TK 4009

Bioproses Industrial
3 Maret 2015

Chapter 9 Industrial Biotechnology in the Chemical

and Pharmaceutical Industries
Global initiatives such as, for example, the United Nations
Environment Program, the World Summit on Sustainable
Development in Johannesburg, and the Global Product
Strategy and Responsible Care program of the International
Council of Chemical Associations (ICCA ) are aimed at
minimizing significant adverse effects of the use and
production of chemicals on the environment and human
health.
The minimization of waste in relation to product is the goal
of both green chemistry and white/industrial biotechnology
where natures catalysts are leading the way in industrial
process designs.

 Since biocatalysts are easily degradable and

non - toxic, procedures using biocatalytic tools
have not only found their way into industrial
large - scale production in the chemical and
pharmaceutical industries, but are also finding
increased application in the research and
development phase. An overview of some of
these processes will begiven in this chapter.

Beta - Lactam Antibiotics

Building Blocks

Beta - Lactam Antibiotics

The Side - Chains
A wide variety of side - chains for - lactam
antibiotics have been developed over the years.
This was originally done by diastereomer
crystallization, which means that a chiral acid
(e.g., camphorsulfonic acid) is added to the
racemate, forming diastereomeric salts, of which
only one crystallizes. This is still the dominating
process for D PG production, although
enzymatic processes have been described.
D - HPG, on the other hand, is only made by an
enzymatic process via a hydantoin

Beta - Lactam Antibiotics

Enzymatic Semi - Synthesis
New - lactam antibiotics were originally made by adding new side
- chains to the fungal fermentation broth, but that had limited
success because of the selective uptake of these compounds by the
fungi. For the chemical coupling of side chain and nucleus, two
processes have been developed, both of which suffer from
disadvantages such as deep cooling (Dane salt method) and reactive
chemicals (Dane salt and Dane anhydride method). Recent
research, initially at NOVO, Denmark, and completed by DSM and
the universities of Delft, Groningen, Nijmegen, and Wageningen in
the Netherlands has led to the development of an enzymatic
coupling process, using the same or similar penicillin acylase as was
used for the removal of the side - chain in the fungal - lactam
antibiotic (see Scheme 9.2 ). For thermodynamic reasons, the D (H)PG amide is used instead of the free acid.

Beta - Lactam Antibiotics

Enzymatic Semi - Synthesis
A production plant for cephalexin based on this
reaction was opened by DSM Chemferm in Barcelona
(Spain) in the late 1990s. The new process has clear
environmental benefits as well as improved product
quality and product stability [4] . Overall, compared
with the traditional chemical routes, the combination
of direct fermentation of the 7 - ADCA structure
together with the biocatalytic side -chain replacement
has led to improvements of 50% or more on
important parameters such as solid waste formation,
emissions to air, energy need, toxicity, and risk
potential and consumption of reagents and solvents

Chiral Building Blocks

The benefi ts of biocatalytic production routes
lie not only in the way a product is
manufactured but also in the knowledge
acquired about the routes not chosen. Thus a
network of bridges between stoichiometric,
catalytic, and biocatalytic reactions is created
upon which new productions can be based

Building Blocks for Polymers

Acrylamide is a building block for polyacrylamide, which is widely
used in the laboratory for separation in chromatography and
electrophoresis or as a water - soluble thickener in wastewater
treatment and paper making. The monomer is made by the
addition of one molecule of water to acrylonitrile, which in turn is
made from naphtha - derived propene and ammonia. The
conversion of acrylonitrile to acrylamide has been done for many
decades using a copper - based catalyst at 80 140 C. Although
the process is efficient, it produces toxic wastewater containing
copper and HCN. The high temperature used leads to undesired
polymerization of acrylamide which makes it necessary to purify
the product.
In the 1970s, in the laboratory of Professor Hideaki Yamada in Kyoto
(Japan) some microorganisms were found which were able to grow
on acrylonitrile. They hydrolyzed the substrate to acrylamide and
subsequently to acrylic acid, which was then further metabolized.

Building Blocks for Polymers

Initially Pseudomonas chloraphis was used, but
later optimized Rhodococcus rhodochrous
became the standard. The process runs at much
lower temperature than the chemical process (0
15 C), avoiding spontaneous polymerization
and subsequent purification. The latter factor
appeared to be the key success factor in
economic terms. Both the substrate and the
product are reactive compounds but the cell free extract tolerates up to 500 g/l of substrate
when immobilized in polyacrylamide.

Building Blocks for Polymers

Polylactic acid ( PLA ) has properties comparable to
those of polyethylene and polypropylene. It is less heat
resistant but much more biodegradable. The joint
venture NatureWorks (now owned by Cargill) has a PLA
plant in Blair (Nebraska) since 2002, with a production
capacity of 140 000 tonnes per year
Another building block for plastics is 1,3 - propanediol,
made by DuPont from glucose in a fermentative
process. The microorganism was heavily optimized by
pathway engineering. 1,3 - Propanediol produced via
fermentation has a lower cost of manufacture than
that produced via the competing chemical processes,
and uses a renewable feedstock

Fine Chemicals: Statins

Increased cholesterol levels are a growing
concern to the health of the human
population and it is no wonder that a
cholesterol - lowering medicine like
atorvastatin (Lipitor ) is the best - selling
drug at the moment worldwide [6] . Statins
are inhibitors of HMG - CoA reductase, an
essential enzyme in the biosynthesis of
cholesterol.

Amino Acids
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Biocatalytic Processes: Business and

Commercial Perspective

Today the chemical industry produces 27 million tonnes

of organic chemicals such as polymers, pharmaceuticals,
fine and specialty chemicals, and more for all segments of
our daily life worth 2000 billion euros worldwide (Figure
9.6 ). Most products are produced by chemical synthesis
starting from simple chemical building blocks produced
from fossil oil.
Industrial biotechnology has been well established in the
chemical industry for decades. However, it contributes
only 50 billion euros or 2% to the chemical industry s
sales volume of 2000 billion euros, mainly in the three
segments pharmaceuticals, fine and specialty chemistry
as well as detergent and hygiene products.

Biocatalytic Processes: Business and

Commercial Perspective
This changing economic environment is already favouring
innovative new products and new processes. Cargill s
polylactic acid is an example of a new polymer based on
biorenewable feedstocks. Lactic acid is produced by
fermentation based on sugar and further on polymerization
by chemical processes. Combining biotechnological and
chemical process steps may represent a prototype for the
future chemical industry. Cargill have already invested in a
140 000 tonnes per year plant.
Since 2004 Evonik have produced the antiknocking agent
ethyl tert - butyl ether with a capacity of 250 000 tonnes
per year using bioethanol as feedstock. DuPont Engineering
Polymers produces Bio - PDO (propanediol) as a starting
material for Sorona and other hybrid polymers

Conclusions
When we devise new routes for bulk chemicals, we must look carefully at
the starting material to be used. More specifically, many important bulk
chemicals (caprolactam, acrylamide, pyridine, etc.) contain one or more
nitrogen atoms. The conversion of molecular nitrogen to ammonia, which
is the feedstock for all nitrogen - containing compounds in the
(petro)chemical industry, is very energy -intensive. Conversely, biomass
contains a lot of nitrogen which has been fixed by nature in the form of
amino acids, proteins, and nucleic acids. Proteins in particular comprise a
large proportion of the biomass and can be conveniently isolated and it
would be very important to consider their constituents (aminoacids) as a
feedstock for the bio - based production of nitrogen - containing bulk
chemicals.
In conclusion, the perspectives for industrial biotechnology in the
chemical and pharmaceutical industry and for the partnership of the
involved sciences of biology, chemistry, and engineering are excellent
today and continue a successful traditionof interactions in the past
century which has led to enormous contributions to the quality of human
life.

Industrial Biotechnology in the Food

and Feed Sector
Since the very beginning of human history, living systems
and their extracts have been used on a fully empirical
basis to solve one of humanity s most basic needs: how
to produce and store food. Cheese and beer production
are two examples of our earliest progress in this area. In
the case of cheese, a biodegradable product, milk, is
transformed into a stable, storable, and tasty derivative.
In this respect it must be underlined that even if the food
and feed sectors are traditionally among the main
application areas of biotechnology, the development of
new ingredients and processes is becoming increasingly
difficult because of tight regulatory constraints.

Food Applications
Starch Transformation
Starch is used to produce food extenders and
sugars syrups such as maltodextrins, glucose,
dextrose (purifi ed glucose), fructose, maltose,
and hydrogenated derivatives (e.g., sorbitol,
mannitol). The main sources of starch are
corn, potato, wheat, barley, rice, cassava, and
sorghum.
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Rancangan Pabrik.

Food Applications
Dairy Industry
Milk transformation into cheese and various
processed food products is an intrinsically
biological process involving enzymes and
microbes,
Today, industrial milk transformation
processes are finely tuned to provide products
with constant organoleptic characteristics
from a variable raw material.

Food Applications
Milk - Clotting Enzymes

Food Applications
Milk - Clotting Enzymes

Cheese Ripening and Flavor

Lipase
Proteases
Lysozyme
Transglutaminase
- Galactosidase

Food Applications
Baking Industry
Amylases
Fungal - amylase from Aspergillus oryzae is the
most widely used enzyme in baking.
Overall, the consequences of amylase action are
increased bread volume and more homogeneous
crumb structure.
Another target for - amylase use is the increase
of shelf - life of baked products through its anti staling effect.

Food Applications
Baking Industry
Xylanases
Insoluble arabinoxylans present in fl our are
involved in the disruption of the stability of
the gas cells in the dough, while soluble
arabinoxylans have positive functional
properties, particularly the maintenance of
moistness in baked products, which is
necessary for good shelf - life performance

Beer - Making Industry

Malting
One of the key features of brewing is the malting
process.
The addition of exogenous enzymes in order to
optimize wort extraction and achieve full - glucan
hydrolysis.

Prevention of Chill Haze in Beer

The interaction of proteins with polyphenols during
beer production results in the formation of a haze,
particularly during cold storage
An alternative remedy is to use proteases. Similarly,
papain has been used to prevent chill haze by
hydrolyzing proteins into peptides

Homework
Modern Biotechnology:
7.4
8.3