Industrial Platform Design for

Probiotic Production using

Different Biofactories

Prof. Dr. rer. Nat. Hesham A. El Enshasy

Chemical Engineering Pilot Plant (CEPP)
Faculty of Chemical and Natural Resources Engineering
University Technology Malaysia (UTM), Skudai, Johor
E-mail: henshasy@cepp.utm.my
 ‘Content

Probiotics (Science and Business)

Market and Future trends

Case Study: breast milk probiotics (novel infant formula)

Bioprocess manufacturing Platform Design

Proposed scaling up model for probiotics

Pr obiotics =
Business
 Global market for
Probiotics

The total market of Probiotics reached 6 US$ Billions by 2004

Most of Probioics business focused on Pharma, Food, Feed Industries

 Probiotics Business
Partners
Lactobacillus strains Bifidobacteriums sp. Others

L. casei B. bifidum S. boulardii

L. rhamnosus B. breve S. thermophilus
L.acidophilus B. infantis E. faecium
L. bulgaricus B. lactis
L. fermentum B. longum
L. lactis
L. johnsonii
L. reuteri
 Probiotics Strain
Selection
Ablility to survive in the extreme conditions of digestive
tract

Adherence to epithelial cells and intestinal mucosa

Colonization potential in the human intestinal tract

Production of antimicrobial substances towards

pathogens

Safety with regard to human use

Stability during storage under normal conditions

 Saccharomyces boulardii

Inhibit pathogen attachment

Inhibit the action of microbial toxins

Stimulate immunoglobulin A

Trophic effects on intestinal mucosa

 Analysis of related
Process
Saccharomyces cerevisiae

Help to feed 6,3 Billion people

Save life for 150 million Diabetics

Produce drugs and vaccines for other

hundred thousands

EVERY DAY
 Pr ocess Keywor ds

High Cell mass production

Adaptive strain to draughness and tolerate to moderate heat

 Determination of process bottleneck(s)

Bioprocess Optimization in Lab. scale

(Development of cultivation strategy to reach the maximal productivity)

Scaling up of the Process

Down Stream
(Separation/Isolation/Purification and increase of product Stability)
Determination of process bottleneck(s)
Up-Stream

Glucose repression

Oxygen limitation
Mixing
Aeration

Foaming effect / Mixing

pH control
 Fed batch
cultivation
Glucose feeding rate [g l -1 h-1 ]

90
0.5 1.0 2.0
35
100
80
30
70
80

Glucose [g l ]
25

-1
CDW [g l ]
-1

60
OD [%]

60 50 20

40 15
40
30
10
20
20
5
10

0 0 0
0 5 10 15 20 25 30 35 40

Time [h]
 Main characteristics of Biotechnological Products

The Product

Mostly are Innovative proudcts with long R&D phase

Big difference in price between (commercial and extra-pure)
In Biopharmaceuticals product (NO COMMERCIAL GRADES, ONLY EXT-PURE)

The Process
Production under highly controlled sterile conditions with extra industrial
Requirements depends on product type and safety (cGMP, HACCP, ISO)

The Business

Long term Investment (High Risk-High Benifit Business)

Highly Competive mark based on Innovation and multi million US$ R&D Cost

Time = (money)

 ‘Platforms in Biotech Industries

Product Based Platforms

Biofactory Based Platforms

Bioprocess Based Platforms

Pre 1940s ‘Biotechnological Products

Baker’s yeast Solvents Organic acids Amino acids

Probiotics Antibiotics Bio-insecticides Enzymes

Pre 1980s

biopolymers Vaccine
Industrial Bioprocessing

SCP Biosurfactants
Post 1980s

Biopharmaceuticals rProteins MAb

Plant Bioactive
compounds BioDiesel X
 ‘Biofactories in Biotech Industries

Mammalian cells
Insect cells

Invertebrate cells

Plant cells

Algae
Filamentous fungi
Yeast
Actinomycetes

Bacteria
 Product Based and Cell Factory Based Platforms

Product Based Platform Cell Factory Based Platform

Less Flexible More flexible

Dedicated for one product Can produce different types

(or branch of product) of products from the same biofactory
(without or with minimal modifications)

Easily applied as Toll-Manuf.

Limited use as Toll-Manuf.
More Expensive
Less Expensive
For well-established products
For well-established products and new products

High-value facility
Low-Value facility (in case of Sale)
(in case of Sale)
Bacterial Cell Platform (Biopharma)
 Current Bioprocess based Platforms

High Cell Density Cultivation Platform (unicellular MO)

1- rProtein Production (Bacteria/Yeast)
(CEPP products / EntoGeneX Co. )
2- Cell mass production of novel probiotics (Bacteria/yeast)
(CEPP products)
3- Non-rProtein production in Bacteria
(CEPP products / EntoGeneX Co.)
4- Cell mass production of nitrogen fixing bacteria
(All Cosmos Co.)

Non-Newtonean fluid fermentation platform

1- Polysaccharide production (Bacteria)
(CEPP products)
 Current Biofactory based Platforms

Filamentous MO cultivation platform

1- Mushroom cultivation for bioactive metabolites production
(CEPP products / Bioalpha Co.)
 CEPP platform will work as

Technology Transfer hub for Biotechnology companies

Technology developer from strain to tonnes of powder

CRO for local and International Companies

Incubator for Biotechnology based SME

Innovative Process Development for already marketed

Molecules
 CEPP as Technology Transfer HUB

1- Technology transfer hub for biotechnology companies:

1.1. Phase I:
- Cell banking
- Technology Evaluation
- Process re-adaptation
- Dissolve of non-process related issues
- Process scaling up and industrialization
- Toll manufacturer to have short time market penetration

1.2. Phase II:

- Consultation during the design and building new facility
(Basic Engineering, Project and process validation)
- Human resource development and training of new staff

1.3. Phase III:

- Master cell bank of the original strain
- RTD centre for continuous process optimization
 Biofactorbased and Bioprocess based platforms
and EDUCATION

Work as important component of the university education

system through teaching and practicing the platform
models and the art of technology integration

Education tool for hand-on operation with industrial case

study rather than teaching different subjects in
segregated modes
Students (starting from undergraduate level) will work in
industrial climate structure. This will improve their
pracitcal skills and they will easily integrated in the
industrial society without lag time
 Biofactorbased and Bioprocess based platforms
and BUSINESS

Minimizing the risk of failure during technology transfer

process

RTD is the main assets of the BioTech based companies .

This system supports the innovation based industry with
minimal direct investment

This provide the high skilled human resource required for

Biotech Industries since students from undegrad. Level
work in industrial projects and may hired by the
companies doing this project

This type of platforms act as RTD hub and toll

manufacturing facility for SME (full acting incubator) to
help companies for market penetration before large
investment in their own facility.
 Biofactorbased and Bioprocess based platforms
and SOCIETY

Increase the public awareness about Industrial biotech.

production chain and future applications

Illustrate clearly this new technology to public through

visits and public talks by experts to increase the public
awareness

Promote the culture of using biotech. based beneficial

products as (Natural, Safe, Biofriendly) to the society.
This also help the companies to decrease the public
resistance against their new technology
Biopr ocess design for
Pr obiotic production
Microorganis (Type, thermo-adabtation, Draughness-adaptation)

Production facility (Up-stream) and control system

Cultivation mode / Scalability

Down stream requirements

Product formulation (powder, micro-encapsulated, etc.....)

 ‘

Thank You