2_bp Yoga_scallingup Bioprocess.pdf

2/12/2018

Scaling Up in Bioprocess Dr. Prayoga Suryadarma, STP, MT Department of Agroindustrial Technology, FATETA - IPB

Scale-up you need product for testing you need product for marketing you must learn to work on a large scale

have you ever cleaned a 1000 m3 Bioreactor?

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How to Scale-up lab recipe process diagram get equipment

scale up

scale-down design optimize lab recipe scale up

product and plant design

product for testing

Scale-up Definition • To take a manufacturing process from the laboratory scale to a desired large scale at which it is commercially feasible. • 3 Stages – Bench Scale ( 2 – 20 L) – Pilot Scale (100 – 500 L) – Plant Scale (500 – 20,000 L)

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Scale-up Parameters • Geometry – Height to Diameter Ratio is held constant • Called “aspect ratio”

Scale-up Parameters • Agitation-based parameters – Mixing time – Power input per Volume (P/V) – Tip Speed • Gassing-based parameters – Vessel Volumes per Minute (VVM) – Superficial Gas Velocity (Vs) NOTE: Cannot keep all parameters constant during scale up because they scale by different values

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Agitation Parameters Parameter

Definition

Scale-Up Factor

Amount of time it takes the bioreactor to create a homogeneous environment

N2 agitation speed in scale-up N1 agitation speed in scaledown D1 impeller diameter of scale down D2 impeller diameter of scaleup

Why is this Important?

N2=N1(D1/D2)1/4

Mixing Time

P/V ≈N3/D2 Power Input per Volume (P/V)

Amount of power transferred to a volume of cell culture through the agitator shaft and impellers

P- power supplied V- Volume of Bioreactor N- Agitation Speed D- Impeller Diameter

N2=N1(D1/D2) Tip Speed

Related to the shear rate produced from the impellers moving through the cell culture media

N2 agitation speed in scale-up N1 agitation speed in scaledown D1 impeller diameter of scale down D2 impeller diameter of scaleup

•Want to ensure that the materials are well-mixed in a timely manner

•Mammalian cells cannot handle a lot of power introduced into the culture media as it can cause small eddies that will shear the fragile cell membranes •High shear rates can cause the cell membrane to tear and the cells to die. •If scale-up based on constant tip speed is attempted, P/V and mixing time will decrease

Gassing Parameters Parameter

Definition

Vessel Volumes per Minute (VVM)

means the volume of gas flow (usually measured in slpm, standard liters per minute) per bioreactor volume per minute.

Scale-Up Factor

Volume of Gas Flow/time

Vs = Qgas/Av Superficial Gas Velocity (Vs)

volume of gas per crosssectional area of the vessel.

Vs- superficial gas velocity Qgas- gas volumetric flow rate Av- inside cross-sectional area of vessel

Why is this Important? •necessary to ensure that enough oxygen will be supplied to the cells

•increasing Vs causes an increase in foam generation, a decrease in P/V, an increase in oxygen transfer

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Problems Scale-up a Bioprocess • Fundamental knowledge of chemical and physical interactions among complex ingredients is either scarce or non-existent • There is usually a lack of data of physical properties for complex substrate formulations (specific heat capacities, thermal conductivities, phase relationship, rheology, etc)

Scale-up of Aerobic Bioreactors

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Aerobic bioreactors • Most of the industrial bioprocesses are aerobic • Oxygen is an important nutrient for microorganism for growth • The oxygen transfer rate can control the overall rate of the bioprocess in aerobic bioreactors

Widely used types are

Stirred tank reactor

Bubble column

Air lift column

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Parameters Affecting the Oxygen Transfer Rate • the system physical properties • the biochemical properties • the operational conditions(gas flow rate, stirrer tip speed) • the geometrical parameters of bioreactor (kind and size of bioreactor, design and number of stirrers, etc.) The parameters in the first two groups (red text) are determined by the nature of the system and can not be altered freely; the last two groups depend on the process parameters and on the device used

Steps of Scale-up… • Find geometric parameters of the larger scale bioreactor – Stirred tank reactor Vessel diameter, Height, Impeller diameter – Bubble column Height, Diameter • Use scale up criteria to determine operational parameters of the larger scale – Stirred tank reactor Impeller speed, Air flow rate – Bubble column Air flow rate

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Geometric correlations of a stirred tank reactor For Turbine blade impellers

J

H L W E

Di

D

Scale-up criteria

• Constant volumetric mass transfer coefficient(KLa) • Constant power consumption per unit volume(P/V) • Constant impeller tip speed(пND) • Constant Reynolds number(Re) • Constant dissolved oxygen concentration (CO2)

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Scale-up criteria

P/V (30%) Kla (30%) пND(20%) O2 con. (20%)

Percentage of each criteria used in fermentation industry (Garcia & Gomez, 2009)

Constant tip speed

N1= Impeller speed of small bioreactor N2= Impeller speed of Large bioreactor Di1= Impeller diameter of small bioreactor Di2= Impeller diameter of large bioreactor

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Constant Reynolds number

N = Impeller speed D = Impeller diameter ρL= Density of the liquid μL=Viscosity of the liquid

Constant Power consumption per unit volume

Ungassed power consumption ,

(Rushton’s equation)

Np

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Constant Power consumption per unit volume

Ungassed power consumption ,

(Rushton’s equation)

Gassed power consumption ,

Constant Power consumption per unit volume

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Constant volumetric mass transfer coefficient (kLa) •There are large no.of empirical correlations Ex: empirical correlations to determine Kla for Newtonian fluids in stirred tank reactors

(Garcia and Gomez,2009)

Thank you

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