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Claire Komives

y

Advanced control methods have been effectively employed for

industrial chemical processing for decades. Only recently,

however, have model-based strategies been implemented for

biological processes. Some notable advances include the

enhancement of metabolic ux models to describe the

dynamic behavior observed in biochemical reactors. The

combination of more than one type of model in a hybrid

form was shown to perform well for bioprocess control

applications.

Addresses

University, 1 Washington Square, San Jose, CA 95192-0082, USA

e-mail: claire.komives@sjsu.edu

y

Department of Chemical and Petroleum Engineering, 1249 Benedum

Hall, University of Pittsburgh, Pittsburgh, PA 15261, USA

e-mail: rparker@pitt.edu

Current Opinion in Biotechnology 2003, 14:468474

This review comes from a themed issue on

Biochemical engineering

Edited by Jeremy S Edwards and Kenneth J Kauffman

0958-1669/$ see front matter

2003 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.copbio.2003.09.001

Abbreviations

ANN articial neural network

CER carbon dioxide evolution rate

DO dissolved oxygen

FFN feed forward neural network

GA genetic algorithm

OUR oxygen uptake rate

PCA principal component analysis

RBFN radial basis function network

Introduction

Bioprocess technology is currently employed for the

production of several commodity and ne chemicals.

Because of the complex nature of microorganism growth

and product formation in batch and fed-batch cultures,

which are often used in preference to continuous cultures,

the control of bioprocesses continues to present a chal-

lenge to chemical engineers. Extensive developments in

the area of process control have recently begun to impact

bioprocess development, but much work remains to be

done to couple model-based control methods to biochem-

ical reactor technology.

At the heart of bioprocess control is the ability to monitor

important process variables such as pH, temperature,

dissolved oxygen (DO), oxygen uptake rate (OUR) and

carbon dioxide evolution rate (CER). Although additional

measurements have become available recently [1], many

quantities of interest, such as intracellular product levels,

remain inaccessible. However, the inability to measure

certain variables need not keep the bioprocess engineer

from extracting valuable information from a reactor.

Advanced control systems typically employ mathematical

models that describe the process being controlled [2].

The use of a mathematical technique in conjunction with

the measurements can enable the estimation of para-

meters or process variables that cannot be directly mea-

sured. On-line estimation allows performance renement

and the ability to query the metabolic state of the cell and

reactor system. Figure 1 provides a qualitative description

of the relationship between the reliability of on-line

estimation and the complexity of the estimator. The

degree to which one can estimate the state of the system

is dependent on the availability of accurate measure-

ments of process variables such as pH, DO and off-gas

(the gas exiting a bioreactor) composition. More informa-

tive measurements, such as measurements of metabolic

products or intracellular metabolites, can provide a more

comprehensive description of the system. However, these

measurements often suffer from greater inaccuracy and

incomplete information. Thus, the improved perfor-

mance of the estimator is not guaranteed.

This paper will focus on methods to estimate parameters

and process variables that cannot be measured directly,

and the consequent use of these inferred measurements

for the control of bioprocesses. Recent reviews cover the

mathematical modeling aspects of this topic in greater

detail than space allows here [35,6

in measurement methods that enable the estimation of

the metabolic state of the culture will also be discussed.

Emphasis has been placed on published work that incor-

porates experimental validation.

Empirical models

Models based on data-driven relationships can be used for

a variety of purposes. The mathematical structure of the

model and the incorporation of parameters to be esti-

mated can be designed by the user. Empirical models can

range from very simple, for the estimation of a single key

variable, to very complex, for the estimation and control

of the full process state. Recent articles have employed

empirical models ranging in complexity and scope.

The estimation of OUR and CER from measurements

of O

2

and CO

2

in the fermentor off-gas has become

commonplace. Several useful parameters and process

variables can be estimated and controlled on the basis

468

Current Opinion in Biotechnology 2003, 14:468474 www.current-opinion.com

of these measurements [10,11]. The approximation is

made that the concentrations of the gases measured

downstream at the monitor are equal to the partial pres-

sures in the fermentor head space; the incomplete mixing

in the head space and the time delay owing to the volume

ow in the tubing between the fermentor and the monitor

are ignored. To enable the kinetic analysis of bioreactors,

Wu and coworkers [12

function model and were able to identify the system

parameters from input-output data. They obtained excel-

lent agreement between the measured and estimated

values of the OUR and CER within seconds following

a system perturbation.

The black-box or input-output model is an important

type of empirical model. A black-box model is so-called

because the mathematical structure of this empirical

model is not based on rst-principles knowledge of the

process of interest. A popular black-box model in the

recent literature is the articial neural network (ANN)

[13]. The inputs to the model are process measurements.

The measurements are weighted individually or in

groups and then combined using a nonlinear activation

function at a node referred to as a neuron, named after

the nodes in the brain which combine information sent

from the natural senses. A process ANN model is often

composed of an input layer, an output layer, and one or

more hidden layers of nodes. The traditionally used

format of ANN is the feed forward neural network

(FFN). In this network, the outputs of one layer of nodes

serve as the inputs to the following nodes. Given a set of

process measurements, the outputs of the neural network

can be estimated parameter values or process variables.

The weights applied to the inputs in the model are

determined through the training process. To train the

ANN, complete process information, corresponding to

the neural network inputs and outputs, is required and

must be obtained from the data of a set of fermentation

runs. The set of process input and output measurement

values spanned by the experimental data is termed the

experimental space and the ANN will predict outputs

accurately within this range. Should a process modeled

by an ANN operate beyond the experimental space,

commonly referred to as an excursion, the ANN may

return inaccurate output estimates. This is a function of

the extrapolation properties of neural network systems,

which are known, in general, to be poor [13]. For this

reason, control software based on certain input-output

model structures, such as ANNs, is difcult to validate for

pharmaceutical processing.

Valdez-Castro and coworkers [14] used a recurrent train-

able neural network to estimate seven process variables

for a Bacillus thuringiensis fermentation for the production

of an insecticide protein. The control objective was to

maintain the feed rate at a limiting value to enable high

production of the protein product. The model architec-

ture contains an input layer, a hidden layer and an output

layer that back-propagates to the hidden layer. The

advantages of this approach are reported to be a faster

learning process and greater stability as compared with an

FFN. Given the data-intensive nature of ANN training,

and the extrapolation properties discussed above, the

recurrent neural network approach is likely to be superior

for bioreactor modeling and control.

A hybrid ANN can incorporate a priori knowledge of the

process along with the standard neuron-type nodes into

the neural network model in separate functional nodes, as

demonstrated by Fellner and Becker [15]. To incorporate

the process information, a differential equation for the

estimation of diacetyl is included at a functional node.

The estimation model incorporates measurements of pH,

temperature, specic gravity and turbidity, which can all

be measured on-line during beer fermentation. A descrip-

tion of the estimation method is described in a separate

paper [16]. Their approach demonstrated a 46%reduction

in necessary data for training of the model and elimination

of incorrect control decisions by the hybrid structure.

The reduction in the required training data produces a

signicant decrease in the cost and time lost to model

identication. Unfortunately, the ability of the reduced-

data hybrid ANN to extrapolate beyond the experimental

space was not explored.

Figure 1

Current Opinion in Biotechnology

Low

High

Substrate

Biomass

Off-gas

IM

Low

High

DO

pH

T

Metabolic

products

Estimator

performance

Model/estimator complexity

Schematic describing the effects of model complexity on estimator

performance. The shaded regions represent potential bioreactor

measurements. As more detailed information becomes available,

theoretical estimator performance improves. Because of the uncertainty

and error that often exist in higher resolution measurements,

performance improvements are not guaranteed. Measurements include

dissolved oxygen (DO), pH, temperature (T), off-gas, substrate, biomass,

metabolic products and intracellular metabolites (IM).

Bioreactor state estimation and control Komives and Parker 469

www.current-opinion.com Current Opinion in Biotechnology 2003, 14:468474

James and coworkers [17] compared six different methods

for estimating the biomass during the rst 10 h of fed-

batch Alcaligenes eutrophus fermentations. The FFN was

compared with a radial basis function network (RBFN) in

both the black-box and hybrid forms. Like the FFN, a

RBFN is a network of neurons consisting of an input

layer, a hidden layer or layers, and an output layer. Unlike

the FFN, the neurons of the hidden layer are governed by

radial basis functions, which are symmetric about a center

(e.g. Gaussians), and the network output is a weighted

sum of the outputs of the hidden layer(s). The key

difference in these networks is the choice of the threshold

function, sigmoidal for FFNs versus Gaussians or wave-

lets for the RBFN estimators. In addition, the FFN uses a

back-propagation approach for training, whereas the

RBFN does not. Both types of neural network model

in the hybrid form, incorporating a discretized mass

balance differential equation for the biomass, predicted

the biomass well. The hybrid models were superior to the

black-box models in their prediction with regards to the

computed sum of squares errors from a selected run. The

potential advantage of the RBFN model is reduced

sensitivity to sensor noise as compared with the FFN,

which can be signicant with bioprocess monitoring.

Mass balance models

Dynamic elemental mass balances are the traditional

chemical engineering approach to state estimation in

bioreactors. When many by-products are produced it is

difcult to account for all the species without a complex

monitoring system. As an alternative, it is possible to

avoid monitoring all the components by employing the

cybernetic modeling framework [18]. This approach uses

dynamic balances at the reactor scale and reasonable

assumptions regarding the regulatory structure of the

organism. Given the possibility of making accurate mea-

surements of bioreactor process variables, the possibility

of using mass balance models has a high chance of

success. For example, ow-injection analysis (FIA) can

be used to measure many compounds accurately in bior-

eactors, such as enzyme activity, biopolymer content

and turbidity. A sample can be automatically removed

by a sampling system and the analysis is performed

[8,19]. The information can then be used for the estima-

tion of concentrations in the bioreactor. Nilsson and

coworkers [20] controlled the feed rate in a yeast fer-

mentation on lignocellulosic hydrolysates by estimating

the sugar concentration in the bioreactor based on mea-

surements of CER and biomass. The biomass concentra-

tion was measured by FIA.

The ability to monitor the viable biomass concentration

in the bioreactor is more meaningful than the total

number of cells present for state estimation. Capacitance

can be measured from which the amount of viable bio-

mass can be estimated; a build-up of charge across cell

membranes of viable cells can be induced and measured

as the culture capacitance. Estimators for biomass based

on observer theory were developed by Bastin and

Dochain [4] and explored in a Candida utilis fermentation

by November and Van Impe [21]. The on-line measure-

ment of capacitance led to good estimates of the biomass

when appropriate tuning parameters and a lower bound

for the lowinitial values in the reactor were implemented.

Statistical estimation methods

Biomass measurements are frequently subject to experi-

mental error, and numerically differentiating this signal to

estimate specic growth rate amplies the error. The

accurate determination of specic growth rate enables

the calculation of kinetic parameters. Adata lter is able to

smooth out measurement errors and outliers. Neeleman

and van Boxtel [22] applied a backward and forward

extended Kalman lter to the off-line biomass mea-

surements to estimate the specic growth rate, which en-

abled the calculation of kinetic parameters. The use of

backward ltering to reduce estimator sensitivity to

initial condition effects combined with recursive forward

estimation of parameters provided superior performance

in biomass prediction for this case study.

Certain process characteristics, such as batch production,

lead to convenient estimator formulations. In the case of

batch processes, expected dynamic behavior can be

accounted for by enforcing smoothness constraints on

the estimated metabolite proles. Ethanol and residual

sugar concentrations in beer fermentations were recon-

ciled and consequently smoothed using a probabilistic

approach that enabled the calculation of rates with good

accuracy [23]. Experimental results validated the use of

smoothness constraints on the process dynamic response.

Parameters in the model were estimated through a novel

decomposition of the highly nonlinear optimization pro-

blem into a hierarchy, including an unconstrained non-

linear problem followed by four independent constrained

quadratic programming problems [23]. The result was a

stoichiometric model that successfully captured the

dynamic system response and provided estimates of

ethanol and sugar concentrations, and their corresponding

production and consumption rates; refractive index and

broth density were also estimated from on-line measure-

ments throughout the batch.

Database models

Database models have been explored recently as an

efcient approach to using historical data [23]. The

incorporation of information from fermentation runs into

a process model can be a daunting task in light of the

many components present in the broth. The choice of

critical variables can be simplied by using mathematical

tools designed to extract the most signicant variables or

sets of variables from a large dataset. By using these

critical variable sets, the modeling process becomes easier

without sacricing model quality.

470 Biochemical engineering

Current Opinion in Biotechnology 2003, 14:468474 www.current-opinion.com

Multiway principal component analysis (PCA) is an

approach to data reduction that enables the mathematical

classication and reduction of large datasets. The trans-

formation of seed fermentation data into principal com-

ponents enabled Cunha and coworkers [24] to improve

the prediction of nal process productivity as compared

with an analysis of the data only from the automated

main production fermentor. Principal components are

weighted sums of process measurements, or states, that

capture a percentage of the process variability using a

signicantly reduced number of process variables. How-

ever, it was suggested by Takors and coworkers [25] that

relatively large errors would make multivariate PCA

unsuitable for use along the course of a fermentation

run. The identication of critical process parameters for

the development of the process model can also be facili-

tated using information from fermentation runs by per-

forming a decision tree analysis [26]. Like PCA, this

approach begins with the historical fermentation data

from several runs and identies the signicant variables

for effective analysis and modeling of the process by an

automated objective method. Decision tree analysis is

able to incorporate both continuous variables, such as

consumption rates, as well as categorical variables such as

fermentor number and inoculation time. The net result of

both approaches is to reduce the dataset while maintain-

ing the requisite information to classify the outputs.

Optimization algorithms

The use of optimization algorithms to assist in driving

the process towards the production objective is an entic-

ing application of on-line estimation [9]. Here, the focus

shifts from the ability to measure or estimate a parameter

or process variable to the opportunity to improve process

performance using these measurements and estimates.

Ideally, a process should be operated at the optimum

condition, as dened by the operating objective(s), such

as maximum productivity and minimized environmental

impact. To employ an optimization algorithm, a process

model is required. Furthermore, it must be recognized

that the optimum calculated from the model and the

experimentally observed optimum may differ owing

to the presence of process-model mismatch. Some ap-

proaches to estimation and optimization are presented

below. Although the results are often promising, the

mathematical and/or computational burden in employ-

ing these techniques is higher than many of the other

methods discussed in this work.

Neural networks can be used in both estimation and

process optimization. Becker and coworkers [27] applied

an FFN for the control and optimization of a pilot-scale

beer fermentation. Diacetyl is a principal avoring com-

ponent in beer and must be maintained below 0.15 ppm

for product quality; however, there are no cost-effective

ways to measure the diacetyl concentration during the

run. To account for the dynamics, a special neuron, called

a nite impulse response neuron, was incorporated into

the neural network. This special neuron allows for a one-

step-ahead prediction, and measurements during the run

can be used as input data to adapt the prediction along the

course of the fermentation. This dynamic neural network

serves as the process model and allows the optimization to

be performed through the application of variational cal-

culus. The inputs to the model are values of the diacetyl

measured on-line (via a software sensor), pH, tempera-

ture, specic gravity and time. Comparisons of the one-

step-ahead predictions of diacetyl and specic gravity

with the on-line measurements were excellent, and the

optimization of the process enabled a reduction in process

time of 10% averaged over four fermentation runs.

The search for an optimum process condition when a

process model is linear is relatively straightforward. Bio-

logical processes, however, are highly non-linear. Genetic

algorithms (GAs) are optimization routines that operate in

a similar manner to natural genetic selection and which

can be used with nonlinear process models (for more

details see [28]). Na and coworkers [29] employed GAs

to optimize the fed-batch growth of S. cerevisiae on glu-

cose. The approach proved a success for optimizing and

controlling the bioreactor and estimating reactor para-

meters on-line. The strategy for optimizing the process

was to calculate a sequence of feed ow rates and the

corresponding times to switch between these ow rates.

In addition, another GA was used to update the produc-

tion rate and yield parameters on-line. Although generally

successful as nonlinear optimizers, GAs are computation-

ally demanding. In fact, in the study by Na and colleagues

[29] the time taken for the algorithms to compute the next

manipulated variable move was about 25 min, including

the parameter update step.

Chiou and Wang [30] used a hybrid differential evolution

(HDE) algorithm as an approach to state estimation.

Differential evolution and GAs are both types of evolu-

tionary algorithms that are appropriate to use when little

or no a priori knowledge of the process is available,

although the degree of mathematical complexity is high.

In this work, the addition of acceleration and migration

operations enabled faster convergence to the optimum

conditions. The model was tested with an E. coli fer-

mentation for the production of a recombinant protein.

The steady-state performance of the estimator was quite

good. Furthermore, the estimator qualitatively captured

the dynamic behavior, although quantitative estimation

error remained. Whether the dynamic error is the fault of

the estimation algorithmor the proposed model structure

is uncertain.

Another strategy proposed for optimizing a nonlinear

process is the use of Pontryagins maximum principle

[31]. This method involves an off-line analytical solution,

which returns a manipulated variable trajectory, such as a

Bioreactor state estimation and control Komives and Parker 471

www.current-opinion.com Current Opinion in Biotechnology 2003, 14:468474

feed-rate prole, that can be implemented on-line.

Levisauskas and colleagues [32

to maximize protein production in E. coli with a fed-

batch bioreactor. Parameters for a mass balance model of

the process that incorporated cell maintenance require-

ments were determined from three initial experiments

using an evolutionary algorithm [33]. The fermentation

included both the biomass growth phase and the protein

production phase, during which time the biomass growth

slowed but was not halted. During the protein produc-

tion phase, the authors measured higher total protein

production at lower specic growth rates. The quantita-

tive relationship between protein production and growth

rates was incorporated into the model. The resulting

optimization scheme returned the optimal time for

induction and the feed rates that maximized biomass

production in the rst phase and protein production

at the end of batch. With careful experimentation and

a well-designed mass balance model, this approach

resulted in a doubling of the protein production with

only four fermentation experiments.

Mahadevan and Doyle [34] studied the optimization of

recombinant protein production in a fed-batch bioreac-

tor using tools from nonlinear analysis [35]. The princi-

ple advantage of their strategy is to reduce on-line

computation time by input elimination, which uses an

off-line mathematical transformation to simplify the on-

line problem. The solution successfully estimates, and

compensates for, parametric drift in the model. Although

this approach demonstrates the capability of involved

mathematical approaches in bioreactor control and esti-

mation, the cost is often increased off-line complexity or

on-line calculation.

Metabolic ux models

Metabolic ux models describe the relative utilization

of the metabolic pathways in a whole-cell biocatalyst.

Originally, the use of these models required the system

tobeat steadystate. Thetermpseudo-steady-stateallowed

a broader use of these models for approximation of meta-

bolic activity in a dynamic setting. The papers described in

this section touch on improvements in the application of

metabolic ux models for dynamic modeling. Further-

more, it is suggested that this model class may soon be

used for on-line bioreactor state estimation and control.

The use of

13

C labeling for the measurement of meta-

bolites for metabolic ux analysis has been described [36].

El Massaoudi and coworkers [37,38] showed the feasi-

bility of using this technique in a large fermentor (300 L)

by running a parallel, small reactor that they called the

sensor reactor. Fresh production broth from the large

reactor enters the sensor reactor every 20 min for

13

C

labeling and the data are generated for the metabolic ux

analysis. The study establishes the feasibility of this

parallel reactor system for fast data collection that mirrors

the conditions in the large reactor. A future paper will

describe the system for process control.

Sainz and coworkers [39] presented a metabolic ux

model for yeast combined with a dynamic process model

to mathematically represent batch wine fermentation.

The ux model did not contain dynamic terms, but the

model was used with a linear optimization routine to

determine the uxes present with the objective to max-

imize growth and glucose uptake. The uxes determined

were then fed to differential equations for the description

of the process. The combined models were able to

represent the dynamics quite well. Data for the validation

of their model was taken from the literature.

Dynamics of a bioreactor can be studied experimentally

by perturbing a steady state. Herwig and coworkers [40]

developed a dynamic metabolic ux model for use with

transient on-line analysis. To continuously check the

data consistency, a simple statistical evaluation of the

data was performed as originally described in Wang and

Stephanopoulos [41]. Although they have not demon-

strated their approach for on-line estimation or process

control, the effective use of a metabolic ux model under

transient conditions shows promise for non-steady state

metabolic estimation.

Mahadevan and coworkers [42

] combined optimization

with a dynamic metabolic ux model to describe the

diauxic growth of E. coli. The dynamic model is able

to determine the rate of change of the ux constraints.

Unlike the traditional static ux balance, their strategy

enabled the prediction of the reuptake of acetate after

glucose exhaustion in the broth. In the absence of kinetic

parameters, this approach shows great potential for bio-

reactor state estimation.

Advances in monitoring for state estimation

New techniques for process monitoring offer the poten-

tial for considerable insight into the properties of the

broth and cellular dynamics during the course of a fer-

mentation run. Although extensive programs have been

developed in this area, only two techniques will be

described here. Comprehensive reviews can be found

in the recent literature [1,8].

Mid-infrared spectroscopy offers in situ multicomponent

monitoring that suits the requirements for stability, relia-

bility, and extended monitoring time. In addition, no

recirculation loop outside the reactor is required [43

].

Calorimetry is another technique that can involve mea-

surements of both the reactor power input as well as the

generation of metabolic heat. Because of the high surface-

to-volume ratio in small reactors, the technique of calori-

metry has more potential at the large scale than in small-

scale bioreactors. Voisard and colleagues [44] developed

and tested a calorimeter system for a 300 L fermentor.

472 Biochemical engineering

Current Opinion in Biotechnology 2003, 14:468474 www.current-opinion.com

This method shows potential for an effective and low-cost

method to determine the metabolic state of the cells.

Conclusions

Progress has been made in coupling advanced modeling

and control methods to bioreactor technology. Papers de-

scribed here demonstrate excellent agreement between

experimental data and both estimated variables as well as

model trajectories. The incorporation of a priori process

knowledge with neural networks demonstrated shorter

training times for control and estimation applications, as

well as reduced sensitivity to sensor noise over traditional

neural networks. The application of a transfer function or

a Kalman lter to process measurements was shown to

signicantly improve the quality of the dynamic process

model established with the measurements. Evolutionary

algorithms also show much potential for bioreactor opti-

mization and control strategies. Novel approaches with

database models showed that satisfactory models can

be developed with a reduced set of model components.

The models and techniques employed in estimation will

continue to increase in resolution and complexity, respec-

tively, but only as the sensor technology allows mean-

ingful measurements to be collected.

References and recommended reading

Papers of particular interest, published within the annual period of

review, have been highlighted as:

of special interest

of outstanding interest

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Biotechnol 2002, 13:124-127.

2. Morari M, Zariou E: Robust Process Control. UK: Pearson

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3. Van Impe J, Vanrolleghem P, Iserentant D (Ed): Advanced

Instrumentation, Data Interpretation, and Control of

Biotechnological Processes. Dordrecht: Kluwer Academic

Publishers; 1998.

4. Bastin G, Dochain D: On-line Estimation and Adaptive Control of

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6.

scientic approach for practice. J Biotechnol 2001, 85:187-212.

Signicant advances in bioprocess optimization have been achieved,

but there are still bottlenecks for implementation in the industrial setting.

This review covers many areas related to process optimization, modeling

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