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Bioprocess Development:

An Interdisciplinary Challenge

Back ground

Recent advances in biotechnology and public concern


about environmental pollution and the sustainability
of natural resources have rapidly transformed the
nations many manufacturing industries, from
chemical to pharmaceutical, to become more
environmentally benign and bio-based.
For example, almost all major pharmaceutical
companies now dedicate more than 50% of their new
drug development to biotech R&D.
Likewise, large chemical companies, such as DuPont
and Dow Chemicals, are aggressively developing new
bio-based products to replace petrochemical ones.

HISTORY AND APPLICATIONS of BIOTECH

Biotechnology has been


described as the last great
technological innovation of
the twentieth century and
has touched upon almost
every aspect of human life,
from healthcare to
agriculture to the production
of industrial products (Figure
1).

Historical milestones in the


development of biotechnology

Some Major of Industrial Fermentation


Products

Steps in Bioprocess
Development:

Bioprocessing is an essential part of many


food, chemical and pharmaceutical industries.
Bioprocess operations make use of microbial,
animal and plant cells and components of
cells such as enzymes to manufacture
newproducts and destroy harmful wastes.
bioprocesses have been developed for an
enormous range of commercial products,
from relatively cheap materials such as
industrial alcohol and organic solvents, to
expensive specialty chemicals such as
antibiotics, therapeutic proteins and vaccines.

Our ability to harness the capabilities of cells


and enzymes has been closely related to
advancements in microbiology, biochemistry
and cell physiology
Tools of modern biotechnology such as RecDNA, gene probes, cell fusion and tissue
culture offer new opportunities to develop
novel products or improve bioprocessing
methods.
Although new products and processes can be
conceived and partially developed in the
laboratory, bringing modern biotechnology
to industrial fruition requires engineering
skills and know-how.

The interdisciplinary nature of bioprocessing is


evident

Look at the stages of bioprocess development required


for a complete industrial process.(see Fig. below)
These stages involve different types of scientific
expertise.
-(Steps 1-11) are concerned with genetic manipulation
of the host organism (molecular biology and
biochemistry).
Tools : Petri dishes, micropipettes, tubes, PCR machine,
microcentrifuges, nano-or microgram quantities of
restriction enzymes, and electrophoresis gels for DNA
and protein fractionation.;

Figure1.Steps in development of a complete bioprocess for commercial new recProduct

(Step 12) : microbiology and kinetic analysis;


After cloning, the growth and production
characteristics of the cells must be measured

Medium composition,pH, temperature and other


environmental conditions allowing optimal growth
and productivity are determined.
Calculated parameters such as cell growth rate,
specific productivity and product yield are used to
describe performance of the organismOptimum
Condition of Culture

(Step13):Scale-up of the process starts. The first stage


may be a 1- or 2-Litre bench-top bioreactor equipped
with instruments for measuring and adjusting
temperature, pH, DO concentration, stirrer speed and
other process variables.
Information collected: O2 requirements of the cells,
their shear sensitivity, foaming characteristics and
other parameters.
Limitations imposed by the reactor on activity
of the organism must be identified. For example, if the
bioreactor cannot provide O2 to an aerobic
culturestarving or cell damage.
The situation is assessed using measured and
calculated parameters such as mass-transfer
coefficients, mixing time, gas hold-up, rate of oxygen
uptake,etc. It must also be decided whether the culture
is best operated as a batch, semi-batch or continuous
process;

(Step 14): the system is scaled up again to a

pilot-scale bioreactor.

A vessel of capacity 100-1000 litres is built according to


specifications determined from the bench-scale
prototype.
The aim of pilot-scale studies is to examine the
response of cells to scale-up.
Even though the geometry of the reactor, method of
aeration and mixing, impeller design and other features
may be similar in small and large fermenters, the effect
on activity of cells can be great.
Loss of productivity following scale-up may or may not
be recovered; economic projections often need to be
re-assessed as a result of pilot-scale findings.

(Step 15). industrial-scale

If the scale-up step is completed successfully,


design of the industrial-scale operation
commences.
Particular attention is required to ensure the
fermentation can be carried out aseptically.
When recombinant cells or pathogenic
organisms are involved, design of the process
must also reflect containment and safety
requirements.

(Step 16), Downstream processing

An important part of the total process is product


recovery, also known as downstream processing.
Product recovery is often difficult and expensive; for
some recombinant-DNA-derived products, purification
accounts for 80-90% of the total processing cost.
Commercial procedures include filtration, centrifugation
and flotation for separation of cells from the liquid,
mechanical disruption of the cells if the product is
intracellular, solvent extraction, chromatography,
membrane filtration, adsorption, crystallisation and
drying.
Usually First developed and tested using small-scale
apparatus
Disposal of effluent after removal of the desired product
must also be considered.

(Step 17).Packaging &marketing

After the product has been isolated in sufficient


purity it is packaged and marketed.
For new pharmaceuticals such as recombinant
human growth hormone or insulin, preclinical and
clinical trials are required to test the efficacy of the
product.
Only after these trials are carried out and the safety
of the product established, it can be released for
general health-care application.

Bioprocess engineers (or Pharmacyst) with a


detailed knowledge of the production process are
often involved in documenting manufacturing
procedures for submission to regulatory
authorities (FDA or BPOM in Indonesia).

As shown in this example, a broad range of


disciplines is involved in bioprocessing.
Scientists working in this area are constantly
confronted with biological, chemical, physical,
engineering and sometimes medical
questions.
It is important for Pharmacyst to keep
existence both in up stream and down stream
process of bioprocessing.

Description world market of


biotech/fermentation product
Vaccine, Therapeutic proteins
Vitamin B12, B2
Penicillin derivat
Protease, Amilase

Citric acid
Glutamat
EtOH

10

100

200

(x103 ton/year)

Table 1. Major products of biological processing

A Quantitative Approach

The biological characteristics of cells and enzymes often


impose constraints on bioprocessing; therefore knowledge of
them is an important prerequisite for rational bioprocess
(engineering) design. For instance :
- thermostability the operating temperature of reactor?
- susceptibility of an organism to substrate determine
whether substrate is fed all at once or intermittently?
It is equally true, however,that biologists working in
biotechnology must consider the engineering aspects of
bioprocessing; selection or manipulation of organisms
should be carried out to achieve the best results in
production-scale operations.

Another area requiring cooperation and understanding


between engineers and laboratory scientists is medium
formation.
For example, addition of serum may be beneficial to growth
of animal cells, but can significantly reduce product yields
during recovery operations
All areas of bioprocess development; the cell or enzyme
used, the culture conditions provided, the fermentation
equipment and product-recovery operations--are
interdependent. Because improvement in one area can be
disadvantageous to another, ideally, bioprocess
development should proceed using an integrated approach.

As our exploitation of biology continues,


there is an increasing demand for
scientists/pharmacyst trained in bioprocess
technology who can translate newdiscoveries
into industrial-scale production.
As a biotechnologist, you could be expected
to work at the interface of biology/pharmacy
and engineering science.