Chapter 11 Non-ideal Flow and Behavior of Real

Bioreactors

So far we have restricted our discussion to two ideal flow patterns,

well-mixed and plug flow. Although real bioreactors never fully follow
these flow patterns, a large number of designs and operations
approximate these ideals with negligible error. However, some cases
involving in biological reaction systems provide the flow patterns
which are obviously different from these two ideal conditions. For
example, fermenters in cascade which are widely used for ethanol
fermentation process; when bioreactors are scaled up, some
stagnant zones may be developed, especially for high- viscous non-
Newtonian biofluids.

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Furthermore, bypassing or short-circuiting flows also inevitably exist
inside continuously operated bioreactors. The theory of nonideal
flow in bioreacter engineering mainly focuses on describing all of
these phenomena mathematically.

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11.1 Residence Time Distribution Function

In an ideal plug-flow or batch reactor, all the elements of material

leaving the reactors have been inside them for exactly the same
amount of time. The time reaction elements has spent in a reactor
is called residence time.
The ideal plug flow and batch reactors are the only two classes of
reactors in which all the reaction elements present the same
residence time. In all of the other reactors the elements in the feed
spend different times inside the reactors before they finally leave;
that is, there is a distribution of residence times for the reaction
elements within the reactors. For example, consider the CSTR;

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the feed introduced into it at any given time becomes completely
mixed with the material already inside the reactor. In other words,
some of the elements entering the CSTR leave it immediately,
because product stream is being continuously withdrawn from the
reactor; at the same time, others maybe remain in the reactor
forever because all the material is never removed from the reactor
at one time.
Residence time distribution (RTD) function (E function) is
proposed to describe residence time presented by different reaction
elements inside a reactor, therefore:

∝
∫0 Edt = 1

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E
RTD, or E curve

Fraction of exit stream

older than t1
Total area
=1

t1 t
Figure 11.1 Residence Time Distribution (RTD) Function

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The fraction of exit stream of age between t and t + dt is Edt, and
the fraction younger than age t1 is:
t1
∫0 Edt

whereas the fraction of material older than t1 is:

∝ t1
∫t
1
Edt = 1 − ∫ Edt
0

The direct reason responsible for RTD is mixing within a reactor,

thus, RTD can be used to describe all kinds of non-ideal flow
presented within real reactors mathematically.

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Experimental Methods
Since we plan to characterize the extent of non-ideal flow by means
of RTD, we should like to know how to evaluate E for any flow. For
this we resort to the experimental method named stimulus-
response technique.
In our problem the stimulus is usually a tracer input into the feed,
whereas the response is a time record of the tracer leaving the
vessel. Any material that can be detected and which does not
disturb the flow pattern in the vessel can be used as tracer, and
any type of input signal such as a random signal, a periodic signal,
a step signal, or a pulse signal, etc. may be used.

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 Tracer input Tracer output
Vessel
Stimulus Response

Input

Tracer concentration

Tracer concentration
Response Input

Response

Time Time
(a) Random input signal (b) Cyclic input signal

Input
Tracer concentration

Tracer concentration
Input Response

Response

Time Time
(c) Step input signal (d) Pulse input signal

Figure 11.2 Commonly used timulus-response techniques

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The F Curve:
With no tracer initially present anywhere, impose a step input of
tracer of concentration C0 on the fluid stream entering the vessel.
Then a time record of tracer concentration in the exit stream from
the vessel, measured as C/C0, is called the F curve.
The C Curve:
With no tracer initially present anywhere, impose an idealized
instantaneous pulse of tracer on the feed stream. Such an input
is often called a delta function or impulse. The normalized
response is then called the C curve.

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Therefore,

∝
∫0 C (t )dt = 1
where

c(t ) ∝
C (t ) = and Q = ∫ c(t )dt
Q 0

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F Step input signal
1

F curve

0
0 t
Figure 11.3 Typical response signal, called
the F curve, in response to step input

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C Ideal pulse input

Area = 1

0
0 t t
Figure 11.4 Typical downstream signal, called the C curve,
in response to an upstream δ-function input signal

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Let us relate F and C with E for a closed vessel, the closed vessel
being defined as one in which fluid enters and leaves solely by plug
flow, thus with a flat velocity profile. Varying velocities, back
diffusion, swirls, and eddies are not permitted at the entrance and
exit. Real vessels often reasonably satisfy this assumption.
To relate E with C for steady-state flow we note that the RTD for
any batch of entering fluid must be the same as for any leaving
batch. If this were not so, material of different ages would
accumulated within the vessel, thus violating the steady-state
assumption.
Now imagine the following experiment. At time t = 0 introduce a
pulse of tracer into the stream. The C curve for the tracer

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then records when these molecules leave, in other words, their
distribution of ages. Since the C curve represents the RTD for that
particular batch of entering fluid, it must also be the RTD for any
other batch, in particular, any batch in the exit stream. So we have:
C=E

To relate E with F, imagine a steady flow. At time t = 0 a step input

signal is switched on, and then, record the rising concentration of
tracer in the exit stream, the F curve, representing tracer and only
tracer in the exit stream younger than age t at any time t > 0. Thus,
we have:
t
F = ∫ Edt
0

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and
dF
=E
dt
the mean residence time, or holding time, or space-time:

V 1
t or τ = =
F D
We expect that the mean of the E curve is given by t :

∝ ∝
V = ∫ ( Fdt )( ∫ Edt )
0 t

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and
V ∝ ∝ ∝
t = = ∫ [ ∫ Edt ]dt = ∫ tEdt = t E
F 0 t 0

Now, we summarize as follows:

dF
E =C =
dt
t t
F = ∫ Edt = ∫ Cdt
0 0

t = tC = t E

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The Mean:
∝
∫
t= ∝0
tCdt

∫0 Cdt
or
∑ t i C i ∆t i
t=
∑ C i ∆t i

the Variance σ2:

∝ ∝ 2

σ 2 ∫
= 0
(t − t ) 2 Cdt ∫
= ∝
0
t Cdt
−t2
∝
∫0 Cdt ∫0 Cdt

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or
∑ ( t − t ) 2
C ∆t ∑ t 2
C ∆t
σ2 ≅ i i i
= i i i −t2
∑ C i ∆t i ∑ C i ∆t i

Based on the normalized condition of E curve:

∝
t = ∫ tEdt ≅ ∑ ti Ei ∆t
0

and
∝ ∝ 2
σ = ∫ (t − t ) Edt = ∫ t Edt − t 2
2 2
0 0

≅ ∑ t i 2 E i ∆t − t 2

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The Dirac Delta Function:
δ(t − t0) = ∞ at t = t0
δ(t − t0) = 0 elsewhere
∝
∫−∝ δ(t − t0 )dt = 1
and
b
∫a δ(t − t0 ) f (t )dt = f (t0 ) a < t0 < b

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11.2 The RTD in Ideal Reactors
11.2.1 RTDs in Batch and Plug-flow Reactors
The RTDs in plug-flow reactors and ideal batch reactors are the
simplest to consider. All the elements leaving such reactors have
spent precisely the same amount of time within the reactors. The
RTD in such a case is the Dirac delta function, that is:

E (t ) = δ(t − τ)

This means before and after τ no any materials is out of

bioreactors, and just at the time τ all of the materials is harvested.

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11.2.2 Single CSTR RTD
Mass balance for tracer gives:

dc
0 − Fc = V
dt
Integrating with the initial condition c = c0 at t = 0 gives:
t
−
c ( t ) = c0 e τ

and t t
− −
c(t ) c0 e τ e τ
E (t ) = C (t ) = ∝
= =
t
τ
∫0 c(t )dt ∝
∫0 c0 e
−
τ dt

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E(t)

0
0 τ t
Figure 11.5 E curve for PFR

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E(t)
1
τ

0 t
Figure 11.6 E curve for a CSTR

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11.3 Models for Non-Ideal Flow

Many types of models can be used to characterize non-ideal flow

presented within real bioreactors. One-Parameter Models such as
the tanks-in-series model and the dispersion model are widely
used in bioreaction engineering. The dispersion model is mainly
used to design medium continuous sterilization processes
discussed previously or some enzyme catalytic reactions carried
out within tubular reactors. We also introduce Two-Parameter
Model of CSTR with Bypassing and Dead Space at the end of
this section, by which some large scale stirred fermenters can be
described properly.

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11.3.1 The Tanks-in-Series Model

Feed, F

1 2 3
Pulse

Product stream, C3 (t)

Figure 11.7 Tanks in series

The RTD will be analyzed from a tracer pulse injected into the first
reactor and gives:
E (t ) = C3 (t )

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Mass balance on the tracer within the first tank gives:
t
−
τ1
C1 (t ) = e

Mass balance on the tracer within the second reactor gives:

dC2 (t )
Vi = F [C1 (t ) − C2 (t )]
dt
Therefore,

t
−
dC2 (t ) C2 (t ) 1 τi
+ = e
dt τi τi

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With the initial condition C2(t) = 0 at t = 0, we have:

t
−
t τi
C2 (t ) = e
τi

similarly,

t
2 −
t τi
C3 (t ) = e
2τi 3

thus,
t
2 −
t τi
E (t ) = e
2τi 3

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Generalizing this equation to a series of n CSTRs gives its RTD:

t
n −1 −
t τi
E (t ) = e
( n − 1)! τ i n

We introduce:

t t
θ= =
τ nτ i
and

n( nθ) n −1 −nθ
E ( θ) = e
( n − 1)!

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 n=∝ (PFR)
E(θ) n=10

n=1 (CSTR) n=4

1.0
n=2

0 1 θ
Figure 11.8 Tanks-in-series response to a pulse input signal

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 σ2
σθ2 = 2 = ∫0∝ ( θ − 1) 2 E ( θ)dθ
τ
= ∫0∝ θ2 E ( θ)dθ − 2 ∫0∝ θE ( θ)dθ + ∫0∝ E ( θ)dθ

= ∫0∝ θ2 E ( θ)dθ − 1

∝ 2 n( nθ) n −1 −nθ
= ∫0 θ e dθ − 1
( n − 1)!
nn ∝ n +1 −nθ
= ∫0 θ e dθ − 1
( n − 1)!
n n ( n + 1)! 1
= n+2
−1 =
( n − 1)! n n

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So,
1 τ2
n= = 2
σθ2 σ

Also, we can estimate the model parameter n based on the

properties of E(θ):

n( n − 1) n −1 −( n −1)
E ( θ) max = e
( n − 1)!
n
≅ error < 2% for n > 5
2π( n − 1)

The general mass balance on any component A in the ith tank

gives:

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 FC A, i −1 − FC A, i + Vi rA, i = 0
For biomass:

Fxi −1 − Fxi + Vi µxi = 0

Rearranging:

F
xi = xi −1
F − Vi µ

D
= xi −1
D −µ

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Mass balance within the (i-1)th, (i-2)th, …, tanks gives:

D i −1
xi = x1
( D − µ 2 )( D − µ 3 )......( D − µ i −1 )

11.3.2 CSTR with Biomass Recycle

Cell concentration in a single CSTR can be increased by recycling
biomass from the product stream back to the bioreactor. By this
way, much higher rate of substrate conversion and product
formation can be achieved. With cell recycling, the critical dilution
rate for washout is also increased allowing greater operating
flexibility.

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 Fermenter
Feed stream
Cell separator
F, Si

Product stream
V
x F, S, xf, P
S
P

Fr = αF, xr = βx

Recycle stream
Figure 11.9 CSTR with biomass recycling

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We define:

the volumetric flow rate of recycling biomass slurry Fr

α= =
the volumetric flow rate of feed stream F

and
the concentration of biomass contained within recycling slurry x r
β= =
the concentration of biomass inside the fermenter x

Mass balance for biomass gives:

Fr x r + µxV − ( F + Fr ) x = 0

and
µ
D=
1 − α(β − 1)

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 with cell recycling

Biomass concentration x
and productivity x P = Dx

without
P = Dx cell recycling

Dc D cr D
Figure 11.10 CSTR with cell recycling

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