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INTRODUCTION
The following are the important physical parameters for the operation of a
bioreactor: agitation power, agitation speed, broth volume, color, expanded
broth volume (density), foaming, gas flow rate, gas humidity, heat generation
rate, heat transfer rate, liquid feed rate, liquid level, mass, osmotic pressure,
pressure, shear rate, tip speed, temperature, turnover time, and viscosity. 3 Many
of these parameters have important implications in the control of bioreactors.
The following list gives the different parameters that define the chemical
environment inside the reactor: amino acids, carbon dioxide (gas), cation level,
conductivity, inhibitor, intermediate (s), ionic strength, Malliard reaction
products, nitrogen (free and total) , nutrient composition, oxygen, pH,
phosphorous, precursor, product, redox and substrate. 3
All the bioreactors used oxygen at the present time use control strategies for
three basic environmental factors: pH, temperature and dissolved. Invariably,
these control implementations are achieved through regulation of flow rate of
acid / base, flow rate of fluid through the cooling coil, and agitation
respectively. Needless to say, these three parameters are extremely important
for optimal cellular activity. But they alone do not guarantee the maximum
productivity, which is the objective for most of the industrial fermentations.
This paper will explore the control strategies which are used to accomplish this
goal.
Before attempting to understand the details of the control strategies used for
bioprocess, one should be familiar with the common features in the field of
controls. One of the feature integrated into any control system is control
algorithm. The control algorithm is that part of the control system that takes the
available measurements and level of process understanding and decides on the
best way to influence the process with the available manipulated variable to
achieve The desired objective. 4
4. Bioreactor dynamics
The reasons for the above mentioned behaviors are ultimately related to the
complexities of living cells. Finally, many of the important variables which are
desirable for monitoring and control are only measurable with Large time lags
or not measurable at all This gives scope for accurate mathematical models and
/ or state estimation techniques. Fortunately, simple models and single input -
single output feedback loops are available and work well in many cases.
r x = dX / dt = mX (1)
The most commonly used expression that relates the specific growth rate of the
cell to the substrate concentration is Monod's equation, which is given as
m = m max S / (K s + S) (2)
where, m = specific growth rate (hr -1)
m max = maximum specific growth (hr -1)
S = substrate concentration (g / l)
K S = saturation constant for substrate (g / l)
For a continuously fed bioreactor, the cells are continuously supplied substrate
at growth limiting level, and hence they remain in the exponential phase. Since
the cells remain in the exponential phase, Monod's equation can be applied. A
cell balance on the reactor can be written as
For a sterile feed (X f = 0)) and noting that the reaction rate can be written in
terms of the specific growth rate (r x = mX, equation (3) can be reduced to
dX / dt = (m - D) X (4)
where D = dilution rate = F / V (hr -1)
dS / dt = D (S f - S) - mX / Y x / s (7)
The CSTBR (continuous stirred tank bioreactor) is now completely described
by equations (4) and (7) with m given by equation (2). At steady state (with
fixed Sf and D), the following are the values for m (specific growth rate), S
(substrate concentration) and cell concentration (X)
m = D (8)
DK S = S / (m max - D) (9)
X = Y x / s (S f - S) (10)
Figure 2 Relationship between dilution rate and specific growth rate for a
steady state CSTBR
be derived by looking at the steady state solution of equation (4). The two
solutions are equation (8) and
X = 0 (11)
S = S f (12)
Equation (11) and (12) define a situation called washout. This situation is
encountered whenever the value of dilution rate equals or exceeds m max. A
rigorous discussion of washout would point to the fact that whenever m (S f), ie,
m f evaluated at S is less than? Max, then the critical dilution rate for washout
will occur at D = m (S f), and not at D = m max. 1 The control algorithm should be
completely aware of this unproductive state.
For the given set of equations, numerical solution is required since the system
is described by two coupled nonlinear differential equations, ie, equations (4)
and (7). Linear control theory can be applied only in a limited sense, ie, only
near the steady state when the system model is linearized. 1
A steady state is stable if, for initial conditions near the steady state, all
transients converge to it. If the transients diverge, steady state is called
unstable. The diverging transients always end at some other stable state.
Stability analysis of a steady state would involve Whether the steady state
under consideration is stable or not and the information about state - to - state
transitions in case of unstable steady states. 1
The information about the local stability and dynamics of the steady states is
accomplished through a linear stability analysis. It should be borne in mind that
the results of the linear stability analysis are good only near the steady state.
For general (nonlocal) behavior and information about state - to - state
transitions, generation of the phase plane is suitable. 1
As already discussed, for an open - loop CSTBR with Monod's kinetics, there
exist two steady states, ie, a nontrivial steady state (defined by equation (8), (9),
and (10)), washout and steady-state (defined by equation (11) and (12)). The
Jacobian J for the system defined by equation (4), and (7) with m given by
equation (2) is
where X '= dX / dt
S '= dS / dt
Substituting the values for X 'and S' from equations (4) and (7) yields the value
of Jacobian for the system as
For the nontrivial steady state, stability is guaranteed if the following equations
are satisfied
Which yields
-D - m'X / Y x / s <0 (! 7)
Xm'm / Y x / s> 0 (18)
In case of Monod's equation, m '> 0 for all p. Hence, nontrivial state is always
stable. For the washout state, the conditions for stability are derived from a
similar procedure
m (S f) - D <0 (19)
(m (S f) - D) (D)> 0 (20)
Equations (19) and (20) indicate that D must be greater than m (S f) for the
washout steady state to be stable. Thus, any dilution rate which gives any
realistic solution (X> 0, and S> 0) will result in washout being unstable. The
same conclusion can be derived by the analysis phase plane which is also
discussed in the next subsection.
Construction of the phase plane for open - loop CSTBR be achieved through
integrating equations (5) and (8), selecting several time points, plotting the
values of S and X at each point, then repeating for new initial conditions or
sketched directly from the results of the linear analysis. As shown in Figure 3,
all-state initial conditions result in the achievement of the desired steady. 1
The motive for controlling this reactor would be to maintain a closed - loop
system such that washout could be avoided regardless of flow fluctuations. An
easy-state approach to achieve this would be to measure the cell concentration
and manipulate the flow rate to force the reactor to nontrivial steady. This can
Figure 3 Open loop phase plane for bioreactor with Monod's kinetics (S R is
the feed substrate concentration and alpha and beta are the steady-state cell and
substrate concentrations)
The governing equation for the proportional controller which manipulates the
flow rate as a response to changing cell concentration inside the reactor is given
by
D = D ss + K c (X - X sp) (21)
Where, D = dilution rate that is manipulated by the controller (hr -1)
D ss = dilution rate corresponding to the nontrivial steady state for X = X sp in
open loop CSTBR (hr -1)
K c = controller gain (l / g-hr)
X = cell concentration in the reactor (g / l)
X sp = controller set point and the desired cell concentration in the reactor (g /
l)
Substituting the value of D from equation (21) into equations (4) and (7) shows
that X = 0, S = S f is no longer a steady-state solution. A rigorous analysis for
this system will show that the worst case for this system as X approaches 0
corresponds to D = 0 This is equivalent to saying that the CSTBR wants to
approach the behavior of a batch reactor.
The conditions for the stability of the system under consideration according to
linear stability analysis are
Any positive value of K c is sufficient to satisfy equations (22) and (23), and
hence guarantee stability. This state is not surprising keeping in mind the
stability of nontrivial steady in the open - loop CSTBR. It seems fair to expect
the closed - loop phase plane similar to open - loop phase plane for reasonable
values of K c.
The whole discussion can be summarized as follows. Since the nontrivial state
is always stable for realistic D values, there is little incentive for closed - loop
operation other than to prevent washout from large flow disturbances. The
incentive for closed - loop operation increases significantly if the growth
kinetics are more complex, eg, substrate inhibited growth kinetics. This is
discussed in the next section.
Though Monod's kinetics makes a nice model for substrate - limited cases, it
does not approximate the real cases very well since all the biological systems
are inhibited by high substrate concentration. Hence, understanding these kind
of reactors are important. The dynamics of the CSTBR with substrate inhibition
kinetics leads to an interesting control problem. Interested reader may find
detailed analysis by Dibiasio for an open - loop as well as closed - loop CSTBR
with substrate. 1