Biochemical Engineering

Dr. Amyl Ghanem

Department of Chemical Engineering
Dalhousie University

Outline

What is biochemical engineering?

The catalysts
Relationship to engineering
Historical perspective: penicillin
The industry: facts
The industry:
Food, beer and wine
Industrial chemicals
Pharmaceuticals

Some definitions.

Biotechnology: use or development of methods of direct genetic

manipulation for a socially desirable goal. Sometimes a broader
definition is used, where biotechnology is applied biology.

Biomedical Engineering: engineering on systems to improve human

health

Bioengineering, biological engineering: work on medical or

agricultural systems, draws on electrical, mechanical, industrial and
chemical engineers.

Biochemical Engineering: extension of chemical engineering

principles to systems using a biocatalyst to bring about desired
chemical transformation.

The story of penicillin

Alexander Fleming's photo of the dish with
bacteria and Penicillin mold, 1928

The story of penicillin

15+ years
Discovered by
Alexander Fleming
1928

Fermentation
route was chosen

Chemical synthesis
proved to be too difficult

Full scale production

1940s

Efforts to increase production

cell line selection
medium optimization
process development

Biocatalyst: cells and enzymes

10-20 m

1-5 m

Enzyme:
Acetylcholinesterase
size range in nm

E + S

E-S

E + P

Typical chemical processing

A

temperature
flowrate

A+B

P
P
A
B
B

Reactor

Separation

Cell as a bioreactor
reactor

A
E

C
D

cell
P

Reactor inside a reactor

?
A
P
C
D etc.

Product :
cells
small molecule
enzyme

Separation

Bioprocesses are special.

Cells are living organisms that require specific conditions
for growth, production
Cells grow in culture medium (nutrients) that may
support other cell types (contamination)
Bioproducts are often sensitive to external conditions (T,
pH) and can easily be destroyed (separations)
Product is generally very dilute in bioreactor medium
Many byproducts in medium to remove

.but they have their advantages!

Cells will often perform reactions that are too difficult to
do synthetically (penicillin)
Cells can turn basic nutrients (for example, agricultural
waste) into valuable products
Amazing diversity of products from cells
Cells can be modified to increase product diversity even
more!
Enzymes are highly specific catalysts with high catalytic
power

Engineering Employment Trends

Industry

B.Sc.

M.S.

Ph.D.

2000

1991

2000 1991 2000 1991

Chemical

26.7

43.7

24.1

38.1

28.4

46

Fuels

12.6

21.2

8.5

16.1

7.6

15.3

Electronics

15.6

2.4

22.8

3.2

19

4.8

Food/Consumer Products

11.4

7.2

4.5

4.5

2.8

5.6

Materials

3.3

2.7

7.1

5.8

6.2

5.6

Biotech and Related

Industries

6.9

3.1

14.7

7.7

19.4

Pulp and Paper

2.4

5.1

1.3

3.2

0.9

0.8

Engineering Services

9.8

8.2

10.7

14.9

6.6

11.3

Business Services and

Other*

11.2

6.4

6.3

6.4

6.5

AIChE Career Services Dept, 8/25/00

Industry in Canada: Biotechnology

358 Biotech companies in Canada in 1999

$1.9 billion in revenue
7695 people employed
70% are located in the health or agri foods
sectors
more than 2500 biotech patent applications
every year in Canada

Industry in Canada: Bioproducts

Firms that produce fuels, chemicals, materials and
specialty products using biological feedstocks and
bioprocesses
ex. alcohol from agricultural and forest feedstock, enzyme
production companies

75-100 companies that undertake R&D and

manufacturing
$100-150 million in sales each year
1500-2000 people employed
Very young industry!!

Industry in Canada: Medical Devices

800 manufacturing firms in 2000 (90%
Canadian-owned)
3.1 billion in revenue, 1.6 billion of which
were exports
18,000 people employed
ex) cardiovascular devices and treatments
such as heart valves and ECG systems
in vitro diagnostics; imaging; dental
implants and materials

Industry in Canada: Chemicals

In 2000, there were 1,200 establishments
operating in Canada.
They employed approximately 72,500
employees.
Canadian shipments in 2000 were valued
at $30.2 billion

Industry Focus: Food and beverage

Industry Focus: Food and beverage

Fermentation Products

cheese
soy products
yoghourt
wine, beer
bread

Enzymes

adjust food flavour

adjust food texture
improve nutritional
quality
high fructose corn
syrup

Fermentation
A form of anaerobic respiration occurring in certain
microorganisms (ex. yeasts)
Alcoholic fermentation is a series of biochemical
reactions by which pyruvate is converted to ethanol and
CO2.

Metabolic pathways in e.coli

C6H12O6 2 C2H5OH + 2 CO2

Common yeast saccharomyces cerevisae used in making wine,
beer, bread by above reaction.

Different strains of yeast can tolerate different alcohol

concentrations.
Theoretically, 180 g of sugar will produce 92 g of ethanol
Actual yield is only 84.6 g of ethanol
EtOH (20C) = 0.789 g/mL
volume of ethanol = 84.6 g x mL = 107.2 mL
0.789 g
volume of the alcohol and water contracts by 0.7% so
107.2 mL x 1.007 = 108 mL for an overall alcohol
concentration of 10.8% (v/v:108/1000).

 Brix (B0) is a density measurement that indicates the

percentage of sugar in 100 g of a sugar-water solution.
Brix can be calculated by:

Brix = [g sugar/(g sugar + g water)] x 100

Brix units can be used to predict the alcohol content in

wine.
% potential alcohol (v/v) = 0.57 x Brixinitial

Beer making
Malting: grains (barley, rice) are steeped in water until
germination and then dried before a plant develops. The starches in
the grains get converted to sugars by enzymes.

Brewing: finely ground malt is turned into a sweetened liquid

by adding warm water added and heating to around 75o where the
sugars get dissolved. Grain is filtered out, and its boiled for
sterilization and concentration (wort)

Fermentation: the yeast turns the sugar in the wort into

alcohol, a process that takes about 10 days.

Wine making
(1) Yeast Proliferation - aerobic
oxygen is needed to sterol production
increased yeast robustness
(2) Initial Fermentation - anaerobic
sugar is converted to alcohol
duration times typically 5 - 12 days
(3) Secondary Fermentation - malolactic
lactic bacteria metabolize malic acid to lactic acid
lowered acidity and wine softening occurs
very typical for red wines

Process flowsheet for wine

Factors affecting yeast fermentation

Yeast Species
Temperature
Sugar concentration
pH
Vitamins
Sulfur dioxide (SO2)

Industry Focus: Textiles

Stone washing denim

Indigo dye adheres
to denim surface
traditional
method

Denim is faded by
abrasive action of
pumice stones

weakens the fabric

new method

Cellulase enzyme
removes some of the dye
by partially hydrolyzing the
cotton surface

new looks
lower costs
shorter treatment times
less solid waste

Detergents
Detergent industry is the largest single market for enzymes
at 25 - 30% of total sales
Dirt comes in many forms and includes proteins, starches
and lipids (fats and oils)
proteases, amylases, lipases are enzymes used in
detergents
enzymes allows lower temperatures and less agitation for
washing
Inner core of enzyme plus
preservative bound with CMC

Protective waxy coat that

disperses in the wash

Industrial Chemicals
Examples:
organic acids produced from Aspergillus
niger, citric acid used in soft drinks
Xylanase used for wood pulping and
bleaching

Agricultural
Examples:
Recombinant bovine somatotropin (bST)
for increasing milk production
Bio-insecticides for crop protection
Phyto-vanilla(tm) flavor derived from
tissue culture

Environment
Cleanup of hazardous waste sites using
bacteria that feed on pollutants
Bacteria used for bio-remediation
wastewater treatment
Biosensors: use biological activity to
detect toxic substances
RIS Water tests: antibody based kit to
detect low level of solvents such as
benzene

Fuel ethanol

Industry Focus: Pharmaceuticals

6.5 years
Discovery of
a promising
compound

1 year

Preclinical testing
in animals

Phase I clinical trials

in healthy volunteers

3 years

19 months

Phase III clinical trials

in 1000 to 3000
patients

FDA review and

approval

2 years
Phase II clinical trials
in 100 to 300 patients

Drug may be
prescribed by
physicians

The Drug Development and Approval Process

The drug discovery and approval process takes and average of
15 years and costs almost $400 million
source: Pharmaceutical Research and Manufacturers of America, Washington DC, 1996

Products

Small molecules and metabolites

antibiotics
Protein drugs
Vaccines
Antibodies, Monoclonal antibodies (MAb)

How?
Recombinant DNA technology means bacteria and
yeast can produce human proteins like insulin

Penicillin fermentation

2005 World market for biopharmaceuticals

Enbrel

Amgen/Wyeth

$3,657 US
mil

Procrit/Ep Stimulation of red blood

cells for treatment of
rex

Johnson&Johnson/Ortho
Biotech

$ 3,324 US
mil

Aranesp

Stimulation of red blood

cells for treatment of
anemia associated with
chronic renal failure

Amgen

$ 3,273 US
mil

Rituxan

Leukemia and nonHodgins lymphoma

Genentech/Roche/Biogen

$ 3,154 US
mil

Rheumatoid arthritis
and psoriasis

anemia in HIV patients

Remicade Rheumatoid arthritis

and Crohns disease

Johnson&Johnson/Centocor $ 2,535 US
/Schering Plough
mil

Epogen

Stimulation of red blood

cells for treatment of
anemia associated with
chronic renal failure

Amgen

$ 2,455 US
mil

Neulasta

Stimulation of
Amgen
production of white
blood cells for protection
against chemotherapy
complications

$ 2,288 US
mil

NeoRecor Stimulation of red blood

mon/Epog cells
in

Genentech/Roche/Chugai

$ 1,710 US
mil

Herceptin

Breast cancer

Genentech/Roche

$ 1,629 US
mil

Avonex

MS

Biogen IDEC

$ 1,543 US
mil

Monoclonal antibodies

New challenges.
Increasingly, bacteria
and yeast cannot
correctly form the
human protein:
animal cell culture
ex) mouse cells
require even more
careful treatment

Large quantities???

Opportunities for you?

The Bioproducts industry needs staff that
bridge the key disciplines of biology,
chemistry and engineering
Canadas Innovation Strategy , 2001
Government of Canada
Bioproducts Sector Profile

Main Issues
Types of reactors to provide high oxygen transfer
Appropriate cell and medium selection
Sterilization and maintaining sterility, no cross
contamination
In pharma, product purity and quality impedes process
change
Cells and molecules are sensitive to extreme conditions
Growth rate and reaction rates are small
Product is usually very dilute
Non traditional methods of separation
Often batch operations