Bioprocess Economics II

Katja.otto@bci.uni-dortmund.de

Costs associated with product recovery:

The costs of product recovery in presently applied processes exceed the
costs for the fermentation by a factor 2-4. This is due to:

- high capital investment

- high costs for utilities (e.g. steam in the case of destillation or
membranes in the case of pervaporation or reverse-osmosis)

• Relatively cheap methods (at present):

- crystallisation
- distillation
- extraction
• Relatively expensive methods (at present):
- chromatographic methods
- membrane separations (pervaporation, pertraction, reverse osmosis)

In contrast to the bioreactor costs (which can be assessed relatively

accurately from a limited number of parameters, and are largely independent
of the exact nature of the bioprocess), the costs for product recovery are
difficult to assess in a general model; costs are strongly dependent both on
the method applied and the physical and chemical nature of the product to be
recovered.
A common factor of all methods is, however, that costs are higher at low
product concentration. For the purpose of the examples given in this course,
we assume the product recovery costs to be inversely proportional to the
product concentration to the power of 0.75:

Product recovery costs ($ / kg product) proportional to:

1 1

[product conc.] 0.75

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Summary of (dis)advantages of various product recovery
methods frequently employed in biotechnology
(from: Atkinson (1991), Biochemical Engineering and Biotechnology Handbook)

Effect of biocatalyst properties and process

parameters on costs:
In the following 5 figures, the cost breakdown as described above is used to
determine the effect of a number of process parameters on the synthesis
costs ($ / kg product) of a fictive product with a molecular weight of 100 (g
mol-1):

1) Influence of biocatalyst concentration

2) Influence of biocatalyst activity
3) Influence of biocatalyst lifetime
4) Influence of product inhibition
5) Influence of process time on synthesis costs at a given half-life of
biocatalyst.
Costs in the following figures are all based on the application of a fed-batch
process, using free whole cells as biocatalysts.

1) Biocatalyst concentration

Remark 1: - At low cell

density the space-time
yield is low
=> relatively high
'bioreactor costs' due to a
low product concentration
=> high costs for product
recovery

Remark 2: - At high cell densities

=> 'bioreactor costs' become only a minor part of the total production costs

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1) Biocatalyst activity

Remark 1:
Activity of the biocatalyst <
0.05 U mg-1 cdw
=> high bioreactor costs due
to low space-time yield in the
bioreactor
=> high product recovery
costs due to low final levels of
product concentration

Costs for C-source & nutrients

for cell growth reach a
significant proportion of total
synthesis costs (less kg
product formed per kg cells).

Remark 2:
High specific activities of the biocatalyst => the bioreactor costs become neglegible
Cost savings may then be reached by immobilization of the biocatalyst => cheaper
product recovery process.

1) Biocatalyst lifetime
Remark 1:
Low lifetime of the
biocatalyst
=> High proportion of
total costs being related
to the C-source and
nutrients needed for cell
growth
=> Increased bioreactor
costs biocatalyst but to a
smaller extent
=> Process optimization
should be primarily aimed
at increasing the
biocatalyst lifetime.

Remark 2:
bioreactor costs do not seem to decrease significantly at longer biocatalyst
lifetime. However, the cycle time is not taken into account.
=> longer cycle times may significantly reduce costs for utilities (steam,
electricity) and labour.

1) Product inhibition

Remark 1:
Strong product inhibition
=> High product recovery costs
due to the low final aqueous
concentrations of the product.
=> bioreactor costs are not
strongly affected as long as the
process is restarted as soon as
the product reaches toxic levels.
If no less-susceptible biocatalyst
is available => two-phase
systems

Remark 2:
Low product inhibition => research efforts may be directed towards the selection
of mutants/alternative strains possessing a higher specific activity => lower
bioreactor costs

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1) Process time at a given half-life
of the biocatalyst
Remark 1:
Although the space-time
yield in the bioreactor is
optimal in this area, total
synthesis costs are high
due to low final concen-
trations
=> High costs for product
recovery
=> Relatively low amount of
product produced per kg
cells
=> High costs for C-source
and nutrients

Remark 2: (h)
At the right-hand side of the curve the costs for product recovery and
nutrients still decrease slightly (as both the product concentration and the kg
product formed per kg cells increases). These costs savings, however, are
compensated for by the lower space-time yield in the bioreactor: the total
synthesis costs increase.

Costs in the preceding figures were based on the application of a fed-

batch process, using free whole cells as biocatalyst. With some
adaptations the same model is also applicable to other systems. The
(qualitative) cost effects resulting from those alternatives are
assessed below:

Cost effect of the application of purified enzymes (instead of free cells)

- lower bioreactor costs because of higher space time yields
- higher biocatalyst costs (isolation of enzymes)

Cost effect of the application of immobilized cells or enzymes (instead of

free cells or enzymes):
- lower biocatalyst costs (biocatalyst more stable, easy regeneration of
cells or enzymes)
- extra costs deriving from immobilization process
- higher bioreactor costs because of lower space-time yield: the specific
activity is often lowered by diffusion limitation
- lower product recovery costs: cheaper product recovery (less proteinous
matter)

Cost effects of the use a continuous culture (instead of a batch

process):
- lower bioreactor costs because of higher space-time yield (if biocatalyst or
bioproducer is genetically stable)
- lower labour costs
- higher product recovery costs if substrate is not completely converted and
due to lower product concentrations
- higher incidence of contamination

Cost effect of the use of defined medium (glucose + salts) for cells
growth rather than a crude growth medium (e.g. whey or molasse):
- higher costs for growth of biocatalyst
- lower costs of downstream-processing

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 Examples of effect of process conditions on costs/kg
Use of β-galactosidase for hydrolysis of lactose (e.g. from whey):

Hydrolysis costs for

batch hydrolysis with
free enzyme

Axelsson and Zacchi (1990), Appl. Biochem.

Biotechnol. 45/25: 679-693

Examples of effect of process conditions on costs / kg:

Use of β-galactosidase for hydrolysis of lactose (e.g. from whey):

Hydrolysis costs for

batch hydrolysis
with immobilized
enzyme

Axelsson and Zacchi (1990), Appl. Biochem.

Biotechnol. 45/25: 679-693

Example of the influence of the final product

concentration and the product yield on the total costs
of synthesis: Hinman et al. (1989) Appl.
Biochem. 20/21: 391-401)

Ethanol price as a
function of key xylose
conversion parameters.

The xylose conversion

capital cost is set at
$0.25 per annual gallon
of ethanol from xylose.

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 Maximal productivity (sty) process conditions are not necessarily the
most cost-effective conditions
Productivity [kg MT IC-1 week-1]

Fermentation should be
terminated at I for
maximum productivity, at II
Productivity [kg-1] for minimum costs.
( ) higher and (----) lower
level of raw materials and
energy costs

Running time [days]

=> a longer running time may lead to cost savings on raw

materials, utilities and manpower.

Trade-off between space-time yield in reactor and

costs of biocatalyst

Example: immobilized glucose isomerase (presently used for the large

scale production of high-fructose corn syrup: approx 10 million ton / year).

Product specification:
- product should contain constant percentage of fructose
(42- 45 %)
Process conditions:
- Packed-bed reactor: substrate (glucose) is passed through a
reactor packed with immobilized glucose-isomerase
- Flow rate of glucose input is reduced in time as the activity
decreases with time (due to inactivation of the enzyme)

Important variables for cost-optimization

Time course of GI
deactivation shown
by the decrease in
productivity.

Abu-Reesh and Faqir (1996), Bioprocess Eng. 14: 205-

210)

• temperature
• operating time (time after which the biocatalyst is replaced)

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 Effects of temperature and operating time on the average
residence time (T ) for reactors operating at constant conversion

Optimum
at 1000 h Optimum
at 100 h

=> residence time (reactor volume / flow rate) should be

increased faster with time at higher operating temperatures

What is the optimum temperature (highest space-

time yield) at a given operation time?

Fermentation leading to bulk products:

competition with the chemical industry

Fermentation products successfully produced biotechnologically:

1900-1950:
• Glycerol: (Germany, world war 1; process: a modified yeast-ethanol
fermentation, flux redirected to glycerol by inhibiting ethanol dehydrogenase;
used for production TNT; current world price 1.6 $ / kg))
• Acetone: (England, world war 1; Weizmann process: Clostridium,
acetobutylicum; used for production of the explosive cordite; current world
price 0.53 $ / kg)
• Butanol: (England, world war 1; Weizmann process: Clostridium,
acetobutylicum; current world price 0.75 $ / kg)
• Ethanol: (e.g. Switzerland, world war 2, replacement for gasoline)

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Fermentation leading to bulk products:
competition with the chemical industry
Currently:
• Citric acid (current world price1.5 $ / kg; chemical (multi-step) synthesis is
too expensive)
• Lactate (chiral, food-grade)
• Ethanol (Brazil, USA, current world price: 0.53 $ / l)

Future (?):
• Acetic acid (current world price 0.53 $ / kg )
• Ethanol from wood and waste materials

Cheap oil-derived bulk-chemicals (acetone, butanol, ethene, ethanol, etc.)

will be most strongly effected by a higher oil price. More expensive products
(e.g. indigo will be less strongly effected)

'Invasion' of a market with a new process

Aspects to take into account:

- production costs are often only 30-60 % of selling costs (including profit
and overhead)
- large gap between the break-even-price (when price equals total
production costs) and price at which it is rational to shut down a plant (when
price equals variable costs).

Result: existing producer can 'protect' own market effectively by reducing

the price (2-4 fold): also often at end of patent period
Common mistake: comparing the production costs of product using the new
process to the selling price of product made by the existing process (e.g.
indigo)
Rule of thumb (Van Brunt, 1986): new process should be at least 50%
cheaper the existing process of competitor

Example: ethanol

Ethanol from fermentation has the following advantages:

• Chemical production (by hydration of ethene) relatively

expensive because thermodynamic equilibrium strongly
favours ethene + water.
• Wide array of sugar sources may be used as substrates
• Way to 'dispose' of over-produced agricultural products
(stabilizing effect on e.g. sugar prize)

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 In future, ethanol could possibly take over the central
role of ethylene (ethene) in the current chemical industry
(when oil prices increase)

=> as already practised in India and Brazil since mid-

eighties

Acetic
anhydride Acetic
esters

Chloro- Acetic- Polyvinyl

Vinyl acetate
acetic acid acid acetate

Croton- Acet-
aldehyde aldehyde

2-Ethyl Butyl-
hexanol aldehyde Synthetic
Ethanol Butadiene
rubbers

n-Butanol

Poly- Ethylene Ethylene-

Ethylene
ethylene chloride diamine

Polystyrene Styrene Ethylene Ethylene

oxide glycol

Cheapest sources of sugars for ethanol production:

(calculations show that these sources in the USA are able to produce
enough ethanol to replace all gasoline in the USA)

(Wyman (1994), Bioresource Technology 50: 3-16)

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Producing ethanol from cellulose and lignins is interesting since the process
costs contribute strongly to the selling price: process improvements could
possibly reduce the selling price by almost a factor of 2

(Wyman (1994), Bioresource Technol. 50:3-16)

Use of ethanol instead of gasoline as car fuel may become

economical within 10 years (depending on the oil-price and
improvements in bioprocess):

Acetone/butanol/ethanol
production by
Clostridium
acetobutylicum: selling
price of product is
strongly dependent on
price of carbon-source,
even when a waste
material (whey) is used.

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Comparison of costs for chemical and biotechnological
production of fumaric acid (from: Gangl et al. (1990), Appl. Appl. Biochem. Biotechnol. 24/25: 663-675)

Conclusions with regard to the biotechnological

production of (semi) bulk chemicals:

- most processes can presently not compete successfully

with chemical production methods
- many processes are on-the-shelf:
- can be made operative in short time
- contributes to future economical and political stability
- continuous research on reduction of process costs required

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