BIOPROCESS
PRINCIPLES
Unit Operations in
Upstream & Downstream
Processing
Definition
What is a Unit
operation?
Chemical
and Bioprocess
Industries consist of widely
varying sequences of steps that
have different combinations for
different manufacturing cycles.
However these widely varying steps can be reduced
or broken down to simple operations which are
identical in fundamentals regardless of the material
being processed.
These fundamental operations are
what are called unit operations.
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Historical Definition
This definition was used by A.D Little in
1915 to describe Unit Operations.
Unit operations deal mainly with the
transfer of energy and the transfer and
change of materials primarily by
physical means.
What is a Unit Process?
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Different Unit Operations
Drying
Distillation
Adsorption
Membrane separation
Leaching
Sedimentation
Mixing
Liquid Liquid
Extraction
Absorption
April 7, 2015
TRANSPORT
PHENOMENA
Momentum Transfer
Fluid Flow
Sedimenation
Mixing
Heat Transfer
Drying
Evaporaytion (SHMT)
Distillation
Mass Tranfer
Absorption
Adsorptin
Distillation
Unit Operation in a Bioprocess
(Upstream & Downstream)
Stages of a Bioprocess
A biotechnical process to produce a
product can be subdivided into five
successive major segments, with some
overlap:
upstream processing
fermentation
downstream processing
product finishing
treatment of waste if any
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Stages of a Traditional
Bioprocess
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Stages of a Bioprocess
(Details)
Preparation of sterile medium.
Addition (inoculation) of microbe ( pure culture)
into this medium
Cultivation (incubation) under controlled
conditions
Sterilising fermentation apparatus and preparing
and sterilising feed streams to the fermentor
FERMENTATION
Isolation and purification of the product from the
fermented medium
Packaging of the product
Treatment of the waste products if any
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Unit Operations in a Bioprocess
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Upstream Processing
Pure Upstream processing has essentially
three functions:
Growth of a pure culture of
microorganisms in one or more steps its
scale up and strain development.
Sterilization of the apparatus and piping.
Mixing and sterilizing the necessary raw
materials and fermentation media to be
supplied to the fermentation unit.
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Fermentation Stage
Sometimes considered as an Upstream process
while some bioprocess engineers consider it as a
separate Stage in itself. Never considered as a
downstream processing stage
Actual fermentation is commonly a batch or fed
batch process in a stirred tank fermentor.
It lasts from a few hours to several days.
The optimal conditions for growth of the organisms
and production of the product are established.
Those include temperature, pH, sterile aeration
and, in fed-batch processes, continuous addition of
substrate at its optimal composition.
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
SCALE UP (DEFINITION)
Scale up: The transfer of a process
from small-scale
laboratory equipment
commercial equipment
to large-scale
Shake flash Experiments
Lab scale fermentor (5-10 L)
Pilot scale fermentor (300-3000 L)
Commercial fermentor (10,000-500,000
L)
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Scale up
lab flask
(100 mL)
lab-scale
fermentor
(110 L)
pilot plant
scale
(300-3000 L)
April 7, 2015
commercial scale
(10,000-500,000 L)
Unit Operation in a Bioprocess
(Upstream & Downstream)
Industrial Scale up
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Industrial Fermentation Setting
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Fermentor sizes for various purposes
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Some problems in Scale up
Oxygen transfer is much more difficult to
obtain in large-scale
Mixing and aeration more easily
accomplished in small volumes
Methods of temperature control must
change with scale-up
Sterilization protocols must change with
scale-up
Bioprocess Engineers required with
Chemical Engineering skills: adept in gas
and mass transfer, fluid dynamics, mixing,
thermodynamics
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Downstream processing
Downstream
processing (DSP) encompasses
processes following the fermentation.
all
In
downstream processing, the fermentor is
emptied after the fermentation is complete. The
microorganisms are killed and, if necessary, removed
by ultrafiltration. The liquor may be concentrated by
evaporation. If necessary, the active ingredient may
be isolated by a suitable separation process such as
crystallization, ion-exchanging or chromatography.
The subsequent product finishing is intended to
transform the product into the desired marketable
form, e. g., into a dry pourable granulation. That is
accomplished by classical drying and granulation
processes.
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Unit Operations in
Down Stream Processing
Pre- treatment
Solid /liquid
Separation
Concentration
Purification
Formulation
April 7, 2015
Cell disruption
Stabilization
Sterilization
Pasteurization
Flocculation
Filtration
Sedimentaion
Centrifugation
Membranes
Precipitation
Extraction
Evaporation
Freeze Concentration
Precipitation
Extraction
Diafilteration
Adsorption
Chromatography
Drying
Prilling
Extrusion
Granulation
Tabletting
Unit Operation in a Bioprocess
(Upstream & Downstream)
Relationship
(between cost and
and fermentation concentration)
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Separation Range of
Downstream Unit Operations
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Product Quality Profile
(during Downstream Processing Stages)
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Differences
Upstream
Processing
Downstream
processing
Live Organisms
Large Volume
No organisms
Progressively Less
Volume
Many Components
Progressively less
components
Heterogeneous
mixture
Homogenous Mixture
Fewer Operations
Lower Cost materials
April 7, 2015
Many Operations
Unit Operation in a Bioprocess
Higher
Cost
(Upstream & Downstream)
Downstream Processing
Downstream Processing begins upstream
why?
A holistic approach to DSP is required and
the entire process as a whole should be
considered. The economic use of cheap
industrial fermentation sources could cause
interactions that could increase downstream
processing difficulty and cost.. Hence a balance
should be sought in the whole process which
should be done by the Bioprocess Engineer.
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Research Areas in Upstream
processing
Research areas in upstream processing being carried out
today
Testing, modeling, optimization, control of novel or
improved recombinant and non-recombinant cell
cultures
New biochemical reactors, and new biological
processes to produce useful and high value products.
Basic genome and proteome based biomolecular
engineering studies that lead to improved design and
performance of fermentation and cell culture processes.
By using on-line and real time sensing and monitoring
techniques and high throughput analytical techniques
Quantitative assessment of biomolecular rate processes
inside a cell toward increasing aeration and transfer
rates
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
Research Areas in
Downstream processing
The capability to purify bioproducts in a costeffective manner on a commercial scale and to
meet the required high purity specification for
the medical grade bioproducts is an important
technical goal of R & D.
Research in areas as posttranslational protein
processing,
protein
refolding,
protein
purification techniques, membrane technology,
Various types of chromatography including
bioaffinity systems, separation techniques using
combined
force
fields,
and
filtration
methods.
April 7, 2015
Unit Operation in a Bioprocess
(Upstream & Downstream)
