Biotechnology, Bio-Processing Engineering and Biochemical Engineering

Biotechnology, Bio-processing Engineering and
Biochemical Engineering
Biotechnology is the art and science of converting reactants (substrate) into useful products
by the action of microorganisms or enzymes. Thus, any process in which microbes or living
organisms play a vital role in getting transformation of the feed into useful products is termed
as bioprocessing. It could be by way of converting milk into curd, or fruit juices into wines,
or sugars into alcohol, or the application of yeast in bread making, etc.
Greeks were known to have produced wine as early as 7000 BC, and Egyptians were baking
bread in 4000 BC. However, an understanding of the role played by the living cells was not
emanated until the cell theory was proposed in 1838.
Biotechnology usually implies the use or development of methods of direct genetic
manipulation for a socially desirable goal. Such goals might be the production of a particular
chemical, but they may also involve the production of better plants or seeds or gene therapy,
or the use of specially designed organisms to degrade wastes. Biotechnology may also be
equated with applied biology and therefore treated in a much broader sense. However,
engineering is considered as a subcomponent of biotechnology.
Biochemical Engineering has usually meant the extension of chemical engineering

principles to systems using a biological catalyst to bring about desired chemical
transformations. It is often subdivided into bioreaction engineering and bioseparations.
There is a difference between bioprocess engineering and biochemical engineering. In
addition to chemical engineering, bioprocess engineering would include the work of
mechanical, electrical and industrial engineers to apply the principles of their disciplines to
processes based on using living cells or subcomponents of such cells. The problems of
detailed equipment design, sensor development, control algorithms and manufacturing
strategies can utilize principles from these disciplines. Biochemical engineering is more
limited in the sense that it draws primarily from chemical engineering principles and broader
in the sense that it is not restricted to well-defined artificially constructed processes but can
be applied to natural systems.
The emergence of Biochemical Engineering is of more recent origin, since the biological
industries did not recognize the importance of engineering inputs until the experience of
penicillin manufacture. It is the manufacture of antibiotics which gave a boost to biochemical
industries.
The story of Pencillin: How Biologists and Engineers work

together?
In September 1928, Alexander Fleming at St. Marys Hospital in London was trying to
isolate the bacterium of Staphylococcus aureus, which causes boils (a skin infection). The
technique was to grow the bacterium on the surface of a nutrient solution. One of the dishes
had been contaminated accidentally with a foreign particle. Normally, such a contaminated
plate would be tossed out. However, Fleming noticed that no bacteria grew near the invading
substance as shown in Figure 1.
Figure 1:Photograph of Alexander Flemings original plate showing the growth of the mold
Penicillium notatum and its inhibitory action on bacterial growth
Flemings intelligence realized that this observation was meaningful and not a failed
experiment. He recognized that the cell killing must be due to an antibacterial agent. He
recovered the foreign particle and found that it was a common mold of the Pencillium genus.
Fleming cultivated the mold to grow and using the crude extraction methods then available,
managed to obtain a tiny quantity of secreted material. He then proved that this material had
powerful antimicrobial properties and named the product as Penicillin. Fleming carefully
preserved the culture, but the discovery lay essentially dormant for over a decade.
World war II provided the momentum to revive the discovery. Sulfa drugs have a restricted
range of activity and therefore an antibiotic with minimal side effects was desperately
needed. Howard Florey and Ernst Chain of Oxford decided to work on Flemings
observations. Norman Heatley (biochemist) played a key role in producing sufficient material
for Chain and Florey to test the effectiveness of penicillin. He developed a test to monitor the
amount of penicillin made so as to determine the kinetics of the fermentation. He also
developed a culture technique and devised a novel extraction process to recover the delicate
product. After months of immense effort, they produced enough penicillin to treat some
laboratory animals. Afterwards, they began to treat a patient in London who was suffering
from a blood infection. Initially, the penicillin worked wonderfully and brought the patient to
the point of recovery. Unfortunately, the supply of penicillin was exhausted and the patient
died. However, Florey and Chain remained successful in demonstrating the great potential of
penicillin. But the main issue was to produce it in sufficient amount. To make large amounts
of penicillin would require a process and for such a process development, engineers would be
needed, in addition to life scientists.
The war further complicated the situation. Florey and his associates approached
pharmaceutical firms in USA to persuade them to develop the capacity to produce penicillin,
since the USA was not at war at that time.
Many companies and government laboratories, assisted by many universities, took up the
challenge. Initially, many companies were reluctant to perform the fermentation process
beyond the pilot plant stage. It was thought that the pilot-plant fermentation system could
produce sufficient penicillin to meet the needs of clinical testing, but large-scale production
would soon be done by chemical synthesis. However, chemical synthesis of penicillin proved
to be exceedingly difficult. The early clinical successes were so dramatic that in 1943 the
War Production Board decided to have an increased production of penicillin. The
fermentation route was chosen. The problems facing the fermentation process were indeed
very formidable.
What are the main challenges?

The main problem was to get a valuable product made at very low levels.
The low rate of production per unit volume would require very large and inefficient reactors,
and the low concentration made product recovery and purification very difficult. In 1939 the
final concentration in a typical penicillin fermentation broth was one part per million (ca.
0.001 g/l); gold is more plentiful in sea water. Furthermore, penicillin is a fragile and unstable
product, which places significant constraints on the approaches used for recovery and
purification.
Life scientists at the Northern Regional Research Laboratory made many major contributions
to the penicillin program. One was the development of a corn steep liquor-lactose based
medium. This medium increased productivity about tenfold. A worldwide search by the
laboratory for better producer strains of Penicillium led to the isolation of a Penicillium
chrysogenum strain. This strain, isolated from a moldy cantaloupe proved superior to
hundreds of other isolates tested. Its progeny have been used in almost all commercial
penicillin fermentations.
The other hurdle was to decide on a manufacturing process. One method involved the growth
of the mold on the surface of moist bran. This bran method was discarded because of
difficulties in temperature control, sterilization, and equipment size. In addition, the surface
method used a variety of containers, including milk bottles, and the term bottle plant
indicated such a manufacturing technique. The surface method gave relatively high yields,
but had a long growing cycle and was very labor intensive. The first manufacturing plants
were bottle plants because the method worked and could be implemented quickly.
However, it was clear that the surface method would not meet the full need for penicillin. If
the goal of the war production board was met by bottle plants, it was estimated that the
required bottles would fill a row stretching from New York city to San Francisco.
Engineers at that time favoured a submerged tank process. The submerged process presented
challenges in terms of:
Mold Physiology
Tank design and operation
Large volumes of absolutely clean, oil- and dirt-free sterile air were required
Very large agitators were required, and
the mechanical seal for the agitator shaft had to be designed to prevent the entry of
organisms
Even today, problems of oxygen supply and heat removal are important constraints on
antibiotic fermenter design. Contamination by foreign organisms could degrade the product
as fast as it was formed consume nutrients before they were converted to penicillin, or
produce toxins.
In addition to these challenges in reactor design, there were similar hurdles in product
recovery and purification. The very fragile nature of penicillin required the development of
special techniques. A combination of pH shifts and rapid liquid-liquid extraction proved
useful.
Soon processes using tanks of about 10,000 gal were built. Pfizer completed the first plant for
commercial production of penicillin by submerged fermentation in less than six months. The
plant had 14 tanks each of 7000 gal capacity. Thereby, the United States had the capacity by
the end of World War II to produce enough penicillin for almost 100,000 patients per year
This accomplishment required a high level of multidisciplinary work. For example, Merck
realized that men who understood both engineering and biology were not available. Merck
assigned a chemical engineer and microbiologist together to each aspect of the problem. They
planned, executed, and analyzed the experimental program jointly, almost as if they were one
man.
Progress with penicillin fermentation has continued, as has the need for the interaction of
biologists and engineers. From 1939 to now, the yield of penicillin has gone from 0.001 g/l to
over 50 g/l of fermentation broth. Progress has involved better understanding of mold
physiology, metabolic pathways, penicillin structure, methods of mutation and selection of
mold genetics, process control, and reactor design.
Figure 2: Schematic of penicillin production process

Biotechnology, Bio-Processing Engineering and Biochemical Engineering

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Biotechnology, Bio-Processing Engineering and Biochemical Engineering

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Biotechnology, Bio-processing Engineering and

Biochemical Engineering has usually meant the extension of chemical engineering

The story of Pencillin: How Biologists and Engineers work

What are the main challenges?

Figure 2: Schematic of penicillin production process

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