Computers and Chemical Engineering 34 (2010) 10091017

Contents lists available at ScienceDirect

Computers and Chemical Engineering

journal homepage: www.elsevier.com/locate/compchemeng

Review

Bioprocesses: Modeling needs for process evaluation and sustainability

assessment
Concepcin Jimnez-Gonzlez a , John M. Woodley b,
a

GlaxoSmithKline, Sustainability and Environment, 5 Moore Drive, CS.1152, Research Triangle Park, NC 27709-3398, USA
Center for Process Engineering and Technology, Department of Chemical and Biochemical Engineering, Technical University of Denmark,
Sltofts Plads, DK-2800 Lyngby, Denmark
b

a r t i c l e

i n f o

Article history:
Received 3 September 2009
Received in revised form 14 March 2010
Accepted 17 March 2010
Available online 25 March 2010
Keywords:
Bioprocesses
Biocatalysis
Fermentation
Modeling
Simulation
Life cycle assessment (LCA)
Environmental footprint
Sustainability

a b s t r a c t
The next generation of process engineers will face a new set of challenges, with the need to devise new
bioprocesses, with high selectivity for pharmaceutical manufacture, and for lower value chemicals manufacture based on renewable feedstocks. In this paper the current and predicted future roles of process
system engineering and life cycle inventory and assessment in the design, development and improvement of sustainable bioprocesses are explored. The existing process systems engineering software tools
will prove essential to assist this work. However, the existing tools will also require further development
such that they can also be used to evaluate processes against sustainability metrics, as well as economics
as an integral part of assessments. Finally, property models will also be required based on compounds
not currently present in existing databases. It is clear that many new opportunities for process systems
engineering will be forthcoming in the area of integrated bioprocesses.
2010 Elsevier Ltd. All rights reserved.

Contents
1.
2.
3.

4.

5.
6.
7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
Industrial biotechnology processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
3.1.
Fermentation processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
3.2.
Microbial catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
3.3.
Enzyme processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
The role of process systems engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
4.1.
Evaluation of process options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
4.2.
Evaluation of platform chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
4.3.
Process integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
4.4.
Biorenery design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
4.5.
Biocatalyst design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
Assessing the sustainability of bioprocesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
5.1.
Life cycle inventory and assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014
Mapping modeling needs of bioprocessesan example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016

1. Introduction

Corresponding author.
E-mail address: jw@kt.dtu.dk (J.M. Woodley).
0098-1354/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.compchemeng.2010.03.010

Process systems engineering offers many tools for the chemical engineer. Today, for example, modeling, simulation and process
evaluation tools are routinely applied to optimization problems in

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C. Jimnez-Gonzlez, J.M. Woodley / Computers and Chemical Engineering 34 (2010) 10091017

the bulk chemicals and fuels sector, where small process improvements yield signicant economic returns. In the last 20 years
bioprocesses have become more common. In particular they have
found application in the production of high value products such as
pharmaceuticals (and their intermediates). The process engineering emphasis in these cases is on rapid process implementation
(rather than optimized development). However, in recent years
bioprocesses have also been applied to bigger volume products
such as ne chemicals, bulk chemicals and fuels. In these cases process improvement is the emphasis since this will yield signicant
returns. In addition to the direct process improvements, bioprocesses have also frequently been justied on the basis that they
are processes with potentially lower environmental impact than
their chemical synthetic counterparts. The main synthetic operations in bioprocesses include fermentation, microbial catalysis
and enzyme catalysis. Downstream options are dependent on the
nature of the product (macromolecular or low molecular weight
compounds (small molecules)). Small molecules are frequently
processed in a similar way to other chemical products, although
dilute aqueous solutions bring specic problems which need to be
addressed, both from the viewpoint of process optimization and the
environmental footprint. For instance, the downstream processing
of some small molecule bioprocesses could include large amounts
of organic solvents for extraction from aqueous solutions. In these
cases, the organic solvents require processing, recycle, control and
ultimately safe disposal. Macromolecules require more specialist
operations such as ltration or chromatography. However, in all
cases the molecules are frequently sensitive to extremes of pH and
temperature, placing specic restrictions and constraints on processing methods. Biocatalyst recovery (frequently for recycle) also
necessitates ltration and centrifugation.
From this discussion it is clear that engineers and others
involved in implementing new processes need to address a range
of questions. For example: when should a bioprocess, rather than a
chemical process, be implemented? If a bioprocess is to be implemented, can the existing infrastructure (feedstock, utilities and
plant) be used? How can process plant be adapted for different
biomass in different geographical regions? What is the optimum
biorenery? What options exist for process integration? What are
the environmental, health and safety issues of bioprocesses in comparison with chemical processes? What is the environmental footprint of a bioprocess compared with its chemical counterpart? How
can bioprocesses be designed to maximize process efciency, minimize environmental impact, as well as maximize sustainability?
Many of these questions can currently be addressed qualitatively, but to have real value it is necessary to assess the questions
on a quantitative basis. In order to achieve this effectively therefore,
computer-based tools are required. Over the last decades, process
systems engineering has already developed many of the appropriate tools. Nevertheless, some further developments are required.
For example, in the case of bioprocesses an extra option available to
the engineer is the improvement of the catalyst itself. This requires
models which take into account catalyst properties. In addition, one
can see life cycle inventory and assessment (LCI/A) modeling tools
and methods as a logical extension of process systems engineering. LCI/A methodologies allow for the estimation of environmental
impact across the entire life cycle of a process or product. LCI/A estimations rely heavily on the characterization of the process and its
unit operations using process systems engineering modeling and
simulation techniques.
Hence we are now at the point where process engineering tools
need to be applied to the complete set of bioprocesses, including pharmaceuticals, ne chemicals, bulk chemicals and fuels. In
this paper the specic role of process systems engineering and life
cycle inventory and assessment in the development, design and
improvement of sustainable bioprocesses will be discussed.

2. Scope
Biotechnology is an enormous sector of industry from high
value, low volume products (such as pharmaceuticals) to low value,
high volume products (such as biofuels). To date the majority of
implemented bioprocesses have focused on the former group. The
emphasis here has been on implementing processes effectively to
meet the tough regulatory demands placed on such products. Rapid
process implementation, rather than optimization, has been the
necessary focus of process engineering (e.g. Pollard & Woodley,
2007; Woodley, 2008). The latter group of bio-based products (and
associated processes), represent a different challenge. These are
the new sectors of industrial (also called white) biotechnology
where new opportunities exist for alternative feedstocks based on
renewable resources such as biomass and clean processes with
reduced solvent inventories, renewable catalysts and mild conditions for reaction and separation (e.g. Dale, 2003). Here there
remain some signicant hurdles to achieve full-scale implementation. For example, for cost-effective synthesis one can start from
fermentation of starch or sugars (ultimately from biomass given
suitably cost-effective pretreatment). However, fermentation by its
very nature is a rather inefcient process with a signicant amount
of substrate/reactant required for cell energy, cell growth and
other products. This inherent weakness for use in chemical synthesis has stimulated genetic and metabolic engineering methods to
improve strains. A parallel development with protein engineering
has developed around enzymatic catalysis. Furthermore, the new
bio-economy will require the development of a suitable infrastructure and, like the oil-based counterpart will demand very high
yield processes meaning that process engineering for the future
implementation and development of these processes will have an
increasingly important role, alongside the biological methods for
biocatalyst improvement. In addition, the timely identication of
environmental, health and safety issues to be managed will be crucial to facilitate the development of sustainable bioprocesses. Most
importantly it is imperative that any claims of greenness are considered in the wider framework of sustainability. Attempting to
assess and compare the sustainability of bioprocesses must have a
holistic scope based on life cycle thinking, which is strongly based
on the output of systems engineering modeling and simulation
techniques. Given the maturity of the eld of process systems engineering it is clear that many new opportunities will be forthcoming.
3. Industrial biotechnology processes
Three major types of bioprocess can be identied dependent on
the nature of the biocatalyst. These are outlined beneath and the
key process features are outlined in Table 1.
3.1. Fermentation processes
For a signicant number of chemicals, the use of fermentation has become a standard alternative to fossil-based feedstocks
and technology. Nevertheless the possibility of growing microbial
cells on a variety of sugars (derived from renewable biomass) has
re-invigorated interest in this area. The consequence is that fermentation at a large-scale will become more common in the future
chemical industry. Many different types of fermentation process
(using different strains to produce different products) can take
place in the same process plant which is a signicant advantage. The
plant is relatively simple and the challenges lie in adequate mixing
(sometimes with materials having complex rheology), suitable oxygen input (for aerobic processes) and process control. Downstream,
the separation process depends on the product, but will nearly
always need to avoid high temperatures and extremes of pH. The
solvent is water, meaning that the dilute product stream combined

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Table 1
Process features of the three major types of bioprocess for chemicals production. (I) represents options for immobilized enzyme.
Feature

Fermentation

Microbial catalysis

Enzymatic catalysis

Yield on substrate
Catalyst recycle

Low
Potentially via a continuous process

Medium
Via ltration

High
Via immobilization

Reactor options

Stirred tank
Bubble column

Stirred tank
Bubble column

Stirred tank
Packed bed (I)
Fluidised bed (I)
Membrane

with the presence of many other products presents a signicant

process engineering challenge. Both large molecular weight and
low molecular weight products can be made by fermentation. The
processes either focus on low molecular weight products which can
subsequently be used as platform chemicals or fuels or high molecular weight compounds such as enzymes (for application in a range
of industries, including detergents, textiles and food ingredients) or
therapeutic proteins.

been widely used to assist in the synthesis of high value compounds such as pharmaceuticals and a more limited number of
well-known lower value products such as high fructose corn syrup
(HFCS). Many of these processes have also been modeled (e.g. Chen,
Baganz, & Woodley, 2007). Enzymatic processes can also be carried
out using soluble enzymes (i.e., non-immobilized), although these
present challenges in terms of separating and recycling the catalysts (enzymes) when compared with the immobilized enzyme
processes.

3.2. Microbial catalysis

In fermentation, by denition, the catalyst is growing during the
process. This means that some of the reactant (or substrate) will
inevitably be diverted from the product towards the catalyst, lowering the yield. An alternative (for non-growth associated products)
is to grow the cells rst and subsequently carry out the reaction
to increase the yield. This also enables the possibility of growth
and reaction on different substrates (reactants) or under different
conditions (such as temperature or pH) in each stage. Likewise the
optimal cell concentration for conversion can be selected (Woodley,
2006) after growth and suitable media for effective product recovery have been chosen. For processes requiring oxygen it can be
highly important to select the optimal cell concentration in order
to avoid mass transfer limitations. Several tools are now available
for evaluating the oxygen supply issues in such reactions (Baldwin
& Woodley, 2006; Law, Baldwin, Chen, & Woodley, 2006). The three
potential routes using microbial catalysis are shown in Fig. 1.
3.3. Enzyme processes
The presence of so many products at the end of fermentation
or microbial catalysis is a consequence of the complexity of cells,
where many enzymes catalyze reactions giving a spectrum of products as well as decreasing the yield of the desired product on
the reactant. An alternative, for short pathways, is to isolate the
enzymes and then immobilize them on a solid support or behind
a membrane or via aggregation, such that they are large enough
and have the right properties to be recycled (like a heterogeneous
catalyst). In this way a yield of product on the catalyst of around
510 tonnes/kg immobilized biocatalyst can be achieved, which
typically enables industrial implementation. Such an approach has

4. The role of process systems engineering

4.1. Evaluation of process options
For some higher value products a bioprocess may be the only
route to a given product (to ensure correct folding of a therapeutic
protein for example or the synthesis of an optically pure pharmaceutical intermediate). However, the more usual situation is
that there are other competing routes to the same product. Therefore, for now, biotechnology is just one of a number of options
for the production of chemicals and fuels. The economic drivers
for implementation depend on existing infrastructure, feedstock
costs, feedstock availability as well as the efciency of the relevant
(bio)catalyst and (bio)process technology. At the same time, there
are environmental drivers and, in the wider sense, sustainability
drivers for the selection of different process alternatives.
One example of the current applications of process systems
engineering is the estimation of global warming potential and the
design of processes that minimize this impact. Glasser, Hildebrandt,
Hausberger, Patel, and Glasser (2009) for instance have recently
proposed using process systems engineering tools such as mass
and energy balances, thermodynamics and process work balances
to minimize energy use and green house gas equivalents. This is an
example of how process system engineering together with thermodynamics can be used to set metrics and targets against important
aspects or impacts. It is also an example of current methodologies that tend to focus on one impact and its corresponding leading
metric (in this case, energy consumption).
However, the sustainability drivers normally cover several
impacts and are by no means simple, as they require the balance
of different sets of goals and metrics that can present trade-offs in

Fig. 1. Alternative process scenarios for use of microbial cells for non-growth associated biocatalysis. (Route 1combined fermentation and microbial catalysis; Route
2fermentation separated from microbial catalysis; Route 3fermentation separated from microbial catalysis with intermediate processing to change catalyst concentration.)

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some cases. Objective functions to be optimized should not exclusively be based on economics but increasingly also on sustainability
metrics (e.g. Henderson, Jimenez-Gonzalez, Preston, Constable, &
Woodley, 2008) and integrated with life cycle analysis. This will
need to include evaluation of feedstocks and products as well as
processes, including energy and mass integration. This presents a
fascinating set of alternative routes and technologies from a given
feedstock and/or to a given product(s). Process systems engineering
has a particular role to enable such evaluations on a quantitative
basis, not only from the process perspective, but also from the wider
sustainability aspect. Quantitation is key since it enables rigorous
comparisons and assessments, which build condence in decisionmaking. Process systems engineering also brings the advantages
of rapid computational methods. Such simulations allow alternatives to be quickly evaluated. This is important to enable the use of
tools early in process and product development. Finally, the answer
in a specic case to the problem formulated here will in addition
depend on regional factors. Feedstock availability and cost is highly
dependent on geographical location. A parallel set of evaluations
concerning the need to retrot existing plant, or build new plant,
is also required.
4.2. Evaluation of platform chemicals
While the increasing cost of oil is driving particular interest
in the production of new fuels from biomass there is little doubt
that today of equal importance is the production of chemicals from
biomass. Indeed for the supply of fuels in the future there are many
potential sources aside from biomass. In a world with limited (or
very expensive) oil it is less clear where the chemicals of the future
will originate. There is currently an existing infrastructure based on
the use of the seven established platform chemicals (toluene; benzene; xylene; 1,3-butadiene; propylene; ethene; methane). In the
short term one could consider if we can use the same infrastructure
and just create the seven chemicals from alternative sources. However, in the longer term it will be necessary to devise new processes
based on a different set of platform chemicals. One group will be
based around glucose (the hydrolytic product of starch and cellulose and therefore readily available from biomass). In a biorenery
it will be necessary to develop a structure which can manage a range
of feedstocks, a range of technologies and a range of products. This
presents a considerable challenge for design and optimization as
well as process integration. An interesting example which illustrates the complexity and the challenge that lies ahead is the use
of glucose or fructose to produce 5-hydroxymethylfurfural (HMF)
or 2,5-furandicarboxylic acid (FDA) (Boisen et al., 2009). Greatest
value is obtained by going the whole way from glucose to FDA.
However even in this small reaction pathway there are many alternative technologies. Some can be integrated together, some give the
required yield and selectivity, some are difcult to implement and
others are untested at scale. This illustrates very well the challenge
that design engineers face.
4.3. Process integration
The primary solvent for most bioprocesses, with a few exceptions, is water. Consequently the downstream process is frequently
difcult and this is emphasized by the need to carry out separations at moderate temperatures. Given the dilute nature of the
streams it is frequently the case that the majority of the costs
and environmental, health and safety impacts are therefore in the
downstream process. The dilute nature of the streams has historically also driven the need for energy-intensive separation. For
instance, in some ne chemical and pharmaceutical applications
of biocatalysis, large amounts of organic solvents may be used in
the extraction and purication of products from an aqueous biocat-

alytic reaction stream. For higher volume products, such as liquid

fuels, removal of water becomes an essential requirement to reduce
costs and avoid transporting signicant amounts of water. In other
cases the product may be integrated within a biorenery concept
although at some point water will need to be removed. Consequently the integration of water use, and reuse via recycle, is an
essential part of the design of industrial bioprocess facilities. In
addition, bioprocesses need to be designed with process synthesis
and process integration approaches, thus avoiding a process that
is efcient in one part and inefcient in another. Existing tools of
mass and energy integration such as pinch technology will have
an important role. The issue of water integration in a biorenery
is in many ways analogous to the issue of heat integration in a
conventional renery.
4.4. Biorenery design
Two major types of biorenery have been identied for the
future, based on lignocellulose biomass utilization to provide a
range of sugars (for subsequent (bio)catalysis or fermentation) and
oil-based material (from biomass). In each case the current research
emphasis on bioreneries is to ensure all the fractions of a particular biomass in a given situation are fully exploited. Likewise
the development of downstream products is now being explored.
For example glycerol (as a byproduct of biodiesel production) can
be used as a platform chemical (for example via fermentation to
produce 1,3-propanediol). Another interesting example concerns
the production of bio-ethanol. This is widely developed as a fuel
although there is considerable economic incentive for developing a range of other products (e.g. acetic acid) from ethanol, in
other words using it as a platform chemical (Rass-Hansen, Falsig,
Jrgensen, & Christensen, 2007). It is clear that evaluating integration of product and feed streams in this way, as well as the use of
products as fuels or platform chemicals will be an important role
for process systems engineering. From the sustainability viewpoint,
the utilization of lignocellulosic material has perhaps the highest
desirability, since these materials are typically of low value as a
waste from other processes (e.g. bagasse). There is little doubt that
the increasing range of technologies and opportunities as a result
of enzyme-based or fermentation-based catalysis will give complex
integration problems, which may require new tools.
4.5. Biocatalyst design
A particular feature of bioprocesses is the use of biocatalysts,
which may exist in several forms as indicated earlier and where
options exist for modication. At the simplest level as a protein (isolated enzyme), the options for swapping amino acids via protein
engineering exist. New enzymes which have been modied may
display new tolerance to reactor conditions such as temperature or
pH and may also have improved selectivity or reactivity (activity)
on a given (non-natural) substrate or reactant. Order-of-magnitude
improvements have been found in a number of cases although
understanding the most effective method of making changes to
the enzyme depends on past precedent and, to some extent, structural knowledge (e.g. Hibbert et al., 2005). In the case of microbial
catalysts, individual enzymes can be over-expressed (increasing
reaction rate of a given cell) and the regulatory control scheme xed
to direct the carbon to give improved rates and yields (via metabolic
engineering). Some start has also been made to the development
of pathways where enzymes coming from a variety of sources are
cloned into single host to make a new pathway via a combination of
genetic engineering and de-novo pathway engineering (e.g. Chen et
al., 2006). In all these areas it is clear that those involved in process
systems engineering need to inform the biological engineers about
what is required in a given case and set suitable targets. Philosophi-

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1013

Fig. 2. The three spheres of sustainability through a triple bottom line assessment.

cally it is interesting to note that process implementation may come

via process improvements or alternatively via catalyst improvements. In many cases both will be required. Understanding the
necessary balance between these areas, as well as their integration with each other will be important for the future development
of the eld. Process systems engineering is particularly powerful in
its ability to predict and can therefore be used to direct decisionmaking and process development.
5. Assessing the sustainability of bioprocesses
As discussed before, bioprocesses have frequently been highlighted as greener chemistry or engineering, since they address
many of the green chemistry and green engineering principles
(Anastas & Warner, 2000) by offering reactions that are potentially
more atom economic, operate under mild conditions, use mostly
non-hazardous chemicals and have less protection/deprotection
steps. However, this tends to be true mostly when looking at
the reaction part of the process, in other words, the biocatalysis.
However, it cannot be generalized when analyzing the entire process that in some cases may include the use of a large amount of
organic solvents for downstream processing. This is one of the areas
in which systems engineering, in conjunction with a transparent
application of life cycle inventory and assessment methodologies
can (and must) play a pivotal role.
Determining whether a process is sustainable (or green) is by
no means a simple feat. It is more akin to a multi-variable optimization that is very familiar to systems engineers, and for which
several proposals and methods have been presented (Carvalho,
Gani, & Matos, 2006; Gani, Jrgensen, & Jensen, 2005; Grossmann &
Daichendt, 1996; Uerdingen, Gani, Fisher, & Hungerbuhler, 2003).
For an objective assessment of the sustainability of a process, there
is the need to utilize the tools that system engineers have developed during recent years and apply them with a life cycle approach.
It is necessary to move from the basic analysis of the biocatalysis by
itself (or reactions) and discreet unit operations (separations) and
use a systems engineering approach. This implies utilizing multivariate optimization techniques coupled with life cycle assessment
methodologies for a more objective analysis of their greenness or
sustainability. This would allow us to develop bioprocesses that are
sustainable by design, in such a way that they:
optimize the use of material and energy resources,
eliminate or minimize environment, health and safety hazards by
design, and
integrate life cycle thinking in the design.
In a more general sense, sustainable bioprocesses in particular,
and processes in general are/will be the processes that:

minimize environmental impacts,

are economically viable, and
are socially responsible (OECD, 2002).
Analyzing and comparing sustainability will require a comprehensive assessment that balances the three different spheres
of sustainability (see Fig. 2). This can only be achieved through
a multi-variate optimization that will account for environmental
performance, economic viability and social responsibility (which
includes health and safety aspects). In addition, these assessments
need to leverage the tools of systems engineering to ensure the integration of a holistic approach that considers the entire life cycle of
the process.
Another important concept when assessing the efciency and
the sustainability of processes is the differences between new
process performance and retrot performance. For instance, in
comparing the sustainability or performance of a well-known process with a new bioprocess, a situation that one often encounters
is the fact that initially, the new process may not have the same
level of performance as the established technology, mainly because
they are at different points in the development curve, and therefore
the new process is sub-optimal. On the other hand, the established
process can be retrotted to increase its performance. Retrotting
and new process development is not a new concept from the systems engineering viewpoint. However, additional modeling work
is needed to estimate the achievable performance limits of a
fully developed process and an established process that undergoes retrot. This will allow more meaningful comparisons without
unnecessarily penalizing the new process for its lack of development, or the established process for the lack of timely retrotting.
In the recent past there have been many attempts to measure the
greenness of synthetic routes, and the approaches have generated
a series of green metrics. Most of the approaches have searched for
a simple metric in an attempt to provide a low resolution view of
how green is a given process. E-factor was one of the rst measures
of greenness proposed to highlight the amount of waste generated in order to produce 1 kg of product (Sheldon, 1992, 2007). This
metric, while simple to understand, has several key drawbacks by
focusing on waste instead of efciency, neglecting a view of the type
of waste generated, not accounting for the relative impacts, and the
lack of life cycle thinking. For instance, bioprocesses have in general
large amounts of wastewater produced, which would indicate an
extremely large E-factor, but at the same time the actual impact of
the efuent might not be as large as an E-factor would suggest, since
the waste is relatively benign. Additional metrics have focused on
efciency, especially on mass efciency (or its inverse, mass intensity) which addresses the rst part of the disadvantages of the Efactor (Constable, Curzons, & Cunningham, 2002; ACS GCI PR, 2008;
Constable, Jimenez-Gonzalez, & Lapkin, 2008). However, it has been
widely recognized that measuring the sustainability or even the

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C. Jimnez-Gonzlez, J.M. Woodley / Computers and Chemical Engineering 34 (2010) 10091017

greenness of a process is a multi-objective optimization problem

that must take into consideration the efciency of the entire process regarding the use of mass and energy, the environment, health
and safety characteristics of materials, and the inclusion of life cycle
thinking amongst others (Constable et al., 2001).
Some efforts have been made to comprehensively address and
compare the sustainability of processes in general and bioprocesses in particular. These methodologies have been employed in
some instances to assess the sustainability, environmental, health
and safety aspects of bioprocesses (Cowan, Oxenbll, & Holm,
2008; Jimenez-Gonzalez, Constable, Curzons, & Cunningham,
2001; Jimenez-Gonzalez, Constable, Curzons, & Cunningham, 2002;
Jodicke, Zenklusen, Weidenhaupt, & Hungerbuhler, 1999; Kim &
Dale, 2005, 2006; Kim, Jimenez-Gonzalez, & Dale, 2009; OECD,
2002; Patel et al., 2006; Wolf, 2005). These methodologies attempt
to measure the sustainability of bioprocesses and in some instances
they compare bioprocesses with their chemical alternatives.
For instance, a technology comparison framework (JimenezGonzalez et al., 2002) that accounts for environment, health, safety
and life cycle assessment impacts, was used to compare the established chemical process and a two-enzyme biocatalytic process
for the production of 7-ACA (Henderson et al., 2008). The conclusion of this assessment was that the bioprocess was greener
when compared with the chemical process. This was driven by
the fact that the chemical process uses more hazardous materials,
requires about 25% more process energy than the enzymatic process and, has a larger life cycle environmental impact: for instance,
uses approximately 60% more energy, 16% more mass (excluding
water), has double the greenhouse gas impact and about 30% higher
photochemical ozone creation potential and acidication potential
impacts. However, although this type of assessment is useful and
more common as time passes, there is an ongoing need for modeling methodologies that will seamlessly integrate sustainability
factors during bioprocess design and development. Normally economic factors are an integral consideration, and since the 1970s
environmental factors at the unit operation and sometimes process
levels have been considered. Nevertheless the need for integrating and embedding sustainability principles into bioprocess design
still remains an area of opportunity for process engineers. Systems
thinking and systems engineering are the skill and the discipline
that will need to play an important role to make this happen, and a
holistic view of bioprocesses and their interrelations will be imperative.
5.1. Life cycle inventory and assessment
One of the tools to analyze systems holistically is life cycle inventory and assessment (LCIA). LCIA is a methodology used to evaluate
the environmental prole of an activity or process from the extraction of raw materials to its end-of-life. The resource consumption
and emissions are inventoried and assessed from the perspective of
extraction of raw materials, production, transportation, sales, distribution, use, and nal fate (Fig. 3). Depending on the goal and
scope of the assessment, the boundaries can be set differently; for
instance a cradle-to-gate assessment might be adequate when
comparing two alternative processes to the same product; or a
gate-to-grave assessment may sufce when comparing two different end-of-life technologies. The results of these assessments
can be reported as direct inventory data (for example life cycle
energy, life cycle mass, life cycle emissions), measures of individual
potential impacts (such as global warming or acidication), or as
an aggregate score or index for high-level comparison (for example
Eco-Indicator 99). LCIA methodologies and standards are described
in detail in the literature (CML, 2002; Heijungs, 1992; Hendrickson,
Lave, & Matthews, 2006; ISO, 1997, 2006; PR Consultants, 2001;
US EPA, 2003).

Fig. 3. Life cycle assessment to evaluate the environmental prole of a process from
the extraction of raw materials, production, transportation, sales, distribution, use,
and nal fate.

LCIA methodologies are in a way an extension of systems engineering and provide a directly applicable framework to assess
the sustainability of processes. In addition to the traditional environmental life cycle assessment (which has increasingly included
health and safety impacts), life cycle costing (LCC, or total cost
assessment, TCA) and the more recent social life cycle assessment (SLCA) attempt to complete the holistic view of sustainability
(Heinrich, 2006; Hochschorner & Finnveden, 2006; Hunkeler &
Rebitzer, 2005; Jrgensen, Le Bocq, Nazarkina, & Hauschild, 2008;
Jrgensen, Hauschild, Jrgensen, & Wangel, 2009; Klpffer, 2003;
Rebitzer & Seuring, 2003).
In the area of bioprocesses, the application of LCIA is still not a
widespread practice. There are however, examples on how several
practitioners have applied LCA metrics primarily using case studies
to better understand the wider environmental implications of bioprocesses and to compare them with chemical routes. This type
of assessment has provided some key insights, such as the role
of separations, a more systematic and holistic method to evaluating waste impacts, and the nuances of renewability (Cowan et
al., 2008; Kim & Dale, 2005, 2006; Patel et al., 2006; Vink, Rabago,
Glassner, & Gruber, 2003; Wolf, 2005). For instance, a comparison
of a process using metal catalysts and one using biocatalysts for
the enantioselective reduction of ketoesters in pharmaceutical synthesis was performed using a streamlined LCIA methodology. The
analysis identied unit operations and reaction conditions that had
the largest signicance on the impact of the synthesis. It was also
concluded that whether the metal catalysts were better than biocatalysts depended mainly on the work-up from the use of organic
solvents and energy-intensive steps (Jodicke et al., 1999).
One typical example of the application of LCIA is the relationship of bioprocesses and the utilization of renewable resources.
While the use of renewable resources is indeed a goal from a
sustainability viewpoint, there is more complexity in evaluating
renewability. For example, there are the material resources and
the energy required to produce renewable materials, which in turn
may (or may not) be renewable. There might also be other environmental impacts such as the use of toxic compounds such as
herbicides that might pose environmental trade-offs. Therefore it
is necessary to assess renewability from a life cycle standpoint.
For instance, desired materials that are extracted from plants may
be separated using organic solvents, and then isolated from the
extraction solvent through a series of purication steps (for example additional solvent extraction or distillation). Another example
is the proportion of non-renewable feedstocks as part of a material

C. Jimnez-Gonzlez, J.M. Woodley / Computers and Chemical Engineering 34 (2010) 10091017

supply chain and the contribution of those feedstocks to the overall renewability of the materials used in a bioprocess. For instance,
the production process of furfural based on biomass utilizes materials such as sulfuric acid, methanol or carbon monoxide which are
often derived from fossil sources; in addition to the energy which
is sourced from renewable and non-renewable energy carriers. A
further factor to consider is the potential competing use of land and
the impact derived from potential land-use change, which at this
time is an area of ongoing debate (Fargione, Hill, Tilman, Polasky,
& Hawthorne, 2008; Klverpris, Wenzel, & Nielsen, 2008).
Developing life cycle inventories and assessing the LCIA impacts
of bioprocesses is not a simple endeavor given the large amount
of data needed from different sources. The more materials that are
involved in the bioprocesses, the more life cycle inventory data will
need to be collected, veried and analyzed. On the other hand, the
life cycle inventory data for biomaterials is not always available.
While there have been efforts to increase the body of knowledge of
life cycle inventories and impacts of bioprocesses and materials
either derived from biomass or needed in bioprocesses, considerable challenges remain. These challenges have inuenced the
development and use of streamlined life cycle assessment methodologies and ab initio modeling approaches to estimate the life cycle
impacts of bioprocesses and bio-derived materials. This is precisely
one of the opportunities for systems engineering to add value, as the
development of reliable, consistent, transparent, accurate and easyto-use modeling and streamlined techniques for LCIA will continue
to be an important need to be able to routinely assess the sustainability of bioprocesses.
In the future, the development of true sustainability assessments, with an embedded LCIA approach will be necessary, aligned
with the early modeling needs highlighted in this article. In order
to routinely assess sustainability of bioprocesses and to embed sustainability principles into bioprocess design and development, the
following modeling needs can be highlighted:
Better deterministic models of unit operations that are part of bioprocesses, such as fermentation, biocatalysis. This would need to
include fundamental design parameters to design more resource
efcient bioprocesses.
Development and enhancement of property prediction packages that would facilitate estimations of resources (e.g.

1015

energy requirement) and the utilization of optimization

techniques.
More extensive use of process integration techniques on bioprocesses, especially at the development phase.
Better understanding of life cycle inventory and impacts of bioprocesses and bio-derived materials.
Increased understanding of the uncertainties in modeling bioprocesses, both from the viewpoint of process design and
sustainability assessment.
Improved consistency and transparency of LCIA methodologies
as applied to bioprocesses.
Improved streamlined LCIA methodologies that are easy to use
by academia and industry alike.
More routine application of multi-objective optimization techniques for sustainability assessments of bioprocesses.
Enhanced understanding of the interactions of the environmental, social and economic aspects of bioprocesses for a holistic view
of sustainability.

Addressing these modeling and process understanding needs

will make it possible to integrate sustainability principles into process design and development in a far more rigorous manner.
6. Mapping modeling needs of bioprocessesan example
Henderson et al. (2008) compared the chemical process and a
two-enzyme biocatalytic process for the production of 7-ACA. We
have discussed briey the results of the assessment in terms of
the life cycle impacts of both synthetic routes. We will now use
that example to map some of the modeling needs of bioprocesses
discussed in this paper.
Fig. 4 depicts the different phases evaluated in the assessment, which include the extraction of the raw materials and the
production processes with their corresponding energy and waste
treatment requirements. As can be seen in Fig. 4, the production of
the nal API, formulation, distribution, use and end-of-life considerations are not included in the assessment.
In terms of models used for raw materials, the life cycle impacts
of the materials was modeled using a combination of life cycle
inventory data developed by ab initio methodologies based on
chemical engineering methods and principal component analysis

Fig. 4. Use of models in the 7-ACA evaluation (Henderson et al., 2008).

1016

C. Jimnez-Gonzlez, J.M. Woodley / Computers and Chemical Engineering 34 (2010) 10091017

to ll the data gaps. For most common chemicals and solvents,

most of the life cycle information was available. However, for the
bioprocess, as mentioned above, the availability of life cycle inventory data of substrates, enzymes and feedstocks was limited and
remains under development.
The information describing the production processes was in its
entirety taken from process descriptions, internal reports, batch
records and process data, and no models were used. This type
of data was available since the bioprocess had been run at the
commercial scale. However, if the same type of comparison was
intended to be repeated with a process in either a conceptual design
stage or a process with limited development, it would not be possible given the lack of models.
Relatively standard models were available and used to estimate
the life cycle impacts of energy production and waste treatment.
The waste amounts and compositions were estimated based on the
process descriptions using mass balances directly. Energy requirements were also estimated based on process descriptions using
typical heat transfer models. To calculate energy requirements,
pure component physical property data gaps (e.g. heats of formation) were estimated using molecular modeling based on group
contribution methods, specically the Marrero and Gani method
(Marrero & Gani, 2001). Nevertheless, there remains a need to
increase the accuracy of the models to estimate pure component
properties for complex molecules and enzymes.
7. Future outlook
The development of new bioprocesses as a complement to existing chemical and fuel production methods is an exciting endeavor
that will occupy many process engineers in the future. There will
be a particular role for process systems engineers in this developing sector with the advantages of quantitative decision-making
tools and rapid simulation that this brings, including process design
and sustainability principles. In the future suitable models will
inform developments at the infrastructural level (evaluation of
bioreneries, feedstocks and integration), the process level (evaluation of alternative technologies and process integration) as well
as the catalyst level (evaluation of alternatives for protein and
metabolic engineering). In addition, these models will allow the
integration of sustainability principles into process design and
development.
The further development of process systems engineering tools
(including property prediction packages and the development of
a database for bio-based molecules) will be required. To routinely assess sustainability of bioprocesses will require as well
more robust and transparent environmental life cycle inventory
databases of bio-derived materials; as well as better modeling
and understanding of the social and economic aspects of sustainability and their relationships. Finally, an increasing dialogue
amongst the biochemical engineers, biologists and other disciplines with related areas of expertise will be necessary to enable
the vision of sustainable industrial biotechnology to be fully
exploited.
Acknowledgements
The authors wish to thank GlaxoSmithKlines Biotransformations Team in general, and Peter Sutton, Joseph Adams and Andrew
Collis in particular for their contributions, input and support to this
article and the development of bioprocesses.
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