonking/2013/01/28/the-best-selling-drugs-of-all-time-
humira-joins-the-elite/>.

Liu, H. F., J. Ma, C. Winter, and R. Bayer. "Recovery and Purification Process
Development for Monoclonal Antibody Production." MAbs 2, 5 (2010): 480-99.

National Research Council . Monoclonal Antibody Production. Washington, DC: National
Academy Press, 1999. eBook.
<http://www.nap.edu/openbook.php?record_id=9450&page=R1>.

Nussbaum, A. "Abbott Says Humira Gained Market Share in Crohn's, Psoriasis."
Bloomberg, 20 July 2011.
<http://www.bloomberg.com/news/2011-07-20/abbott-s-freyman-says-humira-gained-
market-share-in-crohn-s-psoriasis.html>.

Ohashi, R., V. Singh, et al. "Perfusion Cell Culture in Disposable." Wave Biotech. (2001).
<http://www.pacificgmp.com/Files/Perfusion_Cell_Cuture.pdf>.

"Pipeline." Genentech. <http://www.gene.com/medical-professionals/pipeline>.

Rodrigues, M., A. Rita, et al. "Technological Progresses in Monoclonal Antibody
Production Systems." Wiley InterScience. (2009).
<http://onlinelibrary.wiley.com/store/10.1002/btpr.348/asset/348_ftp.pdf?v=1&t=hjqcjrta&
s=34fa72d8bd3e2bf44b2e56377e7bccea55af954b>.

Simpson, C. M. "Cost Modeling for Monoclonal Antibody Manufacturing." MIT (2011).

"U.S. Pharmaceutical Sales - Q1 2013." <http://www.drugs.com/stats/top100/sales>.

Yamaguchi, M., Y. Shirai, et al. "Changes in monoclonal antibody productivity of
recombinant BHK cells immobilized in collagen gel particles." Cytotechnology. 23, 1-3
(1997): 5-12.
<http://link.springer.com/article/10.1023/A:1007959400666

Yang, S.T., J Luo, et al. "A fibrous-bed bioreactor for continuous production of
monoclonal antibody by hybridoma" (2004).
<http://www.ncbi.nlm.nih.gov/pubmed/15217104>.


27
11. Bio-Butadiene from Waste Carbon Monoxide
(recommended by Stephen M. Tieri, DuPont)

1,3-Butadiene is a material with a wide variety of applications in the arena of synthetic
materials and polymers; for the production of synthetic rubbers, as a copolymer additive,
and as an ingredient in rocket fuel. For your company, it is a critical feedstock to support
and maintain the continuity of Nylon 6,6 production, via nickel-catalyzed hydrocyanation
to produce adiponitrile (ADN). Previously, 2,3-butanediol (BDO) was a feedstock for
butadiene production for synthetic rubber; however, this production technology was
abandoned in favor of the more cost-effective naphtha-based technology route.

Current forecasts estimate 17-20% average annual growth for bioplastics through 2016,
driven by a mix of internal and external market forces. Your companys interest in
biopolymers is motivated by a number of factors; including consumer demand, a business
desire for feedstock diversification, the increasing price of fossil materials, as a hedge for
petroleum market volatility, and to positively impact global climate change.

Through research efforts and in cooperation with its partners, your company has developed
and acquired innovative technology to produce bio-based 1,3-butadiene by a two-step
process from carbon monoxide. The first step converts waste carbon monoxide via
fermentation to 2,3-butanediol (BDO). Specifically, the research group developed a
microorganism which is the catalyst and basis for this bio-based production route. The
second step thermo-catalytically converts the 2,3-butanediol to 1,3-butadiene. As the
butadiene from this technology has the identical structure and functionality of traditional
petrochemical butadiene, it serves as a direct replacement to produce renewably sourced
polymers without modifications to existing downstream equipment or processes. Early
technology successes resulted in supplemental research funding awarded through
government grants, which have provided partial funding for development and pilot
production programs.

There are a variety of potential sources to provide the necessary CO feed, including CO-
rich gas streams from thermochemical gasification of forestry and agricultural residues and
other types of waste. However, also, the source of CO can be an industrial process, such as
ferrous metal products manufacturing. Existing steel mills produce CO-rich gas streams,
which are well suited to complement your fermentation technology. An important
technology and business advantage is the input gas flexibility of your technology to utilize
any single or combination of four waste gasses from an integrated steel mill, a basic
oxygen furnace (BOF), a blast furnace, and coke-oven manufacturing processes.

Operation of the companys 2,3-BDO pilot plant has been extremely successful, achieving
all of its technology targets and goals. More specifically, the pilot plant demonstrated its
target production of 100 M gpy (M = 1,000), the capability to use raw steel waste gas,
and to tolerate the full range of gas contaminants. Additionally, the technology
demonstrated both the ability to tolerate variations in gas composition and achieved
production rate targets necessary for commercial viability.
28
Recovery and isolation of the intermediate 2,3-BDO from fermentation broth using
convention distillation separation techniques present significant challenges with respect to
process energy consumption, and subsequently economic competitiveness. Current devel-
opment studies in the area of separations indicate a high potential for chromatographic
separation, and/or membrane technologies, to provide the required 2,3-BDO isolation with
a significant reduction in energy requirements compared to distillation alternatives.

Many historical catalysts for dehydration of 2,3-BDO to 1,3-butadiene also produce, and
potentially favor, methylethylketone (MEK). While both butadiene and MEK produced
from your Bio-BDO are valuable monomers, your main interest is in butadiene to support
ADN production. Your partners catalyst technology group has identified and developed
new commercially-viable heterogeneous catalysts for the thermo-catalytic conversion of
butadiene, and is continuing work to optimize conversion, selectivity, and yield.
Demonstrated conversion data for preliminary catalyst formulations production is included
in the table below.

Product BDO Conversion Selectivity Yield
1,3-Butadiene 94% 49% 66% 33% 61% 21%

Now that the research, development, and pilot-plant teams have succeeded in achieving
their milestone targets, corporate leadership is eager to proceed to design the first
commercial-scale production facility. Your company and its technology-development
partners intend to use this technology to attract additional investors and industrial partners
for both feedstock supply and sustainably branded intermediates and polymers. Your
company expects to build and operate this commercial facility, in addition to some future
sister facilities, and does not currently plan to license this specific technology as an
additional revenue source.

Your project team has been assembled to commercialize this new sustainable technology
and design the first commercial-scale plant. Its business objective is to design a
commercial-scale facility to produce polymer grade 1,3-butadiene from raw steel plant
waste gas from an integrated steel manufacturing facility. Your Bio-Butadiene production
facility will be co-located with an existing steel/ferrous metal production plant. Your team
will need to identify the optimal Bio-Butadiene plant capacity/scale for economic viability,
for maximum profitability, and for matching the waste gas supply capacity from an
integrated steel mill, and to quantify the economic sensitivity of the process design and
scale. While the current business intention is to target medium to large-size steel mills for
future facilities, the scope of your teams work includes verifying the extent to which this
steel mill capacity range is a reasonable target. The 1,3-butadiene product purity and
quality will need to meet or exceed current commercial requirements for polymer grade
material, to be acceptable for internal use and for additional sales to perspective external
customers. As your technology has the potential for global application, the business team
is interested in understanding the potential economic differences between locating on
existing steel production sites in China, Japan, and the United States; and to identify the
optimal location for the first plant.
29
The plant design should be as environmentally-friendly as possible, as required by state
and federal emissions legislation. Process materials should be recovered and recycled to
the maximum economic extent. Also, energy consumption should be minimized, to the
extent economically justified. The plant design must also be controllable and safe to
operate. As the process technology integration and design team, you will be there for the
start-up and will have to live with whatever design decisions you have made.

Undoubtedly, you will need additional data and information beyond that given here and
listed in the references below. Cite any literature data used. If required, make reasonable
assumptions, state them, and quantify the extent to which your design or economics are
sensitive to the assumptions you have made.

References
US 20120045807 A1, Process for producing chemicals using microbial fermentation of
substrates comprising carbon monoxide
US 20130177955 A1, Process for production of alcohols by microbial fermentation
WO 2013115659 A2, Recombinant microorganisms and methods of use thereof
US 20130203143 A1, Methods and Systems for the Production of Hydrocarbon Products
Continuous SMB separation of Ethanol and other Oxygenates from Fermentation broth;
http://www.orochem.com/index.php?route=product/categoryinfo&path=3_21_149
2,3-Butanediol, M. Voloch, et al., https://www.msu.edu/~narayan/2-3-Butanediol.pdf
http://petrofed.winwinhosting.net/upload/19-
20%20April%202012/Presentations/Session%203/4_Prabhakar%20nair.pdf
http://www.alternativefuelsworldwide.com/presentations/LanzaTech_JH_Presentation_P
aris_16x9final.pdf
http://www.icis.com/blogs/green-chemicals/2012/08/invista-lanzatech-on-bio-butad/
30
12. 1,3-Propanediol from Crude Glycerol
(recommended by Richard Bockrath, Consultant formerly DuPont)

Background
You work for a Chinese chemical company which supplies intermediates to fiber and
plastic producers. Your company has been working with a local institute to develop a
process for manufacturing 1,3-propanediol from crude glycerol. Your company has
assembled your team to develop a plant design and economic estimate for a 100MM lb/yr
PDO plant based on crude glycerol using the research results from the institute.

Current Situation
1,3-Propanediol (PDO) is used as a monomer, along with terephthalic acid, in
polytrimethylene terephthalate (PTT). PTT, used in fiber and resins, has physical
properties similar to nylon and chemical properties similar to polyethylene terephthalate.
PDO also has many other applications in resin, fiber, and specialty chemicals markets.
These markets are very large and therefore attractive.

Shell and DuPont produced PDO via a chemical route in the 90s and early 2000s. In 2006,
however, DuPont commercialized the first large-scale industrial fermentation to make a
bulk chemical PDO in a joint venture called DuPont Tate & Lyle Bioproducts in
Loudon, TN. The fermentation process uses 40% less energy than the chemical route,
produces fiber grade product of higher purity than the chemical route, and uses a renewable
resource as feedstock. The feedstock was 95DE (dextrose equivalents 95%) corn syrup.
The 95DE is a commodity that can be purchased for $0.12/lb from a corn wet mill.

In addition to the 95DE, the organism requires a variety of nutrients, mostly inorganic salts.
The fermentation is aerobic. Ammonia is the preferred nitrogen source for the organism.
The overall fermentation reaction may be written as:

37 Glucose + 3 NH
3
+ 10 O
2
= 50 PDO + 3 Biomass + 60 CO
2
+ 16 H
2
O

Since its commercialization, the JV has made very large quantities of 1,3 PDO for the
polyester fiber and other major markets. The markets are now firmly established and new
entrants such as your company want a piece of the pie. PDO is currently priced at about
$1.00/lb.

Glycerol Feedstock Alternative
Over the last few years, Chinese institutes have begun to develop fermentation routes
based on glycerol as the feedstock. Glycerol is in abundance in many locations (especially
Asia due to Palm Oil production) since it is a by-product of biodiesel manufacture. While
its price is very depressed right now due to lack of outlets, smart people quickly find uses
for excess, free materials and so prices will rise over time. You will need to look at the
cost of manufacture over a range of crude glycerol prices. Also since the glycerol is the
low end by-product, all of the impurities from bio-diesel manufacture tend to be in it. You
will have to decide if you can use it as is or if it needs to be distilled to a higher quality.

31
Sterility in the fermentation area will be a significant concern. Suitable measures must be
taken to ensure that no adventitious organisms enter the process, eating feedstock and
generating undesired products. Everything entering the fermenter must be sterile, except of
course for the inoculum.

The organism is a genetically engineered microbe. Physical containment and control
technology must, at a minimum, comply with the Chinese equivalent of The Toxic
Substances Control Act (TSCA) Part 725.422. Facilities must be designed to physically
contain the live organism. It is unlikely that the highly engineered organism could survive
in the wild. Nonetheless, prior to removal from containment, the organism must be
deactivated or killed and then properly disposed of. Landfill is adequate for final disposal.
Likewise, operating vents and spills that could contain live organism are to be contained
and treated. The operating vent could be treated with a scrubber using a low concentration
of bleach. Spills could be sent to a tank and heated to sterilization temperature prior to
discharge.

Between fermentation batches, the fermenter is cleaned and sterilized to begin another
batch. Your design may include multiple fermenters. You also need to provide facilities to
grow the organism beginning each batch with a 1 mL vial in the lab containing 10 mg of
live organism.

After fermentation, the biomass may be filtered from the broth, but a filter aid is needed to
make the filter cake easier to handle. It is your decision as to whether the cells should be
disrupted. If the cells are not disrupted, a 1% PDO yield loss may be assumed to occur due
to PDO inside the cells. However, the whole cells would also contain about 90% of the
salts added as nutrients at the beginning of the batch.

The filtered broth may be ion exchanged to remove the remaining salts, using a mixed-bed
system. The broth may also be concentrated in an evaporator at any point in the process,
reducing the equipment size, but increasing the energy consumption. If you concentrate
beyond about 5:1, you should consider boiling point elevation both by the PDO and the
salts, as well as salt solubility limits. Reverse osmosis could also be considered for
removal of the salts.

The refining process must purify the product to its final specification as shown in Table 1.
Distillation is considered a reasonable approach, as long as temperatures are held below
170C.
Table 1. PDO Specifications

Specification Value
Purity on dry basis, wt% 99.98
Glycerol, ppm 50
Mono-functional alcohols, ppm 500
Water, ppm 500
Metals, ppm 0.5
Appearance Clear
32

The plant design should be as environmentally friendly as possible. Recover and recycle
process materials to the maximum economic extent. Also, energy consumption should be
minimized, to the extent economically justified. The plant design must also be controllable
and safe to operate. Remember that you will be present for the start-up and will have to
live with whatever design decisions you have made.

References

U.S. Patent 8,507,250, Liu, et al. August 13, 2013, Methods and genetically engineered
micro-organisms for the combined production of PDO, BDO and PHP by fermentation

U.S. Patent 8,486,67, Liu , et al. July 16, 2013 , Method for producing 1,3-propanediol
using crude glycerol, a by-product from biodiesel production