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Membrane technology in Bioprocessing

What Are Membranes?

Membranes are thin films of synthetic organic or

inorganic (ceramic) materials, which can bring about a
very selective separation between a fluid and its
Dead-end Filtration

Filter Cake Membrane

Crossflow Microfiltration



Membrane Filtration
Mechanical separation processes for
separating gaseous or liquid
Separation with the help of permeable
Wide range of separations - of
miscible components.
Operate without heating
Separation based on size and shape.
Membrane Filtration Types
1. Pressure driven types: 2. Concentration gradient

Nanofiltration(NF) Membrane extraction

Ultra filtration(UF) 3. Electrical potential driven:

Reverse osmosis(RO)
Types of Membrane Filtration:
Micro filtration (MF)
Used during the primary recovery stages of DSP.
used for the separation of particles 0.02-10 m in diameter
membranes with a pore size of approximately f 0.05 to 1.0 m
a molecular weight cut-off (MWCO) of greater than 1000,000
operating pressure of approximately 15 to 60psi
To separate bacteria and yeast - 0.1 to 10m
Used to concentrate bacterial and yeast suspensions
To provide cell free supernatant
Application to animal cells
Ultra filtration :
Pressure driven membrane filtration technique
Separates solutes in the 0.001-0.02 m in range
Membranes are available in a wide range of pore sizes (51000
kD are typical) and surface areas.
Particles larger than the MWCO will be retained by the
membrane, while particles smaller than the MWCO will pass
Pressure: 10-70 psi. Pressure source: Compressed nitrogen gas /
peristaltic pump.
Ultra filtration
Membrane configuration: cross flow.
Membrane : sheet, capillary and tubular
Ultra filtration
Ultra filtration
Factors affect choice:
1. Interaction with proteins

2. Mechanical stability

3. Chemical stability

4. Flux rate

5. Ease of sterilization

6. Cost
Types of Membranes
I. Polymers membranes
cellulose acetate
Polyvinylidene fluoride (PVDF)
Polyethersulfone (PES).
II. Ceramic membranes
Chemical resistance, steam sterilized, longer life time ( 10yrs)
High initial cost
Configuration of UF Unit:
1. Concentration:
2. Purification: Solvent & low MW product
separation from high MW components
3. Useful in removing pyrogens, cell debris and
virus from media.
4. processing of antibiotic broths, DNA purification,
monoclonal antibodies purification, whey
fractionation and lysozyme purification
Ultrafiltration can be operated in various mode Energy Efficient, Inexpensive,
including diafiltration, high-performance Nondestructive & easy to operate
tangential flow filtration (HPTFF) and affinity
Diafiltration :

DF is most often used to

exchange a product into a
desired buffer (e.g., from an
elution buffer into a final
formulation buffer).
Unwanted particles pass
through a membrane while
the make-up of the feed
stream is changed to a more
desirable state through the
addition of a replacement
Applications of DF:
used to prepare the product stream for a
chromatography step
to exchange drug product into the final formulation
buffer, or
other situations where higher or lower
conductivity/pH levels are required
Affinity ultrafiltration
Combination of cross flow membrane filtration with affinity
With in ultrafiltration module or separate unites in sequence.
Affinity ultrafiltration_Instrumentation:
Mixing Chamber: The ligand and the
protein are allowed to equilibrate in free
Ultra filtration: Filtration through a
membrane that retains the protein-
ligand complex
Product separation from the ligand:
by the addition of salt, change in pH, or
by the use of an appropriate displacer.
Recycling of the free ligand
Affinity ultrafiltration
MWCF of NF membranes is between 200-1000 Daltons, which
means pore size ranges between 1-10 nm.
higher operation pressure than either MF or UF.
Operating pressures are usually near 600 kPa (90psi) and can
be as high as 1,000 kPa (150psi).
remove virtually all cysts, bacteria, viruses, and humic
NF membrane Applications:
NF membrane allows water, salt Desalting of organic & aqueous
[NaCl] and other monovalent ions to stream.
pass through the membrane, but Decolourization of dyes &
retains the organic molecules and a
selective portion of divalent ions.
Concentration of desired molecules
Spiral wound membranes are most
in API & Biotech industries
common type of configurations. (fermentation products like
As an alternative to extraction
process for removal of salts.
Reverse Osmosis:
High Water Potential

Low Water Potential

(Pure water phase to salt containing

aqueous phase)

Membrane used are solute

Reverse osmosis
Pressure (10-100bar) is applied to the solvent molecule against
concentration gradient.
Solvent moves from low to high conc.

Results in Concentration of solute

P >
(Osmotic pressure) = CRT;
C Conc. of solute, R- Gas constant, T- Temp.
Reverse osmosis
Reverse Osmosis
RO membranes are effectively non-porous and, therefore,
exclude many low molar mass species such as salt
ions, organics, etc
Membrane pore size-0 .0001 - 0.001 m
Operate in pressure range of 10-100 psi
RO membrane allowing passage of solute molecules.
Solute transport Diffusion or Convection
Concentrated solution becomes even more concentrated
Membrane configuration cross flow.
Cross-flow Vs Dead-end
Cross-flow RO
Reverse Osmosis/ Hyperfiltration
Water Flow




1. Cellulose acetate
2. Polyamide hydrocarbon (PAH)
3. Sulfonated polysulfone (SPS)
Potable water from sea or brackish water.

Used for dewatering & concentration

RO for selective wine filtration was patented in 1992 for volatile acidity (VA) and alcohol
removal in wine1.
RO is a cross-flow process where only very small molecules pass through the membrane,
leaving flavor and aroma constituents untouched1.
Expanded to remove off-aroma compounds of Brett" and Smoke from wine- (wine fault
yeast Brettanomyces bruxellensis)2
To concentrate juice prior to fermentation1.
Not suitable for protein separation

Concentration polarization
Deposition of solute on membrane.
Fouling in RO
Flux tends to decrease with time- irreversible deposition of material.
Fouling in RO
Membrane Modules:
Industrial membrane plants often require hundreds to thousands of
square metres of membrane to perform the separation required on a
useful scale.
There are several ways to economically and efficiently package
membranes to provide a large surface area for effective separation.
From an overall cost standpoint, not only is the cost of membranes per
unit area important, but also the cost of the containment vessel into
which they are mounted.
Membrane Modules:

Plate and frame


Spiral wound

Hollow fibre
Plate and frame
The heart of plate-frame module is the support plate.
Plate is sandwiched between two flat sheet membranes.
The plate is internally porous and provides a flow channel for
the permeate
Commercial plate-frame units are usually horizontal with the
membrane plates mounted vertically.
Tubular modules
It contains as many as 5 to 7 smaller tubes, each 0.5 to 1.0 cm in
diameter, nested inside a single larger tube.
It operate in tangential /cross-flow design

Membrane life upto 2 to 10 years

Spiral Wound :
Membranes are sandwiched together with feed spacers (typical
thickness 0.03 to 0.1 inch) and permeate carrier
They are sealed at each edge and wound up around a perforated
The module diameter ranges from 2.5 to 18 inch and length varies
from 30 to 60 inch.
Spiral Wound :
Hollow fibre
Hybrid-flow Filtration
It combines the dead-end and the cross-flow
Two phases: Production phase and the
Flushing phase
Production phase: Tubes are closed on one
side and a dead-end filtration is performed.
Flushing phase: Tube is open on both sides
and the fraction that did not pass through
the membranes is removed to clean the
membrane surface as in cross-flow

2. Bioprocess Engineering Basic Concepts by Michael L.
Shuler and Fikret Kargi.
3. Biochemical Engineering Fundamentals by James E. Bailey
and David F. Ollis.
4. Principles of Fermentation Technology by Whittaker and