YILDIZ TECHNICAL UNIVERSITY

DEPARTMENT OF BIOENGINEERING

BYM4741 BIOPROCESS ENGINEERING

SCALE-UP TECHNIQUES

2024-2025 FALL

Lecturer : Assist. Prof. Dr. Benan İNAN

• The process of converting a small-scale
biotechnological process performed under laboratory
conditions to an industrial scale is called scale-up.
• It is an important method most used in large volume
production.
• The scale-up process in biological production involves
much more precise and complex calculations than in
industrial production.
• The type of microorganism used, its requirements, the
medium in which production will be carried out and the
reactor type parameters play an important role in the
scale-up process.
• Values determined in laboratory-scale experiments often
cannot be applied with the same success on an industrial
scale. There are many reasons for this.

• Aeration and mixing

• Equipment Volume
• Heat and Mass Transfer
• Scaling up requires teamwork. Chemical engineers,
bioengineers, microbiologists, food engineers etc...
• There are three events that play a role in scaling up.

• Thermodynamic events,
• Kinetic events
• Transport events
For example...
• The solubility of oxygen in liquid does not depend on the size of the
reactor. However, mixing time, mixing speed and impeller geometry
are important parameters.
• The microkinetic behavior of microorganisms does not depend on
fermentor size. But nutrient concentration, pH, temperature, etc.
factors are important parameters.

These two events are independent of scale.

• Transport processes are scale dependent. For example, the
transport of oxygen in the liquid, the transport of nutrients and
oxygen in the liquid to the cell. As the scale for the transport process
increases, the time constant comes into play. If transportation
procedures are not carried out properly, time will increase. Mixing
must be done very well to prevent this from taking longer.
• Heat transfer is important. As the scale increases, the temperature
increases and rapid cooling is required.
• The stability of the vaccine culture and the characteristics of the
microorganism are important. For example, if a cell synthesizes
extracellular polysaccharide, it will increase the viscosity of the liquid.
In this type of production, the media is first optimized under
laboratory conditions.
Then, according to the needs of the organism, parameters
such as mixing speed, ambient oxygen percentage, power
transferred to the liquid are calculated using various
formulas based on small volume production.
For scale growth,
• Generally, one or more parameters are kept constant and
various experiments are performed.
• After the results of the trials are evaluated, the most
suitable production conditions are determined and the
actual production is carried out under these conditions.
WHY SCALE UP?
➢It increases the quality and quantity of the resulting product.

➢It ensures that the materials and resources required for

production are used in the most appropriate amount and in
the most appropriate way.

➢It is used to regulate the economic costs of production.

➢The most appropriate values are obtained by theoretically

calculating the reaction rates, environmental conditions and
production times of both biological and chemical reactions.

➢In this way, production takes place at the optimum level of

efficiency and under stable conditions.
➢Pre-made laboratory experiments and theoretical
calculations allow us to find out as close to exact values as
possible how much raw material is required for actual
production.

➢Inthis way, problems such as excessive use of raw materials

and incomplete product production are eliminated and the
same amount of product is obtained in each production;
quality is maintained.

➢Minimizing problems and unknowns enables controlled and

most cost-effective production.

➢Therefore, resources are used more efficiently and any

income obtained as a result of production is maximized.
ADVANTAGE AND DISADVANTAGE
Advantages:
✓High efficiency
✓Low production cost
✓Controlled production
✓Fast, easy and instant problem resolution
✓High product quality
Disadvantages:
✓Long time
✓Complex calculations
✓Preparation costs
HOW IS SCALE-UP PERFORMED?
• Product
• Type of organism
• Production optimization
• Large-scale examination of production parameters
• Large scale production
• Production evaluation
1. The first studies in scale-up are carried out in laboratory conical
flasks.
2. If success is achieved here, a switch is made to a small volume
laboratory fermenter (5-10 L). The trial used in these stages is
advantageous because it is easy to test the low-cost process
parameters.
3. In the third step, pilot testing begins.
4. Then, studies are continued in a fermenter with a volume of 300-
3000 L. Conditions here are quite close to commercial volume. But
the cost is still low. With computer support, values close to those
obtained under laboratory conditions are obtained.
5. The last stage is the industrial stage where fermentors with a
volume of 10000-400000 L are used. No problems should arise
here anymore.
Erlenmeyer
Flask 5L
Bioreactor Pilot and Industrial
Scale Bioreactors
• The most important part in scale-up studies is to keep the oxygen
rate in the fermenter constant as the fermentor size increases.
• For example, if 200 mmol/hour oxygen is required to achieve
optimum efficiency in a small fermenter, the same rate must be
provided no matter how large the scale becomes. For this, mixing
must be fast and stronger air supply is required.
Studies that need to be done to provide the most ideal
environmental conditions for the growth of the organism
and the production of the product to be formed:

• Nutrient media optimization

• Temperature, pH, mixing speed optimization
• Ambient gas mixture ratio
• Analysis
System characteristics

• Thermodynamics
• Kinetic
• Transport mechanisms
• Similarities between the normal system and the prototype
system:

• Geometric similarity
• Kinematic similarity
• Dynamic similarity
After experiments are carried out on a laboratory scale and the most
suitable production conditions are determined, the estimated values of
large-scale production are determined with theoretical calculations.

o Mixing
o Energy Consumption
o Heat Transfer
o Mass Transfer
o Determination of kLa with Chemical Method
o Sodium sulfide oxidation method
o Absorption of CO2
o Rheology
o Flow to reactor
Recommended methods for scaling up:

❑Studies where energy input is assumed constant

❑Studies in which mixing time was assumed to be constant
❑Studies in which the oxygen transfer coefficient is assumed
to be constant
❑Studies in which environmental conditions (such as
dissolved oxygen) are assumed to be constant
Energy Consumption

• Energy inputs in power consumption are generally

• Mixing (mechanical or magnetic stirrer)
• Ventilation (bubble column)
• It is achieved by liquid circulation (pump).

• Energy inputs are the largest cost in aerobic

bioprocesses.
Mixing speed (N),
Mixer diameter (d),
Density (ρ),
𝑃 = 𝑁𝑝. 𝜌. 𝑁 3 . 𝑑5
Viscosity (η),
Np (power number),
P (power)
• Reynold’s Number
• Relationship between Power Number and Reynolds number:

1
𝑁𝑝 ∝
𝑅𝑒
Mixing
• Ensuring homogeneity in the reactor
• For small scales, stirring is sufficient.
• Mixing processes
• Single phase liquid mixing
• Liquid-liquid mixing
• Gas-liquid mixing
• Solid-liquid mixing
• Three phase mixing
• Mixing degree (m)

𝑠 𝑡 − 𝑠0
𝑚=
𝑠∞ − 𝑠0

𝑠∞ → 𝑠𝑜𝑛𝑠𝑢𝑧𝑑𝑎𝑘𝑖 𝑘𝑜𝑛𝑠𝑎𝑛𝑡𝑟𝑎𝑠𝑦𝑜𝑛𝑠0
→ 𝑏𝑎ş𝑙𝑎𝑛𝑔𝚤ç 𝑘𝑜𝑛𝑠𝑎𝑛𝑡𝑟𝑎𝑠𝑦𝑜𝑛𝑢𝑠(𝑡)
→ ö𝑙çü𝑙𝑒𝑛 𝑘𝑜𝑛𝑠𝑎𝑛𝑡𝑟𝑎𝑠𝑦𝑜𝑛
• Impeller Tip Speed
 Heat Transfer
Dimensionless groups in heat transfer
• Reynold number

• Nusselt number

• Prandtl number
Mass Transfer
Dimensionless groups in mass transfer
• Reynold number

• Sherwood number

• Schmidt number
• Grashoff number

• Peclet number
• Oxygen Mass Transfer Coefficient
• Sodium sulfide oxidation method

• Absorption of CO2
• Product
• Type of organism
• Production optimization
• Large-scale examination of production parameters
• Large scale production
• Production evaluation