DrUM

Fine Chemicals

3
Industrial
BIOTECHNOLOGY

Untung Murdiyatmo, Ph.D.

Kuliah Umum FMIPA-UM 7 Okt 2015

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 What’s it all about? Fine Chemicals

BIOPROCESS TECHNOLOGY
Substrate

Bio-Process Product

Organism
BUSSINES/MONEY

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 Industrial Biotech Process is done in the BIOREACTOR
Fine Chemicals

• Mikrobiologi
• Teknol. Ferm
• Fisiologi Mikroba
• Genetika Mikroba
• Biokimia

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 Fine Chemicals

I. Amino Acids Production

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 Metabolic Pathway of Amino acids Fine Chemicals

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 Fine Chemicals

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 Small Scale Processes
Fine Chemicals

150 L System

NOTE:
Containment is a
concern when
working with
recombinant
micro-organisms

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 Large Scale/Commercial Process – Fine Chemicals
Example: 1. Ajinomoto Co., Mojokerto Factory
2. Cheil Jedang, Pasuruan Factory

300,000L (63,000 gal)

Bioprocessors
30m high
Producing MSG
Corneybacterium used for
production of
200,000 tons MSG
(Glutamate) and
65,000 Tons Lysine

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 Fine Chemicals

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 Fine Chemicals

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 MARKET Fine Chemicals

Global Amino Acids Market to Reach US$11.6 Billion by

2015, According to a New Report by Global Industry
Analysts, Inc.
Major players
• Ajinomoto Group,
• Archer Daniels Midland Company,
• CJ Cheil Jedang,
• Daesang Corporation,
• Evonik,
• Kyowa Hakko Kirin Group,
• Novus International Inc.,
• Royal DSM N.V.,
• Sekisui Medical Co. Ltd., and
• Toronto Research Chemicals Inc.
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 Fine Chemicals

Amino Acids, Production Processes

1. M. Sugimoto

Published Online: 15 APR 2010

DOI: 10.1002/9780470054581.eib025
Copyright © 2009 John Wiley & Sons, Inc. All rights reserved.
Book Title
Encyclopedia of Industrial Biotechnology

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 Fine Chemicals
Processes :
1. Extraction 2. Enzymatic
3. Biocatalysis/Fermentation
• Production Plants for Pharmaceutical Grade L-
Amino Acids :

Ham , France : Extraction from Proteins hydrolyzates

Purification from lower grades ( feed,...)
Konstanz , Germany : Enzymatic resolution
Nanning , China : Biocatalysis and fermentation

• Production Plants for Feed Grade Amino acids

Synthesis
Fermentation

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 Fine Chemicals

L-Amino Acids Extraction from Proteins

Hydrolysates

Serine , Threonine ,
Proline,
Hydroxyproline,
Alanine, Valine,
Isoleucine , Leucine
Phenylalanine,
Histidine, Arginine

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 Fine Chemicals

Extraction from Proteins Hydrolysates

Processes

1.Selection Purification of natural Proteins

2.Acidic Hydrolysis
3.Filtration
4.Ion exchange chromatographic steps
5.Charcoal treatment
6.Ultrafiltration
7.Crystallization 1
8.Charcoal treatment
9.Ultrafiltration
10.Crystallization 2
11.Drying

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 Fine Chemicals

Purification from lower Grade ( feed )

• Typical examples :
1. asp
2. glu
3. gly
4. lys
• Process : Activated charcoal  Ultrafiltration &
Recrystallization
• Origins:
asp : bioconversion of fumaric acid
glu , lys : fermentation
gly : synthesis
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 REXIM S.A. Fine Chemicals

Enzymatic resolution of
L- Methionine

1. DL- Methionine -> N-acetyl-DL-Methionine

2. acylase -> L-met + N-acetyl-D-Met
3. ion exchange separation
-> L- Methionine
-> N-acetyl-D-Met 4. -> N-acetyl-DL-Methionine

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 REXIM S.A. Fine Chemicals

Biocatalysis
1. Fumaric acid + NH3 + fumarase  L-aspartic acid
Process : Bioreaction  filtration  precipitation  filtration  drying

2. L-aspartic + aspartate bdecarboxylase L-alanine

Process: Bioreaction, filtration, precipitation , filtration, drying

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 Fine Chemicals

Fermentation

Sugar + Cornsteep + NH3  L- Valine

Biomass removal, ion exchange ,crystallisation ,filtration, drying

Sugar + Cornsteep + NH3  L- Isoleucine

Biomass removal, ion exchange ,crystallisation ,filtration, drying

GLU LYS  Mostly in INDONESIA, Thailand, Brazil

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Fine Chemicals
 How can we improve process economics?
Fine Chemicals

Better Product Yields

Higher Product Titres
Improved Volumetric Productivity

The Science:
1. Microbiology, incl. Strain improvement.
2. Microbial Physiology and
3. Fermentation Process Technology.

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 Fine Chemicals

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 Fine Chemicals

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 Fine Chemicals

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 Fine Chemicals

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 Fine Chemicals

II. PHARMACEUTICALS

1. ANTIBIOTICS
2. Vaccines
3. Hormones
 Fine Chemicals
HISTORY of Titer Improvement of Penicillin

• Discovered by Alexander Fleming in 1929

• 1941 : Production methods (using Fermenters)
• 1943 – 1945 : Strain improvement & media
modifications  Increased the titer 100 times

• 1950s : Serial mutations (UV, NTG & their

combination) to improve the titer  5000 times
(from 60 microgram/ml  300 mg/ml)
• Further mutations  550 mg/ml  1800 mg/ml

Random Mutation proved to be effective in productivity improvement of

Secondary metabolite such as ANTIBIOTICS
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Figure 15.1

Understanding the metabolism of primary & secondary metabolite

Fine Chemicals

Primary
metabolite Secondary

Penicillin, sugar, or cell number

Cells metabolite
Alcohol, sugar, or cell number

Alcohol
Sugar

Cells

Sugar

Penicillin

Time Time
Figure 15.6

Glucose
feeding Fine Chemicals
Nitrogen
feeding
100

ammonia, penicillin (g/liter  10)

Biomass (g/liter), carbohydrate,
90

80 Penicillin
70

60

50

40
Cells
30

20 Lactose

10 Ammonia
0
20 40 60 80 100 120 140
Fermentation time (h)
Fleming, Florey and Chain were jointly awarded Fine Chemicals
the Nobel Prize for physiology or medicine in 1945, recognising the
tremendous contribution of penicillin to human welfare.

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 Fine Chemicals

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 Fine Chemicals

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 Fine Chemicals

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 Fine Chemicals
Antibiotic medications - penicillin derivatives

Amoxicillin
Amoxicot
Amoxil
Moxilin
Trimox
Wymox

Amoxicillin and Clavulanate Potassium

Augmentin

Penicillin V Potassium
Suspen
Truxcillin
Veetids
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 MARKET Fine Chemicals
• Global Pharmaceutical Market Forecast to 2012
is expected to earn over a trillion dollar in
revenues by 2012.
• Global Antibiotics Market to Reach
US$40.3 Billion by 2015, According to
New Report by Global Industry Analysts,
Inc.

• The global market for Antibiotics is forecast to reach

US$40.3 billion by the year 2015, propelled by intensive
research in new areas of treatment, favorable regulatory
environment and emergence of new drug classes.
• In addition, huge investments ploughed into R&D will aid
inof Fine
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breakthroughs and technological developments.
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 III. PROBIOTICS Fine Chemicals

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 Fine Chemicals

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 Fine Chemicals

Production of Lactobacillus salivarius, a new probiotic

strain isolated from human breast milk, in semi-industrial
scale and studies on its functional characterization

• Probiotics are viable non pathogenic microorganisms that

colonize the intestine, modify the intestinal microflora and
their metabolic activities positively affect the health of the host

• To date, the increasing interests in some of these breast milk

lactobacilli such as L. gasseri, L. salivarius, and L. rhamnosus

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 Fine Chemicals

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 Fine Chemicals
Probiotics Market By
• Products (Functional Foods, Dietary Supplements,
Specialty Nutrients, Animal Feed)
• Applications (Regular, Therapeutic, Preventive Health
Care) and
• Ingredients (Lactobacilli, Bifidobacteria, Yeast) – Global
Trends & Forecasts To 2017

The global probiotic products market

was estimated at $24.23 billion in 2011.
More than 500 probiotic F&B products
have been introduced in the past decade.
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 IV. Biopolymers Fine Chemicals

Biopolymers are obtained via

polymerization of biobased raw materials
through engineered industrial bioprocesses

The raw materials of biopolymers are either

isolated from plants and animals or
synthesized from biomass using enzymes/
microorganisms

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 Applications of BIOPOLYMERS
Fine Chemicals

Coatings
Fibers
Plastics
Adhesives
Cosmetics
Oil Industry
Paper
Textiles/clothing
Water treatment
Biomedical
Pharmaceutical
Automotive
Rubber

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 Examples of Biopolymers
Fine Chemicals

Polyesters Polyphenols
–Polylactic acid –Lignin
–Polyhydroxyalkanoates –Tannin
Proteins –Humic acid
–Silk Lipids
–Soy protein
–Waxes
–Corn protein (zein)
–Surfactants
Polysaccharides
–Xanthan Specialty
–Gellan polymers
–Cellulose –Shellac
–Starch –Natural rubber
–Chitin –Nylon (from castor oil)

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 Biodegradable Polymers Fine Chemicals

Polymers such as polyethylene and

polypropylene persist in the environment for
many years after their disposal

Physical recycling of plastics soiled by food

and other biological substances is often
impractical and undesirable

Biodegradable polymers break down in a

bioactive environment to natural substances
by enzymatic processes and/or hydrolysis

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 Biodegradable Polymers Market Fine Chemicals

Global consumption of biodegradable

polymers increased from 14 million kg
(30.8 million lbs) in 1996 to 68 million kg
(149.6 million lbs) in 2001

U.S. demand for biopolymers is

expected to reach $600 million by 2005
according to a Freedonia Group study

U.S. Congress, Office of Technology Assessment, Biopolymers: Making Materials Nature’s Way-Background Paper, OTA-
BP-E-102 (Washington, DC: U.S. Government Printing Office, September 1993
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 Fine Chemicals

• The global market for biodegradable

polymers will amount to an estimated 932
million pounds in 2011 and is expected
to increase to more than 2.5 billion
pounds in 2016, for a five-year
compound annual growth rate (CAGR) of
22%. That’s according to a new technical
market research report, “Biodegradable
Polymers” (report #PLS025D), from
BCC Research.
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 PHA Production Fine Chemicals

Raw materials Carbon source

Media preparation
Bacteria growth and
Fermentation polymer accumulation

Cell disruption

Washing

Centrifugation
Polymer purification
Drying

PHA

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 PHB-V Fine Chemicals

Polyhydroxybutyrate – polyhydroxyvalerate
(PHB-V) is formed when bacteria is fed a
precise combination of glucose and
propionic acid

PHB-V has properties similar to

polyethylene but degrades into water and
carbon dioxide under aerobic conditions

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