Biochemical Engineering Journal 111 (2016) 6374

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Biochemical Engineering Journal

journal homepage: www.elsevier.com/locate/bej

Regular article

Novel non-uniform adaptive grid renement control

parameterization approach for biochemical processes optimization
Ping Liu a , Guodong Li a , Xinggao Liu a, , Zeyin Zhang b
a
State Key Laboratory of Industry Control Technology, College of Control Science & Engineering, Zhejiang University, Hangzhou 310027, China
b
Department of Mathematics, Zhejiang University, Hangzhou 310027, China

a r t i c l e i n f o a b s t r a c t

Article history: Dynamic optimization is a very important way to increase the productivity or protability of biochemical
Received 22 December 2015 processes. As an efcient approach for solving these biochemical dynamic optimization problems, control
Received in revised form 28 February 2016 vector parameterization encounters the difculty of selecting an optimal discretization level which bal-
Accepted 12 March 2016
ances the computational cost with the desired solution quality to obtain high accuracy solution. To tackle
Available online 15 March 2016
this issue, a new slope analysis is proposed to analyze the control variables and discretization time grid,
results nd that low slope time grid nodes have less effect on the improvement of performance index
Keywords:
and can be regarded as unnecessary nodes, while high ones are important time points. Based on this, a
Bioprocess optimization
Biochemical processes
novel non-uniform adaptive grid renement control parameterization approach is therefore presented,
Grid renement where the slope analysis is applied to rene or to coarsen the time grid so as to obtain a suitable dis-
Non-uniform grid cretization level with a small number of control intervals. By application in three well-known biochemical
Control parameterization optimization problems, results show that the proposed method is able to achieve similar or even better
Dynamic optimization performance indexes with small numbers of control intervals and lower computational costs.
2016 Elsevier B.V. All rights reserved.

1. Introduction programming (NLP) problem by two strategies: complete param-

Many biochemical processes are naturally dynamic systems [1],
which can be described by complex nonlinear differential equa-
tions. In recent years, plenty of methods have been proposed to
increase the productivity or protability of these processes, where
one of the most important ways is the model-based dynamic opti-
mization. Many efforts have been devoted to obtain high quality
optimal operating policies so as to get the best performance index
[27].
Generally, dynamic optimization methods can be classied in
three main groups: iterative dynamic programming (IDP), indirect
and direct methods. Iterative dynamic programming, which applies
the Bellman optimality conditions to obtain high precision solu-
tions, is rstly presented by Luus [8] and has been used by several
authors for the optimization of industrial processes [9,10]. How-
ever, Vassiliadis et al. [11] pointed out that IDP method would be
computationally very costly. Indirect methods, inspired by the prin-
ciples of variational calculus, are based on Pontryagins Minimum
Principle and have been used in biochemical reactors. Alternatively,
direct methods transform the original problem into a nonlinear
Corresponding author.
E-mail address: lxg@zju.edu.cn (X. Liu).
eterization (CP) [12] and control vector parameterization (CVP)
[13,14], then the results can be obtained by solving the NLP prob-
lem. Furthermore, another existing direct discretization method is
the parametrization approach [15], in which analytical expressions
obtained via Pontryiagins Minimum Principle are used in a direct
approach. Once the analytical expressions for the set of optimal
arcs are derived and the optimal sequence of arcs is found, only
the switching points between the different arcs have to be opti-
mized. As such this approach yields the most appropriate/adapted
parametrization and the best cost value. The advantage of this
approach is that it is numerically well conditioned and the param-
eterization is exact and in most cases parsimonious. This approach
has been widely used in biochemical processes, typical application
can be found in [16]. Also results comparing this parametriza-
tion to an adaptive scheme have been reported in for instance
[17]. Meanwhile, stochastic approaches also apply the evolutionary
algorithms (EA) to solve dynamical system optimization in recent
years, the detailed work can be seen in the survey of Conway in [18].
Compared with indirect methods and stochastic algorithms, direct
methods are less costly and there is no requirement to set up and
solve a multipoint boundary value problem associated with Pon-
tryagins Maxium Principle [19]. Consequently, many literatures
focus on the improvement of direct methods [1,2,5,11,2023].

http://dx.doi.org/10.1016/j.bej.2016.03.006
1369-703X/ 2016 Elsevier B.V. All rights reserved.
64 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374

Since the dimension of the NLP problem in CP is much greater Subject to:
than in CVP, this paper focuses on the CVP method. Usually, the

x(t) = f [u(t), x(t), t]
solution quality of CVP method greatly depends on the discretiza-
tion level, accurate solutions require ne discretization. However, E[x0 (t0 ), t0 , x(tf ), tf ] = 0
a very ne discretization may make the discretized NLP problem C[t, x(t|u), u(t)] 0 (2)
become very large scale and/or ill-conditioned [19,20]. Hence, there
t0 t tf
rises a question to select the optimal discretization level which bal-
ances the computational cost due to the number of parameters with u u(t) u
the desired approximation quality.
where x(t) is an (n 1) state vector, u(t) is an (m 1) control vector,
One possible way is the optimization of the discretization grid
J(x(t), u(t)) is the performance index and consists of the perfor-
points. For example, Teo et al. [2426] presented the well-known
mance of the function 0 (x(tf ), tf ) at the terminal time tf and
time-scaling technique to optimize the original time points, where t
the performance of function t f L0 (u(t), x(t), t)dt during t [t0 , tf ].
the length of the time intervals are regarded as additional deci- 0
sion variables. This method is very efcient for bangbang control f [u(t), x(t), t] is the differential equation of dynamic system. The
problems and has been widely used. While, there is a drawback boundary conditions are E[x0 (t0 ), t0 , x(tf ), tf ] and the path con-
that the discretization NLP problem will be more complex and dif- straints are C[t, x(t|u), u(t)]. u and u are the lower and upper
cult to solve [20]. Another possible way is the renement of the bounds on u(t), respectively. The objective of this problem is to nd
discretization mesh. For instance, Schlegel et al. [20] employed the optimal prole u(t) that minimizes J(x(t), u(t)) during t [t0 , tf ].
fast wavelet transformation and the resulting control representa-
tions in wavelet space for grid renement. Garca et al. [27] applied 3. Uniform discretization-based control vector
a renement to all positions in the time grid by halving the step parameterization
size from previous renement iteration until the stopping criteria
were fullled. Hadiyanto et al. [19] proposed a sensitivity-based The idea of control vector parameterization is to discretize and
step size renement method to improve the product quality of bak- approximate the control vector by a basis function with a limited
ing optimization. Bittner et al. [28] presented an automatic density number of parameters [29,30]. Then a low order B-spline function
function-based mesh renement algorithm (DENMRA) for aircraft (for instance piecewise constant function) can be used to represent
trajectory optimization problem. the control vector.
Since the solution of CVP method greatly depends on the chosen Firstly, partition the time horizon [t0 , tf ] into N even stages
discretization level of time grid, a new slope analysis is proposed [tk1 , tk ], k = 1, 2, , N, called time grid,
to analyze the relationship between the control parameters and t0 = t0 < t1 < t2 < . . . < tN = tf (3)
time grid, results show that low slope points have less effect on
the improvement of performance index and can be regarded as where tk is the time grid node. Next, the control vector can be
unnecessary nodes, while high ones are important points. Based expressed as
on this, a novel slope analysis-based time grid renement method

N
is therfore proposed to select optimal time grid nodes so as to N (t) =
u(t) u  k [t ,t ) (t) (4)
obtain high-quality solution for biochemical dynamic optimization k1 k
k=1
problems with a small number of parameters and low computa-
tional cost. To limit the computational effort, the proposed method where u  k u for k = 1, . . ., N and [t ,t ) is dened as
k1 k
starts with a coarse discretization level for the control input, the 
coresponding time grid nodes are then automatically rened by 1, ift [tk1 , tk )
subdividing the high slope nodes and/or excluding the low ones. [t ,t ) (t) = , k = 1, 2, ..., N. (5)
k1 k
0, ift
/ [tk1 , tk )
With this renement, optimization is continued for a selected group
of input parameters in successive iterations. The proposed method By using the piecewise-constant basis function, the control vec-
is applied in three well-known biochemical dynamic optimization tor u(t) in time stage [tk1 , tk ) is approximated as follows:
systems to verify the efciency of the proposed method.
This paper is structured as follows. The statement of biochem- N (t) =  k , t [tk1 , tk ), k = 1, 2, ..., N.
u(t) u (6)
ical dynamic optimization problem is discussed in Section 2 and N
Although Eq. (6) does not dene the value of u (t) at t = tf , it
the uniform discretization-based control vector parameterization
does not affect the evolution of the state trajectory [31].
is presented in Section 3. Resolution of the time grid is discussed
Through this approximate method, the original Problem (P1) is
in Section 4 and the non-uniform adaptive time grid renement
transformed into a nite-dimensional NLP problem.
procedure is presented in Section 5. Section 6 outlines the imple-
mentation of the proposed approach, and the simulation results are
3.1. Problem (P2)
discussed in Section 7. Finally, the conclusion is drawn in Section
N 
8.
 tk
minJ = 0 [x(tf ), tf ] + L0 [ k , x(t), t]dt (7)

tk1
2. Statement of dynamic optimization problem k=1

Subject to:
A class of typical biochemical dynamic optimization problems 
can be stated as the following Bolza form: N
tk
 
Subject to:x (t) =  L0  k , x (t) t dt
  k=1  tk1
E x0 (t0 ) , t0 x tf , tf = 0
2.1. Problem (P1) (8)
 N
k k
tf  C(t, x(t| ),  )(tk1, tk ) (t) 0
minJ(x(t), u(t)) = 0 (x(tf ), tf ) + L0 (u(t), x(t), t)dt (1) k=1
u(t)
t0 u  k u,
k = 1, 2, . . ., N
 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374 65

It is obvious that the objective of Problem (P2) is to nd a set of

decision variables  k , k = 1, 2, , N to minimize the performance
index J and the solution  k , k = 1, 2, , N are the approximate solu-
tion of Problem (P1). Typically, a gradient-based NLP solver can be
used to solve the reformulated Problem (P2) [32]. Here, the gradi-
ent information of the constraints and the objective function with
respect to the decision variables  k is obtained by using the explicit
solution of the arising sensitivity equation systems.

Remark 1. The convergence results of the CVP method are pre-

sented in [33,34], which is also proved in our previous work in [35].
The proof, therefore, is omitted.

Fig. 1. The slopes of r-th control vector.

4. Resolution of the time grid

In general, it is desirable to obtain a solution of Problem (P2) 5.2. Time grid renement strategy
which is close to the true solution of the original Problem (P1).
Based on the theory in [3335], if time grid [tk1 , tk ] 0 with N 5.2.1. Time grid exclusion
, the solution of Problem (P2) will equal to the solution of Problem The idea of time grid exclusion is to eliminate unnecessary grid
(P1). Following this result, a very ne time grid for control vector is nodes in the representation of  k , k = 1, 2, , N.
a reasonable choice. However, it is not a feasible option for practical Theorem 1
biochemical optimization due to the following two reasons: T
Suppose  1 = [ 11 , . . .,  1N ] is the solution of single control
(r = 1) Problem (P2) with corresponding time grid nodes {t0 =
(1) Numerical accuracy. It should be noted that a very ne time t0 , t1 , t2 , . . ., tN = tf }, where tf is xed. If
grid means that a large number of decision variables need to
+
be calculated, which may make the discretized NLP problem |s1,k | + |s1,k | = 0, k = 2, , N, (11)
ill-conditioned [20].
(2) Computational effort. The computational time required for the the adjacent control vectors are equal, namely,
solving of large scale NLP problem increases signicantly with
the number of parameters [19]. Nevertheless, the solution of  1k =  1k+1 . (12)
a dynamic optimization problem with the sequential method
is strongly correlated to the cost for the sensitivity integration Then, the corresponding time grid nodes tk1 and tk can be com-
[16], which is a very large part of the computational effort. bined, and the time stages are eliminated into N 1 segments with
a new set of nodes {t0 = t0 , t1 , t2 , . . ., tN1 = tf }.
Thus a suitable number of decision variables is desired so that T
the solution of Problem (P2) is close to the solution of Problem Proof. Since  1 = [ 11 , . . .,  1N ] is a solution of Problem (P2), the
(P1). This rises the research question on the optimal selection of the performance index J is,
time grid which balances the computational cost with the desired N 
 tk
approximation quality. Based on this, an adaptive non-uniform J (
1 ) = 0 [x(tf ), tf ] + L0 [ 1k , x(t), t]dt. (13)
renement strategy, which generates suitable time grid for control tk1
k=1
variables, is presented in the following section.
+
Denote :={1, 2, , N 1}. Assume |s1,j | + |s1,j | = 0, thus,
5. Non-uniform adaptive time grid renement procedure
 
 
j+1 j j+1 j
| r r / tj tj1 | + | r r / tj+1 tj | = 0, (14)
5.1. Slope analysis of the control vector

As discussed in [19,20], the solution of Problem (P2) greatly since tj =/ tj1 and tj+1 = j =
/ tj , it is obvious that j+1 (j ). Let
depends on the chosen discretization level of time grid, it is worth I:={j, j + 1}, the performance index J can be rewritten as follows,
analyzing the relationship between the control parameters and

N  tk
time grid.
Denition 1: The left slope sr,k
of the r-th control vector  r , r = J( 1 ) = 0 [x(tf ), tf ] + L0 [ 1k , x(t), t]dt
tk1
I
k=1,k/
1, 2, , m at time grid node tk , k = 2, , N 1 is,
 tk

rk+1 rk + L0 [ 1k , x(t), t]dt. (15)

sr,k = . (9)
tk tk1 kI
tk1

+
The right slope sr,k of the r-th control vector  r , r = 1, 2, , m As  j =  j+1 ,
at time grid node tk , k = 2, , N 1 is,  
tj tj+1
j j+1
+  k+1
r k L0 [ 1 , x(t), t]dt + L0 [ 1 , x(t), t]dt
sr,k = r , (10) tj1 tj
tk+1 tk
 tj+1
j
where rk and rk+1 are the control parameters at time intervals = L0 [ 1 , x(t), t]dt. (16)
[tk1 , tk ) and [tk , tk+1 ), respectively. As an example, Fig. 1 illustrates tj1
the slopes of the r-th control vector.
66 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374

Substituting (16) into (15) gives desired solution quality, we mainly subdivide the important time
 grid nodes. Based on the previous testing, the choice for the time

N tk
grid subdivision tolerance is recommended in the range i = 0.22.
J( 1 ) = 0 [x(tf ), tf ] + L0 [ 1k , x(t), t]dt
I
k=1,k/
tk1 Remark 3. The slope analysis of control variables is separately,
 tj+1 which means that each ur (t), r = 1, 2, ..., m has its own rened
+
j
L[ 1 , x(t), t]dt. (17) time grid. For multivariable dynamic optimization problems, these
tj1 rened time grids should be re-integrated into one.

Finally, there are N 1 grid nodes in (17), denote a new set of time 5.3. Time grid renement for multivariable dynamic optimization
nodes as {t0 = t0 , t1 , t2 , . . ., tN1 = tf } and the corresponding con-
T
trol parameters are  1 := [ 11 , . . .,  1N1 ] , the performance index Since there are many multivariable dynamic optimization
is problems in biochemical processes, such as fed-batch bioreactor
N1 
problems, the time grid renement is expanded as follows.
 tk
J( 1 ) = J ( 1 ) = 0 [x(tf ), tf ] + L0 [ 1k , x(t), t]dt. (18) Algorithm 1. Renement strategy for multivariable dynamic opti-
tk1 mization
k=1

Thus, Theorem 1 is proved. Given: l-th iteration control vector  (l) , time grid
T (l) :=[t0 , t1 , ..., tN (l) ], tolerance e , i .
Remark 2. For multivariable dynamic optimization problem,
Denote R to mark the renement.
Theorem 1 is also suitable. Denote  k = [ 1k , . . .,  m k+1 =
k ] and 
for k = 1,2,. . .,N(l) -1 do
[ 1k+1 , . . .,  m k and  k+1 into (12), the result then
k+1 ], substitute 
for r = 1,2,. . .,m do
can be obtained. +
Calculate sr,k = (rk+1 rk )/(tk tk1 ), sr,k = (rk+1
Based on Theorem 1, the time grid nodes, which have no sig- rk )/(tk+1 tk ).
+
nicant effect on the improvement of the approximation accuracy, if |sr,k | + |sr,k | e then
can be excluded in the sense that slopes satisfy Rrk : = 0 (record the exclusion node).
+
else if (|sr,k | i or |sr,k | i )
+
|sr,k | + |sr,k | e , r = 1, 2, ..., m, k = 1, 2, ..., N, (19)
Rrk : = 2 (record the subdivision node).
where e is a given tolerance. This can easily be accomplished by else
combining time intervals [tk1 , tk ] and [tk , tk+1 ] into [tk1 , tk+1 ]. Rrk : = 1 (record the original node).
It should be noted that the choosing of time grid exclusion tol- end if
erance will affect the judgment of the unnecessary time grid nodes. end for
In order to obtain high accuracy optimization result, e could not
Rk max([R1k , R2k , ..., Rm
k
]) .
be a big value. Therefore, the choice for the time grid exclusion
tolerance is recommended in the range e = 00.08. Rene time grid [tk1 , tk ] and [tk , tk+1 ] with new nodes.
end for
5.2.2. Time grid subdivision The rened time grid T (l) [t0 , t1 , t2 , . . ., tN (l) ] (N
(l) is the new
The key point in time grid subdivision grid renement lies in number of time grid nodes).
identifying those regions of the control prole which require a
higher discretization level. To limit the computational effort, the 6. Algorithm outline
renement starts the optimization with a coarse time grid as previ-
ous methods [1921]. However, the coarse time grid is insufcient Based on the specic details of the slope-based non-uniform
to obtain high quality solution. It is needed to rene these regions adaptive time grid renement, Algorithm 2 gives an overview of
to approximate the true control prole of Problem (P1). The imple- the proposed method and the ow chart is shown in Fig. 2.
mentation of time grid subdivision is shown as follows.
Remark 4. Basically, a heuristic stopping criterion is formulated
based on checking the relative improvement of the objective func-
(1) If the left slope sr,k satises
tion if

|sr,k | i , r = 1, 2, ..., m, k = 1, 2, ..., N (20) |J (l) J (l1) | J (22)

where i is a given tolerance (i > e ). Then the time interval where J is a specied tolerance. However, since a very ne time
[tk1 ,tk ] will be subdivided into NE stages. grid may lead to ill-conditioned Problem (P2), another stopping
criterion is proposed if
+
(2) If the right slope sr,k satises min{tj } tmin , j = 1, 2, , N 1 (23)

+ where tj is a time interval.

|sr,k | i , r = 1, 2, ..., m, k = 1, 2, ..., N (21)
Algorithm 2. Slope-based non-uniform adaptive grid renement
where i is a given tolerance (i > e ), the time interval [tk , tk+1 ] CVP algorithm
will be subdivided into NE stages.
It should be noted that the time grid subdivision tolerance will Choose initial stages, control parameters and time grid: N (1) ,
(1)
inuence the renement and the computation speed. If i 0, ur (0), (r = 1, ..., m), T (1) .
which means that all time grid nodes will be subdivided and could Specify tolerance e , i and J .
obtain better performance index, however the computation cost Choose maximum number of renement iterations: lmax
will increase a lot. To balance the computational cost withthe for l = 1,2,. . .,lmax do
 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374 67

Fig. 2. Flow chart of the SNR-CVP approach.

(l) Remark 5. It should be noted that a next dynamic optimization

Initialize piecewise constant parameterization: ur (t) =
N (l) Problem (P2)(l) will be generated during the renement, it is nec-
k
 r (l)tk1 ,tk (t). essary to initialize the new optimization Problem (P2) (l) . Since N(l)
k=1
is the number of stages, it is easy to know that,
Solve dynamic optimization Problem (P2)(l) .
Optimal solution  (l) , J (l) . N (l) = size(T (l) ) 1 . (24)
if (|J*(l) J*(l1) |>J for (l > 1) and l < lmax ) then
Rene time grid using Algorithm 1 T (l) . j
Meanwhile, the new control parameters r (l)(j = 2, ..., N (l) , r =
else 1, ..., m, l > 1) are initialized based on the solution of the previous
Exit. Problem (P2) (l1) (l > 1), the rules are as follows,
end if
t min{T (l) (2 : 1 : end) T (l) (1 : 1 : end 1)} (nd the (l) j
minimal time interval).if ttmin then (1) If the time grid T j (j = 2, ..., N (l) ) is an exclusion node, r (l) is
Exit. the mean value of these excluded control parameters obtained
end if in last iteration.
(l) j
Calculate the new stages N (l) based on T (l) . (2) If the time grid T j (j = 2, ..., N (l) ) is a subdivision node, r (l) is
j initialized using the corresponding control parameter obtained
Obtain the initial control parameters r (l)(j = 1, 2, ..., N (l) , r =
1, ..., m). in last iteration.
(l) j
end for (3) If the time grid T j (j = 2, ..., N (l) ) is a reserved node, r (l) equals
Optimal solution on adaptive time grid:  =  (l) , J = J (l) . to the previous control parameter (Table 1).
68 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374

Table 1 Table 2
Abbreviation description. Test results for case 1.

Abbreviation Description Iter. SNR-CVP UR-CVP

Iter. Iterations P J(max) tcpu (s) P J(max) tcpu (s)

SNR-CVP Slope-based non-uniform renement CVP approach
UR-CVP Uniform discretization renement CVP approach 1 8 0.0480462 1.30 8 0.0480462 1.31
P The number of optimization parameters 2 9 0.0480515 1.00 16 0.0480515 3.74
# The best numerical result of literature 3 11 0.0480543 1.78 24 0.0480534 8.52
tcpu Computation time 4 13 0.0480553 6.80 32 0.0480544 13.82
N (0) Initial stages Total tcpu (s) 10.88 27.39
ur (0) Initial control parameters
T (0) Initial time grid
lmax Maximum number of renement iterations
e Time grid exclusion tolerance Table 3
i Time grid subdivision tolerance Result comparison for case 1.
J Performance index tolerance
Case 1 Journals Method J(max)

Catalysts Comput. Chem. Eng. [41] ICRS/DS 0.04800

mix- Comput. Chem. Eng. [42] LARES-PR 0.0479
ing IIM-CSIC [39] DOTcvp 0.04805#
J. Optim. Theory Appl. [40] Theoretical solution 0.0480556
Current work SNR-CVP 0.0480553

the paremeters ki (i = 1,2,3) [1,3638]. The dynamic optimization

problem has the form:
Fig. 3. Schematic diagram of catalyst mixing.
maxJ = x3 (tf )
u(t)
Subject to : Dynamic equations(25)
k1 = 1, k2 = 10, k3 = 1
7. Case studies x1 (0) = 1, x2 (0) = 0, x3 (0) = 0 (26)

Three real-world biochemical dynamic optimization problems 0 u(t) 1

are applied to demonstrate the efciency of the adaptive rene-
ment parameterization. For comparison, the uniform discretization
multiplied renement CVP method is employed as the comparative
basis. All of these computations are carried on a PC constituted by
Intel Xeon E31230 processor 3.20 GHz. Furthermore, the SQP solver
FMINCON (SQP), which is also applied in the famous dynamic opti-
mization software DOTcvp, is employed in this work to solve the
dynamic optimization Problems (P2). During the test, the 4-th order
Runge-Kutta intergrator is used to solve the dynamic system and
the integration tolerance is 106 .
7.1. Case 1: optimal mixing policies of catalysts
Case 1 is a dynamic optimization problem for a plug-ow
isothermal reactor with catalysts A and B, along the reactor length.
The reactions are shown in Fig. 3.
Denote x1 (t), x2 (t), and x3 (t) as the mole fractions of the sub-
stances A, B, and C. The dynamic differential-algebraic equations
are:
dx1 (t)/dt = u(t)(k2 x2 (t) k1 x1 (t))
dx2 (t)/dt = u(t)(k1 x1 (t) k2 x2 (t)) (1 u(t))k3 x2 (t) ,
x3 (t) = 1 x1 (t) x2 (t)
tf = 1
0 t tf
During the test, the initial stages are set to 8 and the initial
time grid is T (0) = [0, 1/8, 1/4, ..., 1], the initial control parameter
u(0) = 0.95 is set according to [39,40], and the maximum number
of renement iterations lmax = 5, the tolerances e = 1.2, i = 0.08
and J = 106 are set. Table 2 lists the result comparison of SNR-
CVP and UR-CVP methods. It can be seen that the SNR-CVP approach
obtains a performance index of 0.0480553 with 13 parameters and
10.88 s. Compared with the performance index of 0.0480544 with
32 parameters and 27.39 s obtained by UR-CVP method, results
show that SNR-CVP method needs fewer parameters and lower
computation cost to achieve a better result, which demonstrates
that a non-uniform parameterization is more efcient than the
uniform parameterization of comparable accuracy. Furthermore,
the comparison with previous literature results [3942] in Table 3
shows the solution of SNR-CVP is excellent, further reveals the
effectiveness of the method.
Fig. 4 gives the time grid renement process of SNR-CVP
method. It could be found out that in successive iteration, the
high slope time grid nodes are subdivided and the low ones
are corasened. Fig. 5 gives the comparison of control proles
between SNR-CVP and UR-CVP, results reveal the time grid adjust-
(25) ment of SNR-CVP and a smooth optimal operation trajectory is
obtained.

7.2. Case 2: optimal operation of Park-Ramirez fed-batch

where t denotes residence time from the instance of entry to the bioreactor
reactor, k1 , k2 and k3 are the velocity constants of reactions 1 3,
respectively. u(t) is the fraction of the catalyst formed by the sub- Case 2 considers the maximization of secreted protein in a fed-
stance. The object is to maximize the production of species C with batch bioreactor with single control variable, which is originally
 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374 69

(a) 2 (b) 5 5

0 0

1.5 5 5

10 Left slope 10 Right slope

0 0.5 1 0 0.5 1
1

1.5

0.5
1

Initial grid
Refined grid
0
0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1
Iteration=1 Iteration=2

(c) 5 5 (d) 5 5

0 0
0 0
5 5
5 5
10 10
Left slope Right slope Left slope Right slope
10 10 15 15
0 0.5 1 0 0.5 1 0 0.5 1 0 0.5 1

2 2

1.5 1.5

1 1

0.5 0.5
Refined grid Refined grid
0 0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Iteration=3 Iteration=4

Fig. 4. Time grid renement of iteration 1 4 for case 1.

0.24
1
0.235

0.23

0.225
Optimal profiles

0.22
0.2 0.3 0.4 0.5 0.6

Fig. 6. Schematic diagram of a fed-batch bioreactor.

0
SNRCVP
URCVP

0 0.2 0.4 0.6 0.8 1

Length
dx1 (t)/dt = g1 (t)[x2 (t) x1 (t)] u(t)x1 (t)/x5 (t)
Fig. 5. Comparison of control proles for SNR-CVP and UR-CVP methods.
dx2 (t)/dt = g2 (t)x3 (t) u(t)x2 (t)/x5 (t)

dx3 (t)/dt = g3 (t)x3 (t) u(t)x3 (t)/x5 (t) (27)

formulated by Park and Ramirez [43]. The system of the bioreactor
is illustrated in Fig. 6. dx4 (t)/dt = 7.3g3 (t)x3 (t) + u(t)[20 x4 (t)]/x5 (t)
The dynamic balances for the fed-batch reactor are described by
the following equations [11]: dx5 (t)/dt = u(t)
70 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374

(a) 2 (b) 2 2

1.8
0 0

2 2
Left slope Right slope
4 4
0 5 10 15 0 5 10 15
1
2
0.8
1.5

0.5
Initial grid Refined grid
0 0
0 5 10 15 0 5 10 15
Iteration=1 Iteration=2

(c) 5 5 (d) 10
10
0 0 0
0
10 10
5 5
20 20
Left slope Right slope Left slope Right slope
10 10 30 30
0 5 10 15 0 5 10 15 0 5 10 15 0 5 10 15

2 2
1.5 1.5
1 1
0.5 0.5
Refined grid Refined grid
0 0
0 5 10 15 0 5 10 15
Iteration=3 Iteration=4

Fig. 7. Time grid renement of iteration 14 for case 2.

with Table 4
Test results of case 2.
g1 (t) = 4.75g3 (t)/(0.12 + g3 (t))
Iter. SNR-CVP UR-CVP
g2 (t) = x4 (t)e5x4 (t) /(0.1 + x4 (t)) (28)
P J(max) tcpu (s) P J(max) tcpu (s)
g3 (t) = 21.87x4 (t)/((x4 (t) + 0.4)(x4 (t) + 62.5)) 1 20 32.4533 8.41 20 32.4533 8.83
2 23 32.6309 12.83 40 32.6326 26.38
where x1 (t) and x2 (t) are the concentration of the secreted protein 3 33 32.6866 20.27 60 32.6887 64.84
and the total protein (g/L), x3 (t) is the culture cell concentration 4 49 32.7146 47.50 80 32.6902 123.30
(g/L), x4 (t) is the substrate concentration (g/L), x5 (t) is the holdup Total tcpu (s) 89.01 223.35
volume (L), u(t) is the glucose feed rate (L/h). The objective is to
maximize the mass of protein produced with t = 15 h. The dynamic
optimization problem has the form:
maxJ = x1 (tf )x5 (tf ) achieves a better maximal protein product of 32.7146 g with
u(t) fewer parameters and lower computation cost compared with
Subject to : Dynamic equations(27) the UR-CVP method. Luus et al. [44] used an iterative dynamic
x(0) = [0 0 1 5 1]T (29) programming algorithm to obtain a value of 32.46. Tholuder et al.
[9] achieved a value of 32.47 by employing a ltered iterative
tf = 15h dynamic programming (FIDP) procedure with 3651 s CPU time.
0 u(t) 2.5 Eva et al. [11] presented a mesh rening technique with CVP
method to obtain a value of 32.480 with 316 s computation time.
During the test, N (0) = 20 is set and T (0) = Angira et al. [45] applied a trigonometric differential evolution
[0, 3/4, 6/4, 9/4, ..., 15], the initial control parameter u(0) = 0.5 (TDE) approach for solving this problem with a value of 32.684494
is set according to DOTcvp [39], and lmax is 4. Results obtained by and 308.1328 s CPU time. Chen et al. [1] proposed a hybrid CVP
UR-CVP and SNR-CVP with tolerance J = 105 , e = 0.5, i = 0.06 to solve this problem with a value of 32.68712. It can be found
are shown in Table 4. It can be seen that SNR-CVP approach that the result obtained by the SNR-CVP method is better than the
 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374 71

Table 5 Table 6
Comparison of test results for case 2. Test results of case 3.

Case 2 Journals Method J(max) tcpu (s) Iter. SNR-CVP UR-CVP

Park-Ramirez Ind. Eng. Chem. IDP 32.46 P J(max) tcpu (s) P J(max) tcpu (s)
bioreactor Res. [44]
Int. J. Contr. [9] FIDP 32.47 3651 1 20 6.1477 20.48 20 6.1477 25.16
Comput. Chem. second-order 32.480 316 2 24 6.1507 18.94 40 6.1508 41.47
Eng. [11] CVP 3 34 6.1512 37.51 60 6.1511 112.85
Comput. Chem. TDE 32.684494 308.1328 4 74 6.1514 27.58 80 6.1512 182.65
Eng. [45] Total tcpu (s) 104.51 362.13
#
IEEE Trans. ndCVP-HGPSO 32.68712
Automat. Sci.
Eng. [1] Table 7
Current work SNR-CVP 32.7146 89.01 Comparison of test results for case 3.

Case 3 Journals Method J(max)

Lee-Ramirez Comput. Chem. Eng. [11] second-order CVP 6.15

2.5
bioreactor Comput. Chem. Eng. [48] NSGA-II 6.1504#
Bioprocess. Biosyst. Eng. [47] ACADO 6.15
Current work SNR-CVP 6.1514
Glucose feed rate [L/h]

dynamic optimization problem has the form:

SNRCVP  tf
max J = x1 (tf )x4 (tf ) Q u2 (t)dt
u1 (t),u2 (t) t0
Subject to : dx1 /dt = u1 (t) + u2 (t)

dx2 /dt = (x3 , x5 , x6 , x7 )x2 x2 (u1 (t) + u2 (t))/x1

0 f
0 5 10 15
dx3 /dt = Cn u1 (t)/x1 x3 (u1 (t) + u2 (t))/x1 Y 1 (x3 , x5 , x6 , x7 )x2
Time [h]
dx4 /dt = Rfp x2 x4 (u1 (t) + u2 (t))/x1
Fig. 8. Optimal control prole for case 2. f
dx5 /dt = Ci u2 (t)/x1 x5 (u1 (t) + u2 (t))/x1

15 dx6 /dt = k1 x6
x1 [g/L]
x2 [g/L] dx7 /dt = k2 (1 x7 )
x3 [g/L]
x4 [g/L] T
x(0) = [ 1 0.1 40 0 0 1 0]
x5 [L]
10 t0 = 0

tf = 10(h)

0 u1 (t) 1
5
0 u2 (t) 1
(30)

0 parameters (x3 , x5 , x6 , x7 ), Cn , Y 1 , Rfp , Ci , k1 , k2 can be found in
0 5
TIme [h]
Fig. 9. Optimal state proles for case 2.
best result reported in [1], which shows a good solution quality
(Table 5).
Fig. 7 shows the time grid renement process of SNR-CVP
approach, which reveals the adjustment of time grid during the
optimization. Fig. 8 illustrates the control prole of SNR-CVP and
the corresponding state proles are shown in Fig. 9.
7.3. Case 3: multivariable optimal control of Lee-Ramirez
bioreactor
Case 3 considers the multivariable dynamic optimization of a
fed-batch reactor for induced foreign protein production by recom-
binant bacteria, as presented by Lee and Ramirez [46]. The objective
is to maximize the protability of the process using the nutrient and
the inducer feeding rates (u1 (t) and u2 (t)) as the control vector. The
where xi (t), (i = 1, 2, ..., 7) are the state variables and the detailed
f f
10 15 [46,47] and are shown in Appendix. The ratio of the cost of inducer
to the value of the protein production Q = 0 is considered (Table 5).
During the test, N (0) = 20 and T (0) = [0, 1/2, 1, 3/2, ..., 10] are
set, the initial control parameters u1 (0) = 0.5 and u2 (0) = 0.5
are set according to [39], the maximum number of renement
iterations lmax is 4. Table 6 shows the results of SNR-CVP and UR-
CVP methods, where tolerance J = 10-5 , e = 0.2, i = 0.01 are
adopted. It can be seen that the proposed renement method is ef-
cient to solve the multivariable dynamic optimization problem. By
using the non-uniform renement strategy, fewer parameters are
increased in successive iteration when compared with the uniform
renement CVP method. Thus, the computation time is efciently
decreased. Eva et al. [11] proposed a novel renement method using
restricted second-order information to solve this problem with a
result of 6.15. Sarkar et al. [48] presented a non-dominated sorting
genetic algorithm to solve this problem and obtained a performance
index of 6.1504. Logist et al. [47] obtained a same result as Sarkars
by employing the ACADO Toolkit. The results of literatures and SNR-
CVP method are reported in Table 7, it can be seen that the proposed
method is able to obtain similar or even better performance index.
72 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374

(a) 2 (b) 0.8 0.8

left slope Right slope

Slopes of u1

Slopes of u1
0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 5 10 0 5 10
0.8 0.8
left slope Right slope
1

Slopes of u2

Slopes of u2
0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 5 10 0 5 10
2
0
Initial grid Refined grid
0 2
0 2 4 6 8 10 0 2 4 6 8 10
Iteration=1 Iteration=2

(c) 1.5 3 (d) 4 4

left slope Right slope left slope Right slope

Slopes of u1

Slopes of u1
Slopes of u1

Slopes of u1

1 2
2 2
0.5 1
0 0
0 0

0.5 1 2 2
0 5 10 0 5 10 0 5 10 0 5 10
2 4 6 6
Slopes
left slope of u1 Slopes of u1
Right slope Slopes
left slope of u1 Slopes of u1
Right slope
Slopes of u2

Slopes of u2
Slopes of u2

Slopes of u2

4 4
1 2
2 2
0 0
0 0

1 2 2 2
0 5 10 0 5 10 0 5 10 0 5 10
2 2
Slopes of u1 Slopes of u1 Slopes of u1 Slopes of u1
0 0
Refined grid Refined grid
2 2
0 2 4 6 8 10 0 2 4 6 8 10
Iteration=3 Itertaion=4

Fig. 10. Time grid renement of iteration 14 for case 3.

Fig. 10 shows the time grid renement process of SNR-CVP Acknowledgments

method, where each control variable is analyzed and a nal non-
uniform rened time grid is obtained by using Algorithm 1. Fig. 11 This work was supported by the National Natural Science Joint
illustrates the control proles of SNR-CVP and UR-CVP. Funds of NSFC-CNPC of China (Grant U1162130), National High
Technology Research and Development Program of China (863,
Grant 2006AA05Z226), Zhejiang Province Natural Science Founda-
8. Conclusion
tion (LY16B040003), Shanghai Aerospace Science and Technology
Innovation Fund and Aerospace Science and Technology Innovation
This paper presents an efcient non-uniform adaptive grid
Fund of China Aerospace Science and Technology Corporation.
renement control parameterization approach for biochemical
dynamic optimization to increase the productivity or protability
of biochemical processes. By using a new slope analysis of control Appendix A.
variables and discretization time grid, important time grid nodes
and unnecessary nodes can be discriminated. Hence, a suitable The parameters of case 3 are shown as follows:
discretization level of control variables which balances the com-
putational cost with the desired solution quality is obtained by The detailed parameters of (x3 , x5 , x6 , x7 ), Rfp , k1 , k2 are,
rening or coarsening time grid nodes in successive iteration.
By application in three well-known biochemical optimization max x3 kcr
problems, numerical results show that the proposed method can (x3 , x5 , x6 , x7 ) = {x6 + x7 }, (A1)
kCN + x3 + x32 /ks kcr + x5
adjust the time grid efciently by using the non-uniform rene-
ment strategy. Especially, the multivariable problems are also
fmax x3 fIO + x5
applicable. Therefore, the proposed method is able to achieve sim- Rfp = ( )( ), (A2)
ilar or even better performance indexes with a small number of kCN + x3 + x32 /ks kI + x5
parameters compared with uniform renement CVP method and
other optimization methods in literature, whereas the computa- k11 x5
k1 = k2 = . (A3)
tional costs are lower. k1x + x5
 P. Liu et al. / Biochemical Engineering Journal 111 (2016) 6374 73

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