Production Of Pharmaceutical Compounds Through Microbial Fermentation
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ProClin Preservative for Diagnostic Reagents SAFC Pharma ®
®
Packaging Information pipeline partners
Production of Pharmaceutical Compounds
Through Microbial Fermentation Silvian Shama, Ph.D., cGMP Fermentation Development Manager
Overview
Microbial Fermentation–an Introduction
The original definition of fermentation is ‘the anaerobic
Microbial fermentation is the basis for the production
conversion of sugar to carbon dioxide and alcohol
of a wide range of pharmaceutical products, targeting
by yeast’, and most of us will have had first-hand
practically any medical indication. Examples range
experience of the fermentation process through its
from anti cancer cytotoxic drugs and vaccines,
most famous and popular use - the brewing of beer.
anti infectious disease antibiotics and vaccines, to
This original definition has been expanded over time
hormonal disorder therapy and many other indications.
to ‘the conversion of organic materials into relatively
Natural biosynthesis of endogenous molecules
simple substances by microorganisms- essentially
involves specific multi-step complex routes, some
efficient, flexible bio factories.’ During their growth
of which can be manipulated for the biosynthesis of
and lifespan microorganisms build a wide range of
foreign molecules. Microorganisms may be genetically
different molecules types required for viability and
modified (recombinant technology) or metabolically
multiplication; adaptation to changing environment;
engineered by substantial alteration of their
stressful conditions and defence against hostile,
endogenous routes.
competitive microbial threats.
The key elements of fermentation development are
Microorganisms that are typically used within the
strain selection and optimization, media and process
pharmaceutical industry include: prokaryotes such
development, and finally, scale-up to maximize
as Bacteria (e.g. Escherichia coli, Staphylococcus
productivity. Downstream processing utilizes various
aureus) and Streptomycetes (e.g. Streptomyces spp,
technologies for extracting, concentrating and purifying
Actinomyces spp), eukaryotes such as Filamentous
the product from a dilute fermentation broth.
Fungi (e.g., Nigrospora spp, Aspergillus spp,) and Yeast (e.g. Saccharomyces cereviciae, Pichia pastoris).
Fermentation derived product diversity- the recovery
The molecules that are of primary interest to the
product out of the whole molecular repertoire-
pharmaceutical industry are small molecules such
makes fermentation technology a multi- disciplinary
as short peptides and low molecular weight organic
methodology encompassing microbiology, organic
molecules, larger molecules including proteins and
chemistry, biochemistry and molecular biology.
nucleic acids (DNA, RNA) and macromolecules such as lipids and carbohydrate polymers, plus various combinations of product types, for example
and selective purification of the specific desired
When fermenting volumes larger than 10L, necessary biosafety measures are taken, especially when Risk
lipopolysaccharides, lipopeptides, peptidoglycan.
Group 2 (RG2) pathogens are used. These include
Any of these product types could potentially serve as
facility design and special operational procedures.
a drug’s Active Pharmaceutical Ingredient (API).
As these products can be toxic and hazardous, their
Biosafety Level 2 Large Scale (BSL2-LS) containment
recovery and purification require adequate chemical/ biochemical facilities and equipment including isolators for handling High-Potent APIs (HPAPIs). Under cGMP fermentation procedures, quality is built into the entire process ensuring that regulatory agencies requirements are met in terms of safety, product identity, quality and purity.
www.safcpharma.com
ProClin Preservative for Diagnostic Reagents SAFC Pharma ®
®
Packaging Information pipeline partners
Why Choose Microbial Fermentation? Fermentation is the only route to chemical APIs that
A further approach is to reduce the protein expressed
relies solely on microorganisms with no equivalent in
to the minimal effective domain (Nanobodies/
other processes. Examples of its applications include
Peptibodies in the case of antibodies). The principal
mammalian cells, antibiotics/secondary metabolites
advantages of fermentation over the mammalian
made in fungi serving as anti cancer or anti infectious
system, as illustrated in the table below, are time and
agents, or lipid A made in gram negative bacteria
yield which ultimately translate to cost.
serving as adjuvants. These organic molecules can be obtained through multi-step synthesis from their building blocks.
Microbial Fermentation
Mammalian Culture
However, organic molecules are very complex in
Generation time
20 minutes-hours
hours-days
nature, potentially encompassing structures such
Growth length
1-4 days
10-14 days
Product types
Proteins Secondary metabolites Cell wall components DNA
higher costs than the fermentation option.
Crude protein titer
1-15g/L
1-5g/L
The semi-synthetic approach draws upon the
Media cost
low
high
advantages of fermentation in the generation of new
Growth sensitivity
low
high
Post translational modifications
Some available in yeast
Yes
as chiral centers, large stereospecific rings or unique conjugated double bond systems. Going down the synthetic route not only requires significant development but is time consuming and entails
drugs. Natural molecules are produced through fermentation then modified synthetically, reducing toxicity, increasing potency and selectivity, and overcoming bacterial resistance to traditional antibiotics.
Proteins
Therapeutic proteins requiring modification, for
Fermentation might also be the sole source for natural therapeutic proteins exclusively expressed in microbial systems. Proteins are complex molecules of mid to high molecular weight. Their functionality and stability largely depend upon their secondary and tertiary structure, as well as various post-translational modifications, mainly glycosilation. The synthetic
example glycosilation of antibodies were, until recently, expressed in mammalian cell cultures. Driven by cost considerations, scientists looked to express glycosilated therapeutic proteins in microbial systems, resulting in a novel approach – Glycoengineeringwhereby the endogenous glycosilation pathway in high yield expression recombinant yeast was modified. The
option is limited to very short peptides.
modified pathway reproduced the human pathway
Recombinant technology enables the expression
antibody fragments.
of foreign gene encoding for therapeutic proteins in microbial systems, including those from human source. Using microbial fermentation is advantageous for expression of proteins that do not require post-translational modifications as microbial systems, such as E. coli, lack post-translational mechanics.
therefore allowing the expression of humanized
Conclusion Although not a new technology, microbial fermentation continues to evolve and is now frequently the preferred production method for chemical compounds and therapeutic proteins, offering an optimal economic route, which allows pharmaceutical companies to shorten production processes and time to market.
SAFC®, SAFC Pharma® and Sigma-Aldrich® are registered trademarks of Sigma-Aldrich Biotechnology L.P. and Sigma-Aldrich Co. © 2009 SAFC All rights reserved.
www.safcpharma.com
®
Packaging Information pipeline partners
Production of Pharmaceutical Compounds
Through Microbial Fermentation Silvian Shama, Ph.D., cGMP Fermentation Development Manager
Overview
Microbial Fermentation–an Introduction
The original definition of fermentation is ‘the anaerobic
Microbial fermentation is the basis for the production
conversion of sugar to carbon dioxide and alcohol
of a wide range of pharmaceutical products, targeting
by yeast’, and most of us will have had first-hand
practically any medical indication. Examples range
experience of the fermentation process through its
from anti cancer cytotoxic drugs and vaccines,
most famous and popular use - the brewing of beer.
anti infectious disease antibiotics and vaccines, to
This original definition has been expanded over time
hormonal disorder therapy and many other indications.
to ‘the conversion of organic materials into relatively
Natural biosynthesis of endogenous molecules
simple substances by microorganisms- essentially
involves specific multi-step complex routes, some
efficient, flexible bio factories.’ During their growth
of which can be manipulated for the biosynthesis of
and lifespan microorganisms build a wide range of
foreign molecules. Microorganisms may be genetically
different molecules types required for viability and
modified (recombinant technology) or metabolically
multiplication; adaptation to changing environment;
engineered by substantial alteration of their
stressful conditions and defence against hostile,
endogenous routes.
competitive microbial threats.
The key elements of fermentation development are
Microorganisms that are typically used within the
strain selection and optimization, media and process
pharmaceutical industry include: prokaryotes such
development, and finally, scale-up to maximize
as Bacteria (e.g. Escherichia coli, Staphylococcus
productivity. Downstream processing utilizes various
aureus) and Streptomycetes (e.g. Streptomyces spp,
technologies for extracting, concentrating and purifying
Actinomyces spp), eukaryotes such as Filamentous
the product from a dilute fermentation broth.
Fungi (e.g., Nigrospora spp, Aspergillus spp,) and Yeast (e.g. Saccharomyces cereviciae, Pichia pastoris).
Fermentation derived product diversity- the recovery
The molecules that are of primary interest to the
product out of the whole molecular repertoire-
pharmaceutical industry are small molecules such
makes fermentation technology a multi- disciplinary
as short peptides and low molecular weight organic
methodology encompassing microbiology, organic
molecules, larger molecules including proteins and
chemistry, biochemistry and molecular biology.
nucleic acids (DNA, RNA) and macromolecules such as lipids and carbohydrate polymers, plus various combinations of product types, for example
and selective purification of the specific desired
When fermenting volumes larger than 10L, necessary biosafety measures are taken, especially when Risk
lipopolysaccharides, lipopeptides, peptidoglycan.
Group 2 (RG2) pathogens are used. These include
Any of these product types could potentially serve as
facility design and special operational procedures.
a drug’s Active Pharmaceutical Ingredient (API).
As these products can be toxic and hazardous, their
Biosafety Level 2 Large Scale (BSL2-LS) containment
recovery and purification require adequate chemical/ biochemical facilities and equipment including isolators for handling High-Potent APIs (HPAPIs). Under cGMP fermentation procedures, quality is built into the entire process ensuring that regulatory agencies requirements are met in terms of safety, product identity, quality and purity.
www.safcpharma.com
ProClin Preservative for Diagnostic Reagents SAFC Pharma ®
®
Packaging Information pipeline partners
Why Choose Microbial Fermentation? Fermentation is the only route to chemical APIs that
A further approach is to reduce the protein expressed
relies solely on microorganisms with no equivalent in
to the minimal effective domain (Nanobodies/
other processes. Examples of its applications include
Peptibodies in the case of antibodies). The principal
mammalian cells, antibiotics/secondary metabolites
advantages of fermentation over the mammalian
made in fungi serving as anti cancer or anti infectious
system, as illustrated in the table below, are time and
agents, or lipid A made in gram negative bacteria
yield which ultimately translate to cost.
serving as adjuvants. These organic molecules can be obtained through multi-step synthesis from their building blocks.
Microbial Fermentation
Mammalian Culture
However, organic molecules are very complex in
Generation time
20 minutes-hours
hours-days
nature, potentially encompassing structures such
Growth length
1-4 days
10-14 days
Product types
Proteins Secondary metabolites Cell wall components DNA
higher costs than the fermentation option.
Crude protein titer
1-15g/L
1-5g/L
The semi-synthetic approach draws upon the
Media cost
low
high
advantages of fermentation in the generation of new
Growth sensitivity
low
high
Post translational modifications
Some available in yeast
Yes
as chiral centers, large stereospecific rings or unique conjugated double bond systems. Going down the synthetic route not only requires significant development but is time consuming and entails
drugs. Natural molecules are produced through fermentation then modified synthetically, reducing toxicity, increasing potency and selectivity, and overcoming bacterial resistance to traditional antibiotics.
Proteins
Therapeutic proteins requiring modification, for
Fermentation might also be the sole source for natural therapeutic proteins exclusively expressed in microbial systems. Proteins are complex molecules of mid to high molecular weight. Their functionality and stability largely depend upon their secondary and tertiary structure, as well as various post-translational modifications, mainly glycosilation. The synthetic
example glycosilation of antibodies were, until recently, expressed in mammalian cell cultures. Driven by cost considerations, scientists looked to express glycosilated therapeutic proteins in microbial systems, resulting in a novel approach – Glycoengineeringwhereby the endogenous glycosilation pathway in high yield expression recombinant yeast was modified. The
option is limited to very short peptides.
modified pathway reproduced the human pathway
Recombinant technology enables the expression
antibody fragments.
of foreign gene encoding for therapeutic proteins in microbial systems, including those from human source. Using microbial fermentation is advantageous for expression of proteins that do not require post-translational modifications as microbial systems, such as E. coli, lack post-translational mechanics.
therefore allowing the expression of humanized
Conclusion Although not a new technology, microbial fermentation continues to evolve and is now frequently the preferred production method for chemical compounds and therapeutic proteins, offering an optimal economic route, which allows pharmaceutical companies to shorten production processes and time to market.
SAFC®, SAFC Pharma® and Sigma-Aldrich® are registered trademarks of Sigma-Aldrich Biotechnology L.P. and Sigma-Aldrich Co. © 2009 SAFC All rights reserved.
www.safcpharma.com
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