Food Bioprocess Technol (2017) 10:413–433
DOI 10.1007/s11947-016-1855-2
REVIEW
Applications of Response Surface Methodology in the Food
Industry Processes
Mahmoud Yolmeh 1 & Seid Mahdi Jafari 1
Received: 8 August 2016 / Accepted: 19 December 2016 / Published online: 11 January 2017
# Springer Science+Business Media New York 2017
Abstract Response surface methodology (RSM) is a tech-
nique widely used to optimize various processes. This review
presents the state-of-the-art applications of RSM in the opti-
mization of different food processes such as extraction, dry-
ing, blanching, enzymatic hydrolysis and clarification, pro-
duction of microbial metabolites, and formulation. The prin-
ciples of RSM, its implementation steps, and different designs
(full factorial design (FFD), Box-Behnken design (BBD), and
central composite design (CCD)) are described. Furthermore,
this work presents a comprehensive study of RSM literature
recently published about the various food process fields and
evaluating their RSM elements summarized in tables. Finally,
the challenges and future prospects of using this statistical
technique in the food industry processes are discussed. It can
be concluded that appropriate selection of RSM design, inde-
pendent variables (screening), and levels of the factors signif-
icantly influences the successful application of RSM. In addi-
tion, validity evaluation of the optimum conditions predicted
through RSM is crucial too.
Keywords Response surface methodology . Extraction .
Drying . Biotechnology . Optimization . Food industry
Introduction
The food industry is seeking to improve system perfor-
mance and to enhance process efficiency without
* Seid Mahdi Jafari
smjafari@gau.ac.ir
1
Faculty of Food Science and Technology, University of Agricultural
Sciences and Natural Resources, Gorgan, Iran
increasing cost and time. Finding a condition with the best
output for a system is the main purpose of Boptimization^
which has been commonly used (Baş & Boyacı, 2007). In
the past, optimization in food processes has been performed
through investigating the effect of one-parameter changes
on a response while all others are held at a constant level
(Bezerra et al., 2008). The main disadvantages of this meth-
od are the interactive effects among the variables, which are
not considered and there is a lack of explanation of the
complete effect of the factors on the response. In addition,
this method increases the number of experiments needed to
conduct the research, which leads to increased cost and time
(Baş & Boyacı, 2007; Bezerra et al., 2008).
In order to resolve this problem, optimization studies can
be carried out by using multivariate statistic methods.
Response surface methodology (RSM) is the most popular
multivariate statistic technique, which has been used in the
optimization of food processes (Baş & Boyacı, 2007). RSM
is a collection of statistical and mathematical methods
established on the fit of a polynomial model to the data that
must depict the behavior of a data set with the purpose of
making statistical predictions. The approach is useful for op-
timizing, designing, developing, and improving processes
where a response or responses are affected by several
variables (Ghorbannezhad et al., 2016; Kaushik et al., 2006).
Before using the RSM approach, the correct experimental
design must be selected that will designate which treatments
should be done in the experimental region being studied. For
this purpose, experimental designs for quadratic response sur-
faces, such as three-level factorial, central composite, and
Box-Behnken, should be applied (Bruns et al., 2006).
Generally speaking, RSM is an appropriate approach and
widely used to optimize food industry processes. However,
some researchers are not familiar with this approach. This
misusing can be attributed to perform inappropriate
414
experimental design, inappropriate screening of independent
variables, and improper selection of levels for independent
variables. We have tried to address these issues in this study.
In addition, this paper presents a comprehensive summary of
literature recently published on optimization of food processes
by using RSM. BCan RSM be utilized for optimization of all
food industry processes without any limitation?^ Before ad-
dressing this challenge, the principles of the approach are first
presented.
Theory and Steps of RSM
The RSM approach was developed by Box and colleagues in
the 1950s, with the major advantage being the reduced num-
ber of experiments that are required to appraise multiple pa-
rameters and their interactions (Bruns et al., 2006; Ge et al.,
2002). The term BResponse Surface Methodology^ was de-
rived from the graphical view created after fitting the mathe-
matical model. RSM depicts the effect of the independent
variables on the dependent variables. In addition, the approach
also generates an empirical model.
Before beginning the discussion on the principles and ap-
plications of RSM in optimization of food processes, it is
necessary to introduce and clarify some important terms.
BExperimental domain^ is the experimental field that will
be investigated, which is defined by the maximum and mini-
mum limits of the independent variables. BExperimental
design^ is a specific system of experiments defined by a ma-
trix created with the different level combinations of the inde-
pendent variables. Central composite, Box-Behnken, and
Doehlert designs are examples of experimental designs.
BIndependent variables^ or Bfactors^ are input variables
which can be changed independently of each other. BRuns^
are series of tests that form an experiment. BDependent
variables^ or Bresponses^ are output variables which are in-
fluenced by several independent variables. BResidual^ is the
difference between the experimental and calculated result for a
determinate set of conditions. A low value of this index is
necessary for a good mathematical model fitted on experimen-
tal data (Bezerra et al., 2008).
In the following section, a summary of RSM principles has
been presented. For more information, readers are referred to
Bezerra et al. (2008) and Myers et al. (2016).
Screening of Independent Variables
A wide range of factors usually affect the food industry pro-
cesses; therefore, the evaluation of individual effect of each
factor is impossible due to high cost and number of runs need-
ed. To avoid this, the researcher might choose to first use a
Bscreening design^ to recognize those factors which have
large effects on the response. Indeed, the screening is the first
Food Bioprocess Technol (2017) 10:413–433
step of optimizing. This step can be done using full or frac-
tional factorial designs (for 2–4 factors) and fractional facto-
rial or Plackett-Burman design (for 5 or more factors). In such
designs, only main effects are estimated; interactions between
independent variables are usually considered insignificant and
are neglected. The Plackett-Burman design type is a two level
fractional factorial screening design for studying N-1 vari-
ables using N runs, where N is a multiple of 4. The screened
factors then are provided to RSM for optimization (Lundstedt
et al., 1998; Myers et al., 2016).
Selection of a Regression Model
The least square multiple regression methodology is usually
applied to investigate the relationship between the indepen-
dent and dependent variables. A multiple regression equation
can be used to fit the second-order polynomial equation based
on the experimental data as follows:
y ¼ β0 þ ∑ki¼1 βi X i þ ∑ki¼1 βii X 2i þ ∑ki≠ j¼1 βij X i X j þ ε
where y represents the predicted response, β0 is the model
intercept, and βi, βii, and βij are the regression coefficients
for the linear, quadratic, and interactive effects of the mod-
el, respectively. Xi and Xj are the factors and k is the num-
ber of factors (Ghorbannezhad et al., 2016). The model
used for optimizing food processes in the RSM meth-
odology is not always a second order. The regression
coefficients that have a statistically significant effect
on response should be considered in the equation.
Therefore, if quadratic terms are not statistically signif-
icant, those coefficients are removed and equation will
be linear (Myers et al., 2016).
Coding the Factor Levels
After screening for the important factors and selection of the
regression model, the levels of factors are defined. This step is
very important and the success of optimizing the process de-
pends on this step. Given that, the factors have different units
and ranges; before executing a regression analysis, the factors
must be normalized. Codification of the levels of factors re-
quires converting each studied value into a range without di-
mensions (−1 to +1). A studied value (zi) can be converted to a
coded value (xi) by the following formula:


xi ¼ zi −zi 0 =Δzi βd
where Δzi represents the difference from the real value in the
higher or lower value from the real value at the central point
(zi0), and βd represents the major coded limit value of each
variable (Bezerra et al., 2008).
Food Bioprocess Technol (2017) 10:413–433
Verification of the Fitted Model
It is possible to calculate the estimated response using the
model equation and regression coefficients. However, verifi-
cation of the model adequacy must be checked to determine if
it is appropriate or not. Several techniques are available, such
as prediction error sum of squares (PRESS) residuals, the
lack-of-fit test, and residual analysis. The coefficient of deter-
mination (R2) is used to evaluate the general predictive capa-
bility of the fitted model. However, R2 index alone cannot
demonstrate the accuracy of the model, because the index is
a measure for amount of the decreasing changeability of re-
sponse achieved by using the repressor variables in the model.
In addition, increasing a variable to the model will increase R2
without considering the statistical significance of the addition-
al variable. Thus, a high value of R2 is not necessarily indic-
ative of the accuracy of the model. The absolute average de-
viation (AAD) is a better measure of accuracy. AAD is the
average of the absolute deviations from a central point and is a
summary statistic of statistical dispersion or variability, which
is calculated by the following formula:
 p .
AAD ¼ ∑ jyi exp–yi calj=yi exp p  100
i¼1
where p, yi exp, and yi cal represent the number of experi-
ment, experimental, and calculated responses, respectively.
Both R2 and AAD should be evaluated to check the accu-
racy of the model. R2 must be near 1 and the AAD between
the estimated and observed data must be as low as possible.
The suitable values of R2 and AAD imply that the fitted
model depicts the correct behavior of the process and it
can be successfully used for optimization of food processes
(Ghorbannezhad et al., 2016).
Moreover, residual analyses (plots of observed-predicted
values versus the factors and responses) would be a valuable
criterion for this assessment. Using residual plots, you can
assess whether the observed error (residuals) is consistent with
stochastic error. The residuals should not be either systemati-
cally high or low. In addition, the residuals should be centered
on zero throughout the range of fitted values, as is obvious in
Fig. 1a. In other words, the model is correct on average for all
fitted values. Further, in ordinary least squares context, ran-
dom errors are assumed to produce residuals that are normally
distributed. Therefore, the residuals should fall in a symmet-
rical pattern and have a constant spread throughout the range
(Myers et al., 2016).
Figure 1b shows a problematic residual plot that is unde-
sirable. The non-random pattern in the residuals indicates that
the deterministic portion (predictor variables) of the model is
not capturing some explanatory information, which is
Bleaking^ into the residuals. The graph could represent several
ways in which the model is not explaining all that is possible.
415
Possibilities are including missing variables and/or higher-
order term of a variable in the model to explain the curvature,
and/or interaction between terms already in the model.
Identifying and fixing the problem so that the predictors
now explain the information that they missed before should
produce a good-looking set of residuals (Myers et al., 2016).
Various criteria (R2, AAD, residual analysis, and lack-
of-fit) are used to evaluate the suitability of response sur-
face models for fitting the data, which will be reviewed
here. Nearly in all RSM studies, R2 has been used to eval-
uate the general predictive capability of the fitted model.
However, R2 is not a sufficient index for this evaluation
and other criteria should be investigated. Residual analysis
and lack-of-fit evaluations have not been applied in some
papers (as shown in Tables 2, 3, and 4); however, lack-of-
fit value was inappropriate in some of them (the P value of
lack-of-fit should be insignificant (P > 0.05) for a suitable
fitting of response surface models). Unfortunately, AAD
criterion has not been considered in any of the papers
reviewed here even though it is a useful value to assay
the suitability of fitting the response surface model, as
mentioned earlier (Ghorbannezhad et al., 2016).
Graphical Presentation of the Model
The visualization of the predicted model equation can be ap-
peared by the response contour and surface plots, as shown in
Fig. 2. These plots are theoretical three-dimensional outputs of
the RSM approach, which indicate the relationship between
the dependent and independent variables. The response con-
tour and surface plots are used to describe changes in response
by changes in the independent variables. Contour plot is a
two-dimensional screen of the surface plot, in which, ranges
of constant dependent variables is drawn in the plane of the
independent variables. Indeed, the contour plots improve un-
derstanding the shape of a responses surface. As the target
point (minimum, maximum, or in ranged point) is located in
the center of the system (experimental region), the contour
plots show a circle or ellipses status. When the target point
is neither a maximum nor a minimum point, the contour plots
show parabolic or hyperbolic system contours. It must be
noted that these plots display visualization of estimated
responses, not the real responses (Baş & Boyacı, 2007;
Myers et al., 2016).
Determination of Optimal Conditions
It is possible to calculate the optimum point (maximum or
minimum point) through the first derivate of the mathematical
equation which depicts the response surface and equates it to
zero:
y ¼ β 0 þ β1 x1 þ β2 x2 þ β11 x1 2 þ β22 x2 2 þ β 12 x1 x2
416
Fig. 1 Plot of residual fit of
regression model for response. a
Appropriate residual fit. b
Inappropriate residual fit
The optimum point is found by calculating Δy/Δx1 and
Δy/Δx2 and setting zero:
Δy=Δx1 ¼ β1 þ 2β 11 x1 þ β12 x2 ¼ 0
Δy=Δx2 ¼ β2 þ 2β 22 x2 þ β12 x1 ¼ 0
The above equations are solved to determine the values of
x1 and x2. These values reveal the coded value of the factors,
which give the maximum or minimum response. For optimi-
zation of process, the target point has to be found in the ranges
of studied factors.
Generally, in the food industry, researchers are interest-
ed in optimization of several responses concurrently,
which is complicated compared to optimization of pro-
cesses with only one response. For this purpose, a desir-
ability function is used which is a multi-criteria method-
ology. This methodology makes a desirability function for
Food Bioprocess Technol (2017) 10:413–433
each individual response. The desirability function ap-
proach is one of the most widely used methods in industry
for the optimization of multiple-response processes. It is
based on the idea that the Bquality^ of a product or pro-
cess which has multiple quality characteristics, with one
of them outside of some Bdesired^ limits, is completely
unacceptable. The method finds operating conditions of X
that provide the Bmost desirable^ response values. For
each response Yi (x), a desirability function di (Yi) assigns
numbers between 0 and 1 to the possible values of Yi,
with di (Yi) = 0 representing a completely undesirable
value of Yi and di (Yi) = 1 representing a completely de-
sirable or ideal response value. The individual desirabili-
ties are then combined using the geometric mean, which
gives the overall desirability (D).
D ¼ ðd 1 ðY 1 Þ d 2 ðY 2 Þ…d k ðY k ÞÞ1=k
Food Bioprocess Technol (2017) 10:413–433
Fig. 2 Response surface (left)
and contour (right) plots of the
predicted model equation
where k represents the number of responses. It should be
noted that if any response Yi is completely undesirable,
then the overall desirability is zero.
Applying desirability function in food processes has
several advantages such as economy, efficiency, and ob-
jectivity in optimizing the multiple-responses processes
(Bezerra et al., 2008).
Measurement of response under the predicted optimum
conditions and comparison of the observed responses with
the responses predicted through the model is another impor-
tant point. The difference between observed and predicted
responses must be as low as possible; this represents the pre-
dicted optimal conditions are valid (Myers et al., 2016).
Design of Experiments in RSM
An important section of RSM is the design of experiments that
is commonly abbreviated as DoE. The purpose of DoE is the
choice of the points where the response should be studied. A
comparison of some popular DoE methodologies is given in
the following section.
Full Factorial Design
Full factorial design has the appropriate efficiency and is com-
parable with other designs such as central composite design
(CCD). However, the full factorial design (FFD) has not a
417
good efficiency in the modeling of quadratic functions and
when the number of factors is higher than 2. Because in this
case, a large number of experimental runs is required than can
usually be provided in practice and compared to the designs
that apply a smaller number of experimental runs such as CCD
and Box-Behnken design. If the number of design variables
becomes large, a fraction of a full factorial design can be used
at the cost of estimating only a few combinations among var-
iables. This is called fractional factorial design and is usually
used for screening important design variables. For a 3n facto-
rial design, a (1/3)p fraction can be constructed, resulting in
3n–p points (Montgomery, 2008). FFD is appropriate to obtain
a lot of information about the main effects in a proportionately
few number of runs. However, FFD is not appropriate to eval-
uate the interaction between factors due to deficiency of this
design to provide information about interactions. The chroma-
tography and isolation applications are the main fields of FFD
(Bezerra et al., 2008; Myers et al., 2016). Figure 3a shows a
FFD based on the study of all variables in three levels.
Box-Behnken Design
The design that applies three levels (−1, 0, +1) for each factor
for the first time was designed by Box and Behnken (1960).
The Box-Behnken design (BBD) comprises a specific subset
of the factorial combinations from the 3k factorial design. In
addition, in a BBD, the experimental points are situated on a
hypersphere equally distant from the central point (Fig. 3b).
418
Fig. 3 Experimental designs
based on the study of all variables
in three levels. a Full factorial
design (FFD). b Box-Behnken
design (BBD). c Central
composite design (CCD)
Although BBD is not rotatable, like CCD, some of its designs
could be rotatable. Applying this design is popular in food
processes due to its economical design. BBD is appropriate
to evaluate interaction between factors and especially to study
processes without extreme points (where high levels of factors
involved in the process is difficult to implement, such as high
temperature and pressure next to each other). In addition,
BBD is not appropriate to study factors with more than three
levels. In other words, only triplex levels (−1, 0, +1) are ap-
plied (Myers et al., 2016). The number of BBD experiments
can be calculated by the following equation:
N ¼ 2k ðk−1Þ þ cp
where k is the number of factors and cp is the number of the
central points (Fig. 3b).
Central Composite Design
A second-order model can be constructed efficiently with
CCD. Box and Wilson (1951) developed this approach for
the first time. The CCD (Fig. 3c) consists of three point types:
(1) factorial points, (2) a central point, and (3) axial points
which are at a distance α from the central point. CCD is
appropriate for sequential experimentation and provides a
Food Bioprocess Technol (2017) 10:413–433
reasonable amount of information for testing lack-of-fit while
not involving an unusually large number of experimental runs.
Also, CCD is appropriate to study factors with three and/or
five levels. However, a CCD considers extreme points, which
is not advisable for special processes such as extraction of a
compound sensitive to high temperature and pressure (Myers
et al., 2016). Experimental runs in CCD can be estimated by:
N ¼ k 2 þ 2k þ cp
where k is the number of independent variables and cp is the
replicate number of the central point.
α values can be calculated by α = 2(k − p)/4; only quintuplet
levels are applied for the all factors (−α, −1, 0, +1, +α). α
value could be equal to 1 (face centered), which means this
design has only three levels and the design space is then a cube
rather than a sphere (Myers et al., 2016).
Table 1 shows the coded values of experimental matrix for
using FFD, BBD, and CCD designs. As it is obvious, the
number of experiments in BBD is lower than FFD and
CCD, 13 in the case of BBD compared to 27 and 15 for
FFD and CCD, respectively.
It should be acknowledged that software programs such
as Design Expert, Minitab, and SPSS greatly facilitate de-
sign and modeling by RSM. They typically normalize the
Food Bioprocess Technol (2017) 10:413–433 419

Table 1 Some experimental

matrices for RSM designs based Experiment no. Full factorial design Box-Behnken design Central composite
on three level variables (FFD) (BBD) design (CCD)

X1 X2 X3 X1 X2 X3 X1 X2 X3

1 −1 0 0 −1 −1 0 −1 −1 −1 Factorial points
2 −1 0 −1 1 −1 0 1 −1 −1
3 −1 −1 −1 −1 1 0 −1 1 −1
4 −1 −1 0 1 1 0 1 1 −1
5 −1 0 1 −1 0 −1 −1 −1 1
6 −1 1 0 1 0 −1 1 −1 1
7 −1 1 1 −1 0 1 −1 1 1
8 −1 −1 1 1 0 1 1 1 1
9 −1 1 −1 0 −1 −1 −α 0 0 Axial points
10 0 0 0 0 1 −1 α 0 0
11 0 0 −1 0 −1 1 0 −α 0
12 0 −1 −1 0 1 1 0 α 0
13 0 −1 0 0 0 0 0 0 −α
14 0 0 1 0 0 α
15 0 1 0 0 0 0 Central point
16 0 1 1
17 0 −1 1 0 0 0
18 0 1 −1 0 0 −1
19 1 0 0 0 −1 −1
20 1 0 −1 0 −1 0
21 1 −1 −1 0 0 1
22 1 −1 0 0 1 0
23 1 0 1 0 1 1
24 1 1 0 0 −1 1
25 1 1 1 0 1 −1
26 1 −1 1
27 1 1 −1

factors before performing the regression modeling, readily
create graphical output so that the modeling results are
easily understood, allow for the creation of desirability
functions, and offer easy transformation of the responses
if needed.
Applications of RSM in the Food Industry
In this section, we have reviewed some RSM studies pub-
lished in different fields of food industry processes during
the last few years. Generally, these processes involve CCD
and BBD designs.
Optimization of the Extraction Processes
In recent years, numerous studies have been published in the
literature about extraction of oil, protein, phenolic com-
pounds, pigments, polysaccharides, hydrocolloids, etc. by
applying RSM in order to optimize the process conditions.
There are several techniques for extraction of various bioac-
tive compounds such as maceration, ultrasonic-assisted ex-
traction (UAE), microwave-assisted extraction (MAE), super-
critical fluid extraction, and enzymatic extraction (Sarfarazi
et al., 2015; Khazaei et al., 2016; Wang, et al., 2012). In these
techniques, several factors including time, pH, temperature,
reagents concentration, irradiation time, flow rate, and solvent
to solid ratio affect extraction yield and process efficiency
which can be considered as independent variables in RSM.
We have classified the recent extraction studies into 12
groups based on target compound and each group involves
different independent variables and specific objectives; stud-
ies of phenolic compounds and polysaccharides comprise the
major works in this field (Table 2). Maximizing the extraction
yield (MEY) has been the main target for these studies.
Quality of analyte (target compound) is also important in ad-
dition to the yield, which RSM can introduce in the optimal
conditions for multiple-response processes. Among
Table 2 Some applications of RSM on extraction of different ingredients in the food industry
420

Target Process Independent variables Design Number of Randomization RSM Modeling validity Validation of Ref.
compound replication at modeling criteria predicted
central point graphical optimum
Number (types) Levels presented R2 Residual Lack- conditions
analyses of-fit

Vitamin Vitamin B3 from pork 2 (formic acid and ammonium 3 BBD 5 Done Done A – – Done (Saccani et al.,
products formate) 2005)
Vitamin E from wheat germ 3 (pressure, temperature, and flow 3 CCD 3 Not done Done SA A A Done (Ge et al., 2002)
rate CO2)
Pigment Natural pigments from annatto 4 (temperature, time, duty cycle, 5 CCD 7 Done Done A A A Done (Yolmeh et al.,
seed and seed to solvent ratio) 2014)
Anthocyanin from purple 3 (temperature, time, and 3 BBD 5 Done Done A SA A Not done (Fan et al., 2008)
sweet potato solid-liquid ratio)
Anthocyanin from purple 3 (SO2 concentration, time, and 3 CCD 4 Not done Done – – – Not done (Gao & Mazza,
sunflower hulls hull size) 1996)
Chlorophylls from Phaseolus 3 (number of extractions, 3 – 2 Done Done A – – Not done (Cubas et al.,
vulgaris L. extraction, and homogenization 2008)
time)
Natural dye from petals of the 3 (time, temperature, and mass of 5 BBD 6 Not done Done A A A Not done (Sinha et al., 2012)
flame of forest petals)
Lycopene from tomato 5 (solvent/meal ratio, number of 5 CCD 6 Not done Done A A I Done (D. Kaur et al.,
processing waste skin extraction, temperature, particle 2008)
size, and time)
Pigments from prickly pear 3 (temperature, time, and mass of 3 BBD 5 Done Done A A – Done (Maran &
the fruit) Manikandan,
2012)
Phenolic Phenolic compounds from 4 (temperature, time, pH, and ratio) 3 CCD 3 Not done Done A – – Not done (S. Rodrigues
compounds coconut shell powder et al., 2008)
Phenolic compounds from 4 (microwave power, time, ethanol 3 BBD 5 Not done Done SA A A Done (Bai et al., 2010)
apple pomace concentration, and ratio of
solvent to raw material)
Bioactive compounds from 3 (buffer to solid ratio, temperature, 5 CCD 6 Not done Done A A A Done (Gan & Latiff,
Parika speciosa pod and time) 2011)
Phenolic compounds from 3 (combination of solvent 3 BBD 3 Done Done A – A Done (Yang et al., 2009)
bark of Phyllanthus concentration, time, and
emblica L. temperature)
Bioactive compounds from 3 (ethanol content, temperature, 5 CCD 6 Done Done A A A Not done (Gong et al., 2012)
marigold and time)
Phenolic compounds from 3 (ethanol content, pH, and time) 3 CCD 2 Not done Done A – – Not done (Mylonaki et al.,
olive (Olea europaea) leaf 2008)
Phenolic compounds from 3 (ethanol to water ratio, 3 BBD 3 Done Done A A A Not done (Juntachote et al.,
lemon grass, galangal, holy temperature, and time) 2006)
basil, and rosemary
Protein Gelatine from grass carp 4 (HCl concentration, pretreatment, 3 BBD – Not done Done A – A Not done (Kasankala et al.,
(Catenopharyngodon temperature, and time) 2007)
idella) fish skin
Collagen from grass carp 3 BBD 5 Done Done A A A Not done
Food Bioprocess Technol (2017) 10:413–433
Table 2 (continued)

Target Process Independent variables Design Number of Randomization RSM Modeling validity Validation of Ref.
compound replication at modeling criteria predicted
central point graphical optimum
Number (types) Levels presented R2 Residual Lack- conditions
analyses of-fit

3 (acetic-acid concentration, time, (L. Wang et al.,

and temperature) 2008)
Protein from pumpkin seeds 3 (liquid: solid ratio, NaCl 3 CCD 3 Not done Done A – – Done (Tabaraki &
concentration, and time) Nateghi, 2011)
Antioxidants Natural antioxidants from rice 3 (ethanol concentration, 3 CCD 2 Done Done A – A Done (Pompeu et al.,
bran temperature, and time) 2009)
Phenolic antioxidants from 3 (ethanol proportion, HCl 5 CCD 3 Not done Done A Done (Wijngaard &
Food Bioprocess Technol (2017) 10:413–433

A –
fruits of Euterpe oleracea concentration, and temperature) Brunton, 2010)
Antioxidants from apple 3 (ethanol concentration, 5 CCD 6 Done Done A A A Not done (H. Sin et al.,
pomace temperature, and time) 2006a, b)
Juice Sapodilla juice from sapodilla 2 (temperature, and time) 3 CCD 4 Done Done A – I Done (Lee et al., 2006)
Banana juice from banana 2 (temperature and time) 3 CCD 5 Done Done A – A Not done (Zhong & Wang,
2010)
Polysaccharide Polysaccharide from dried 3 (ultrasonic power, ratio of water 3 BBD 5 Not done Done A – A Done (Gan et al., 2010)
longan pulp to material, and time)
Alcohol insoluble 2 (temperature and time) 5 CCD 5 Not done Done A A – Done (Aliakbarian et al.,
polysaccharides from 2008; J. H. Xie
Parkia speciosa pod et al., 2010)
Polysaccharide from 3 (temperature, time, and 3 CCD 3 Not done Done A – A Done (Xie et al., 2012)
Cyclocarya paliurus water/material ratio)
(Batal.) Iljinskaja
Polysaccharide from waste of 2 (temperature and time) 5 CCD 5 Not done Done A A A Not done (Yoshida et al.,
corn starch 2010)
Oil Oil from olive 2 (malaxation time and enzyme 3 FFD 3 Not done Done A A I Not done Aliakbarian et al.,
concentration) 2008)
Oil from pomegranate seed oil 3 (pressure, temperature and CO2 5 CCD 3 Done Done A – – Not done (Liu et al., 2003)
flow rate)
Hydrocolloids Hydrocolloid from cress seed 4 (water: seed, pH, temperature, 3 CCD 8 Done Done A A A Done (Karazhiyan et al.,
and time) 2011)
Flavonoid Flavonoid from Spearmint 3 (temperature, pressure, and 3 CCD 6 Done Done A – A Not done (Bimakr et al.,
leaves co-solvent flow rate) 2012)
Essential oil Rosemary essential oil from 3 (processing pressure, moisture 5 CCD 8 Not done Done A – A Not done (Rezzoug et al.,
rosemary leave content, and processing time) 2005)
Essential oil from rhizomes of 4 (temperature, pressure, time, and 5 CCD 6 Not done Done A – I Not done ( Wang et al.,
Cyperus rotundus Linn Co2 flow rate) 2012)
Pectin Pectin from lemon by-product 3 (temperature, pH, and time) 3 CCD 1 Not done Done A A A Not done (Masmoudi et al.,
2008)
Pectin acid from passion fruit 3 (temperature, pH, and time) 5 CCD 1 Not done Done A A A Not done (Masmoudi et al.,
peel 2008)
421

A appropriate, I inappropriate, SA semi-appropriate; −: not studied, FFD full factorial design, BBD Box-Behnken design, CCD central composite design
422
independent variables studied in optimization of extraction
processes, temperature, time, pH, and solid to solvent ratio
were most widely used. Also, the CCD was the major design
in the extraction studies by RSM. Randomization of experi-
ments and replication on central point are important criteria
that should be used in RSM designs to validate RSM model-
ing; however, it was not observed in some published papers,
as shown in Table 2. Validation of predicted optimum condi-
tions is another important issue when applying the RSM ap-
proach, which was not seen in some of these studies. Among
papers reviewed in Table 2, Sarfarazi et al. (2015), Khazaei
et al. (2016), Yolmeh et al. (2014), Maran and Manikandan
(2012), Yang et al. (2009), Gan et al. (2010), and Karazhiyan
et al. (2011) employed RSM appropriately since they have
applied the randomization, RSM modeling graphical presen-
tation, modeling validity criteria, and validation of predicted
optimum conditions adequately in their studies. However,
RSM has been used inappropriately in the rest of them.
Most of the studies reviewed in Table 2 revealed that RSM
was successfully applied to optimize extraction conditions by
different techniques, because of good R2-adj and R2-pred
values, insignificant P values for lack-of-fit value, and good
compatibility of the predicted and experimental values.
Therefore, the RSM algorithm could accurately estimate the
results.
Optimization of the Drying Processes
Drying is one of the techniques to improve the shelf life of
foods such as fruits and vegetables which have a large mois-
ture content (Kumar, et al., 2014). There are various tech-
niques for drying and dehydration of foods such as hot air
drying, osmotic dehydration, microwave-vacuum drying, flu-
idized bed drying, IR-assisted freeze drying, and microwave-
assisted hot air drying (Madamba, 2002). Producing a dried
product with good quality is dependent on several factors such
as temperature, time, thickness, air speed, vacuum rate, micro-
wave power, concentration of osmotic solution, etc. (Burande,
et al., 2008). Thus, optimization of these process conditions is
important in terms of improving the quality and minimizing
the process costs.
Statistical approaches such as RSM can introduce the op-
timal conditions for the drying process based on several pro-
cess responses such as water loss, solid gain, final moisture,
color, and rehydration ratio. Table 3 shows different studies
which have applied RSM to optimize drying conditions cate-
gorized by the type of drying technique. Temperature, time,
osmotic solution concentration, and the product thickness
have been widely used as independent variables in these op-
timizing studies on drying processes. As it is obvious in
Table 3, in most of these studies, CCD has been applied in
order to investigate and optimize the drying conditions. Also,
compared with the previous section (extraction processes),
Food Bioprocess Technol (2017) 10:413–433
higher number of papers considering drying optimization
have implemented validation of predicted optimum condi-
tions. Among papers reviewed in Table 3, Madamba (2002)
has employed RSM appropriately because of the randomiza-
tion, RSM modeling graphical presentation, modeling validity
criteria, and validation of predicted optimum conditions
adequately.
Application of RSM in the Formulation Processes
Since several factors are considered in formulation of food
products, researcher are seeking for optimization of each re-
sponse (factor) which could be performed by RSM, as this
approach is useful for multi-response processes. RSM has
been used for optimizing formulations of different foods such
as functional short dough biscuits (Gallagher, et al., 2003),
soy-coffee beverage (Felberg, et al., 2010), low-calorie mixed
fruit jelly (Acosta, et al., 2008), extruded snack food (Thakur
& Saxena, 2000), cream (Moulai Mostefa et al., 2006), gluten-
free bread (McCarthy, et al., 2005; Sanchez, et al., 2004), pork
frankfurters (Pappa, et al., 2000), walnut oil-in-water beverage
emulsion (Gharibzahedi, et al., 2012), Iranian white brine
cheese (Alizadeh, et al., 2005), homogenized infant foods
(Martinez, et al., 2004), and sweet potato-based pasta
(Singh, et al., 2004). Gharibzahedi et al. (2012) studied the
effects of Arabic gum content and walnut-oil concentration on
properties of prepared emulsions, namely turbidity loss rate,
density, particle size, and stability, using RSM. They reported
that the optimum formulation was containing 3% (w/w) wal-
nut oil and 9.62% (w/w) Arabic gum.
The above studies successfully used RSM to optimize for-
mulation processes revealed by suitable validity criteria (good
R2-adj and R2-pred values, insignificant P values for lack-of-
fit, and good compatibility of the predicted and experimental
values). In these studies that applied RSM to optimize formu-
lation, different factors as independent variable were investi-
gated, which are dependent on case to case; for instance, in the
work of Gharibzahedi et al. (2012), concentrations of hydro-
colloid, oil, sweetener, and conditions of process such as tem-
perature and pH were the main independent variables. On the
other hand, physicochemical, textural, and rheological prop-
erties were the main dependent variables.
Application of RSM in Microencapsulation
and Controlled-Release Processes
Microencapsulation is a technique in which very small parti-
cles or droplets are surrounded by a wall material to give small
capsules. The technique is widely used in the food and drug
industry to protect bioactives from environmental deteriora-
tive factors and also to develop and produce improved food
and drug delivery systems. However, there are many factors
influencing the stability and functionality of the
Table 3 Some applications of RSM on different drying processes in the food industry

Drying method Sample Independent variables Design Number of Randomization RSM Modeling validity Validation of predicted Ref.
replication at modeling criteria optimum conditions
Number (types) Levels central point graphical
presented R2 Residual Lack-
analyses of-fit

Hot air drying Olive leaves 3 (temperature, air velocity, and 5 CCD 6 Not done Done A A A Not done (Erbay & Icier,
time) 2009)
Agricultural (temperature, thickness, vacuum 3 BBD 3 Done Done A A A Done (Kumar et al.,
crops pressure, air speed, and RH) 2014;
Madamba,
2002)
Food Bioprocess Technol (2017) 10:413–433

Osmotic Potato 4 (temperature, sucrose 5 CCD 7 Not done Done A A A Not done (Eren &
dehydration concentration, salt Kaymak-Erte-
concentration, and time) kin, 2007)
Kiwifruit 4 (sucrose concentration, slice 5 CCD 7 Not done Done A – A Not done (Cao et al., 2006)
thickness, temperature, and
time)
Carrot cubes 3 (time, temperature, and NaCl 5 CCD 6 Done Done A A A Not done (Bahadur Singh
concentration) et al., 2007)
Aonla slices 4 (temperature, solution to fruit 3 CCD 3 Done Done A A A Not done (Alam et al.,
ratio (STFR), sugar 2010)
concentration, and time)
Diced green 4 (salt, sorbitol, temperature, and 5 CCD 6 Done Done A A A Not done (Ozdemir et al.,
peppers time) 2008)
Red paprika 2 (sucrose concentration, and 5 CCD 5 Not done Done A – A Done (Ade-Omowaye
(Capsicum sodium chloride et al., 2002)
annuum L.) concentration)
Microwave-vacuum Apple slices 3 (microwave power, vacuum 5 CCD 9 Not done Done A A A Done (Han et al., 2010)
drying level, and initial moisture
content)
Button 3 (microwave power, system 5 CCD 6 Not done Done A – A Not done (Han et al., 2010)
mushrooms pressure, and thickness)
(Agaricus
bisporous)
Fluidized bed drying Green peas 4 (temperature, tempering time, 5 CCD 7 Not done Done A – – Not done (Burande et al.,
pretreatment, and mass 2008)
per unit area)
FIR-assisted freeze Yam slices 3 (temperature, distance, and 3 BBD 3 Not done Done A A A Done (Lin et al., 2007)
thickness)
Microwave-assisted Okra 3 (air velocity, air temperature, 5 CCD 6 Not done Done A – A Not done (Kumar et al.,
hot air drying and MW power) 2014)

A Appropriate, I inappropriate, SA semi-appropriate, FFD full factorial design, BBD Box-Behnken design, CCD central composite design
423
424
microcapsules, such as the type of wall material, the properties
of the core materials (volatility and concentration), the char-
acteristics of the initial emulsion (droplets size, total solids,
and viscosity), and the conditions of the drying process (tem-
perature, air flow, and humidity) (Jafari, et al., 2008). Thus, it
is important to optimize the microencapsulation process by
techniques such as RSM.
In the recent years, some researchers have applied RSM
to optimize the parameters of the microencapsulation pro-
cess efficiently for oils, probiotics, vitamins, minerals, and
controlled-release of tablets. For instance, Chen et al.
(2006) developed an optimal composition for encapsulat-
ing probiotics with sodium alginate blended with peptides,
fructooligosaccharides, and isomaltooligosaccharides as
the wall materials through the RSM model. They reported
that optimal combination of wall materials for the micro-
capsules was found to be 3% sodium alginate mixed with
1% peptides, 3% fructooligosaccharides, and 0%
isomaltooligosaccharides. In another study, these research-
er reported that 1% sodium alginate mixed with 1% peptide
and 3% fructooligosaccharides as wall materials would
provide the highest protection for the probiotics
(Bifidobacterium bifidum, Bifidobacterium longum, and,
Lactobacillus acidophilus) (Chen, et al., 2005).
Results of Kha et al. (2014), which optimized microencap-
sulation of gac oil using spray drying by RSM, revealed that a
combination with wall concentration of 29.5% and oil load of
0.2 was the optimum condition for the microencapsulation.
Huynh et al. (2008) introduced a condition with 40% feed
concentration (w/w), 18% oil concentration, and 65 °C outlet
air temperature as optimum conditions of the microencapsu-
lation. Similarly, microencapsulation of rice bran oil, sunflow-
er oil, and flaxseed oil has been optimized using RSM by Suh
et al. (2007), Ahn et al. (2008), and Tonon et al. (2011), re-
spectively. Recently, Assadpour et al. (2016) applied RSM for
nano-emulsification and encapsulation of folic acid and Salimi
et al. (2015) encapsulated lycopene through emulsification
optimization by RSM.
Pharmaceutical formulators are also seeking to find the
right combination of pellets, which will produce a product
with optimum properties. Optimizing formulation is very
important when it is a controlled-release dosage form, be-
cause many factors can affect the release rate. RSM has
been used to optimize formulation of drugs in the develop-
ment of a product with controlled-release property. For ex-
ample, Kim et al. (2007) studied formulation and optimiza-
tion of a novel oral controlled delivery system for
tamsulosin hydrochloride using RSM. They found combi-
nation of 10% hydroxypropyl methylcellulose and 10% hy-
droxypropyl methylcellulose phthalate at a coating level of
25% as optimal coating formulation. In another study, Ko
et al. (2003) developed and optimized chitosan microparti-
cles for controlled drug release using RSM. They reported
Food Bioprocess Technol (2017) 10:413–433
that the optimum rate of drug release was observed at 1.8%
chitosan concentration, a pH 8.7 for the tripolyphosphate
solution and 9.7 min cross-linking time. In addition to these
studies, controlled-release of AZT-loaded microspheres,
nicardipine hydrochloride, and mucoadhesive tablets of
atenolol have been optimized using RSM by Abu-Izza
et al. (1996), Huang et al. (2005), and Singh et al. (2006),
respectively.
Optimization of the Enzymatic Hydrolysis
and Clarification
The enzymatic hydrolysis depends on many factors such as
type and specificity of the enzyme, hydrolysis time, enzyme
concentration, incubation temperature, and pH. Since the
enzymatic hydrolysis is widely used in the food industry,
it is necessary to investigate enzymatic performance during
hydrolysis and optimize the process for obtaining a high
yield by utilizing low-enzyme contents. Classical tech-
niques are laborious, time consuming, and often do not
guarantee the determination of optimal conditions
(Kurozawa, et al., 2008). Recently, RSM has been applied
for the optimization of enzymatic hydrolysis processes. For
instance, Kurozawa et al. (2008) studied optimization of the
enzymatic hydrolysis of chicken meat using RSM, and their
results revealed that a condition with 52.5 °C, 4.2% (w/w)
enzyme/substrate ratio, and pH of 8.00 was found as the
optimum conditions. In another study, Pericin et al.
(2009) reported 0.137% (v/v) enzyme concentration,
0.84% (w/v) NaCl concentration, and 32.5 h as the optimum
conditions for enzymatic hydrolysis of protein isolate from
hull-less pumpkin oil cake. Results of Kaur et al. (2009)
showed that a condition with the enzyme concentration
0.70 mg/100 g guava pulp, 7.27 h incubation, and 43.3 °C
is ideal for enzymatic hydrolysis pretreatment of juice re-
covery from guava fruit. Similarly, RSM has been used to
optimize the enzymatic hydrolysis condition of dogfish
(Squalus acanthias) muscle (Schwabe & Büllesbach,
2013), maize starch (Kunamneni & Singh, 2005), whey
protein isolate (Cheison, et al., 2007), and pectin
(Rodríguez-Nogales, et al., 2007).
The turbidity and viscosity of fruit juice are caused mainly
by the polysaccharides such as pectin, cellulose, hemicellu-
lose, lignin, and starch. These colloids may lead to the fouling
problem during the filtration process, and an enzymatic treat-
ment is necessary to prevent this problem with enzymes such
as pectinase and cellulose. Generally, these enzymes increase
juice yield, soluble solids content, and clarity in fruit and
vegetable juices (Alvarez & Canet, 1999). A number of fac-
tors could affect the enzymatic clarification such as enzyme
concentration, time, and temperature incubation of the
treatment. Usually, in these studies, the responses are
turbidity, clarity, viscosity, and antioxidant activity. RSM has
Food Bioprocess Technol (2017) 10:413–433
been used successfully to optimize enzymatic clarification
processes. For instance, Rai et al. (2004) found 99.27 min
time, 41.89 °C temperature, and 0.0004% (w/v) concentration
of pectinase as the best conditions for clarification of mosambi
juice using CCD. Lee et al. (2006) reported that 0.084%
pectinase concentration, incubation temperature of 43.2 °C,
and incubation time of 80 min are the best conditions for
clarifying banana juice. The results of Chen et al. (2012) re-
vealed that the optimal enzymatic clarification of green aspar-
agus juice using CCD is pectinase concentration of 1.45%,
incubation temperature of 40.56 °C and pH of 4.43. In some
other published works, RSM has been used for optimizing
enzymatic clarification of sapodilla juice (Sin et al., 2006a,
b), litchis (Litchi Chinensis Sonn.) juice (Sanchez et al.,
2004), white pitaya juice (Nur‘Aliaa, et al., 2010), and pome-
granate juice (Neifar et al., 2011).
Optimization of the Blanching Process
Blanching is a heat treatment which is widely used in the agro-
food sector and particularly important in the processing of
green vegetables to inactivate the enzymes involved in the
spoilage of fresh vegetables (Garrote, et al., 2004). There are
different techniques for blanching such as steam or hot water,
microwave, and ultrasound. Several factors are important dur-
ing blanching, including temperature, time, thickness, particle
size, ultrasound and microwave power, and concentration of
solvents, which should be optimized in order to achieve an
appropriate blanching process. RSM has been used to opti-
mize different blanching processes by considering parameters
such as enzymatic activity (EA), vitamin C content, color, etc.
as dependent variables or responses (Yolmeh & Najafzadeh,
2014). As an example, Jackson et al. (1996) studied optimi-
zation of blanching for banana chips using RSM and reported
that the crispiest chips could be produced at blanching condi-
tions of 69 °C and 22 min. Alvarez and Canet (1999) studied
optimization of stepwise blanching of frozen-thawed potato
tissues and showed that ranges of temperature of 60–65 °C
and time of 25–35 min were optimum conditions for the
blanching. Ismail and Revathi (2006) evaluated the effects
of blanching time, evaporation time, temperature, and hydro-
colloid on physical properties of chili (Capsicum annum var
kulai) puree by RSM. They reported that a complete inactiva-
tion of the enzymes was obtained with the blanching temper-
ature of 100 °C for 6 min. First-order reaction kinetics fitted
adequately to predict color loss and pectin in order to improve
the viscosity and total soluble solids of the puree.
Mestdagh et al. (2008) used a CCD to investigate the effect
of blanching time and temperature on the extraction of reduc-
ing sugars from potato strips and slices. Their results revealed
that blanching at 70 °C for 10 min was more efficient than
lower temperatures that appeared more time consuming.
However, the extraction yield of reducing sugars was over
425
10% lower when the potato cuts were blanched in water that
was previously used for blanching, leading to over 10% less
reduction in the final acrylamide content too. Yolmeh and
Najafzadeh (2014) investigated the ultrasound blanching of
green bean by RSM and they found that a temperature of
90 °C, sonication time of 58.27 s, and duty cycle of 0.79 s
were optimum conditions in which residual peroxidase activ-
ity and vitamin C loss were measured as 9.64 and 8.92%,
respectively. In addition to these examples, other studies have
also been carried out to optimize blanching of frozen Jalapeno
pepper (Capsicum annuum), potato (Solanum tuberosum L),
frozen/thawed mashed potatoes, and olive leaf through RSM
by Quintero-Ramos et al. (1998), Reyes-Moreno et al. (2002),
Fernandez et al. (2006), and Stamatopoulos et al. (2012),
respectively.
Application of RSM in Production of Microbial Enzymes
and Other Metabolites
Production of microbial enzymes and metabolites in microor-
ganisms is highly affected by several factors, such as type of
carbon and nitrogen sources, temperature, pH, metal ions,
incubation time, and inoculum volume (Açıkel, et al., 2010;
Liew, et al., 2005). Therefore, it is significant to optimize the
production conditions of microbial enzymes and metabolites,
which can be carried out by conventional and statistical tech-
niques. Statistical experimental approaches such as RSM are
much better since they suggest simultaneous, systematic, and
efficient variation of all the components for process optimiza-
tion economically (Abdel-Fattah, 2002).
As shown in Table 4, the highest EA of xylanase was mea-
sured at 61 U/mL from Chaetomium thermophilum by
Katapodis et al. (2007). They reported that this EA was ob-
served in 3.9% (w/v) wheat straw and 0.7% (w/v) sodium
nitrate. The highest EA of lipase was observed at 6230 IU/
mL from Candida sp. 99–125 by He and Tan (2006) at 4.18%
(w/v) soybean oil, 5.84% soybean powder, 0.284% K2HPO4,
0.1% KH2PO4, 0.1% (NH4)2SO4, 0.05% MgSO4, and 0.1%
Span 60 as the optimum culture medium. The highest EA of
α-amylase was measured at 6583 U/g from Aspergillus oryzae
by Francis et al. (2003) at 30 °C, an initial moisture of 70%,
and an inoculum rate of 1 × 107 spores/g dry substrate as the
optimum conditions. The highest EA of phytase was observed
at 2250 U/L from Escherichia coli by Sunitha et al. (1999) at
11.75 g/L trptone, yeast extract 5.88 g/L, and 5.32 g/L NaCl as
the optimum condition. The highest EA of protease was
measured at 1939 U/mL from Bacillus sp. by Puri et al.
(2002) at 15 mg/mL starch, 7.5 mg/mL peptone, 144 h
incubation time, and 1% inoculums density as the optimum
condition.
It is clear in Table 4 that glucose, oil, and yeast extract were
used most widely as independent variables in optimizing pro-
duction studies of the microbial enzymes and some other
Table 4 Some applications of RSM on production of microbial enzymes and some other metabolites in the food industry
426

Enzyme or Microorganism Independent variables Design Number of Randomization RSM modeling Modeling validity Validation of predicted Ref.
metabolite replication at graphical criteria optimum conditions
Number (types) Levels central point presented
R2 Residual Lack-
analyses of-fit

Xylanase Bacillus circulans 3 (xylan, pH, and cultivation time) 3 FFD 1 Not done Done A – – Not done (Bocchini et al.,
2002)
Xylanase Chaetomium 2 (NaNO3, and wheat straw) 5 CCD 3 Not done Done A – – Done (Katapodis et al.,
thermophilum 2007)
Xylanase Streptomyces sp. 3 (wheat bran, KNO3, and xylose) 5 CCD 5 Done Done A A A Done (Coman &
P12-137 Bahrim, 2011)
Lipase Rhizopus delemar 5 (sucrose, molasses sucrose, yeast 3 BBD 6 Done Done A A A Not done (Açıkel et al.,
extract, sunflower oil, and 2010)
Tween 80)
Lipase Aspergillus carneus 5 (sunflower oil, peptone, glucose, 3 CCD 7 Done Done A A A Done (Kaushik et al.,
agitation rate, and inoculum 2006)
period)
Lipase B. subtilis PTCC 1720 4 (temperature, sucrose, peptone, 5 CCD 5 Done Done A A A Done (Esmaeili et al.,
and corn oil) 2015)
Lipase Candida sp. 99-125 3 (Soybean oil, soybean powder, and 5 CCD 6 Not done Done A – – Done (He & Tan, 2006)
K2HPO4)
Lipase Candida cylindracea 5 (yeast extract, malt extract, 5 CCD 3 Done Done A – – Done (Muralidhar
peptone, glucose, and Tween 80) et al., 2001)
α-amylase Aspergillus oryzae 4 (medium, temperature, moisture 3 BBD 3 Not done Done A – – Done (Francis et al.,
content, and number of spores) 2003)
α-amylase Bacillus sp. 4 (starch, glycerol, YE, and 5 CCD 6 Not done Done A A A Done (Tanyildizi et al.,
peptone) 2005)
α-amylase B. amyloliquefaciens 3 (substrate, incubation period, and 3 BBD 6 Done Done A A A Done (Gangadharan
CaCl2) et al., 2008)
Phytase Pichia anomala 3 (glucose, beef extract, and 5 CCD 8 Not done Done A – I Done (Vohra &
inoculum size) Satyanarayan-
a, 2002)
Phytase Escherichia coli 3 (tryptone, yeast extract, and 5 CCD 4 Done Done A – – Not done (Sunitha et al.,
NaCl) 1999)
Phytase Kodamaea ohmeri BG3 3 (oats, ammonium sulfate, and 5 CCD 6 Not done Done A – – Done (Li et al., 2008)
pH)
Protease B. subtilis PTCC 1720 4 (temperature, sucrose, peptone, 5 CCD 5 Done Done A A A Done (Esmaeili et al.,
and corn oil) 2015)
Alkaline B. mojavensis 5 (casamino acids, glucose, 3 CCD 8 Done Done A – – Not done (Beg et al., 2003)
protease inoculum age, incubation time,
and agitation)
Protease Pseudomonas sp. 3 (pH, temperature, and inoculum 5 CCD 1 Not done Done A – – Done (Dutta et al.,
volume) 2004)
Alkaline Bacillus sp. 4 (starch, peptone, inoculum 3 CCD 6 Not done Done A – – Done (Puri et al., 2002)
protease density, and incubation time)
Aspergillus niger 2 (agitation, and aeration) 5 CCD 5 Done Done A – – Not done (Liu et al., 2003)
Food Bioprocess Technol (2017) 10:413–433
Table 4 (continued)

Enzyme or Microorganism Independent variables Design Number of Randomization RSM modeling Modeling validity Validation of predicted Ref.
metabolite replication at graphical criteria optimum conditions
Number (types) Levels central point presented
R2 Residual Lack-
analyses of-fit

Glucose
oxidase
Pectinase Kluyveromyces 3 (temperature, pH, and time) 5 CCD 6 Done Done A A A Not done (Moyo et al.,
wickerhamii 2003)
Nattokinase B. subtilis 4 (glucose, peptone, magnesium 5 CCD 5 Not done Done A A I Not done (Deepak et al.,
sulfate, and calcium chloride) 2008)
Inulinase Kluyveromyces S120 3 (inulin, corn steep liquor, and 3 BBD 3 Not done Done Not done (Xiong et al.,
Food Bioprocess Technol (2017) 10:413–433

A – –
(NH4)2SO4) 2007)
Elastase Bacillus sp. EL31410 6 (glucose, casein, corn steep flour, 6 CCD 3 Not done Done A – – Not done (Q. Chen et al.,
K2HPO4, MgSO4O7H2, and pH) 2002)
β glucanase Bacillus subtilis 6 (barley flour, corn flour, soybean 3 CCD 4 Not done Done A – – Done (Tang et al.,
ZJF-1A5 flour, KH2PO4, MgSO4.7H2O, 2004)
and CaCl2)
Hydrogen Ethanoligenens 3 (glucose, Fe2+, and Mg2+) 3 BBD 3 Done Done A – – Done (Guo et al.,
harbinense B49 2009)
Ethanol Sago starch 3 (temperature, time, and pH) 5 CCD 6 Done Done A – – Not done (Ratnam et al.,
2003)
– Recombinant 5 (medium type, glucose, 5 CCD 5 Not done Done A A – Done (Nikerel et al.,
Escherichia coli (NH4)2HPO4, KH2PO4, and 2006)
Mg SO4)
– Lactobacillus rhamnosus 4 (pH, vitamin solution, glucose, 5 CCD 6 Done Done A – A Done (Liew et al.,
and yeast extract) 2005)
Biosurfactant Lactococcus lactis 53 6 (peptone, meat extract, yeast 3 FFD 3 Done Done A A – Not done (L. Rodrigues
and Streptococcus extract, lactose, ammonium et al., 2006)
thermophilus A citrate, and KH2PO4)
Bacteriocin B. licheniformis strain 3 (temperature, pH, and cheese 5 CCD 3 Not done Done A – – Not done (Cladera-Olivera
P40 whey) et al., 2004)

A appropriate, I inappropriate, SA semi-appropriate, FFD full factorial design, BBD Box-Behnken design, CCD central composite design
427
428
metabolites. Among papers reviewed in Table 4, Coman and
Bahrim (2011), Kaushik et al. (2006), Esmaeili et al. (2015),
Gangadharan et al. (2008), and Liew et al. (2005) employed
RSM more appropriately.
Challenges of Applying RSM in Food Processes
It was shown that there are much potential for applying RSM in
the food industry processes. However, this technique is not al-
ways successful and there are some important points to consider
when using it for achieving a successful performance including:
& Correct choice of the range of independent variables:
Enough preliminary work or experience is needed to select
the appropriate range of each factor, which directly affects
the success of RSM optimization.
& Correct selection of the polynomial model: A second-
order equation is used commonly in RSM methodology.
If the trend of the responses in the studied range of factors
is not suitable to depict with second-order equation, the
range of independent variables or the form of the depen-
dent should be transformed to a suitable form, in which the
trend of the responses could be depicted with this equation
(Baş & Boyacı, 2007). The RSM approach needs to be
regressed with a polynomial equation. In addition, the
number of terms in polynomial equation is limited to num-
ber of design points, as well as choice of the suitable
polynomial equation can be very laborious because each
response needs its own distinct polynomial equation.
Thus, the accuracy of the RSM modeling can be increased
through combining with other modeling techniques such
as artificial neural network (ANN).
ANNs present an option to the polynomial regression
method as a modeling approach. ANNs are presented
Table 5 Some applications of RSM combined with ANNs in the food industry processes
Analyte Sample Analytical technique
Natural dye Annatto seed MAE
Herbicide Water HPLC
Neuroprotective peptide Mixture of HPLC
peptide
Cis- and trans- resveratrol Australian Capillary zone
wine electrophoresis
Hydrochlorothiazide and Pharmaceutical HPLC
amiloride
Food Bioprocess Technol (2017) 10:413–433
usually as systems of interconnected Bneurons^ which can
compute values from inputs, and are capable of machine
learning as well as pattern recognition giving to their adap-
tive nature. This approach presents an interesting chance to
preparing non-linear modeling for response surface and op-
timization of food industry processes (Tran, et al., 2007).
The ANN technique applies modeling of complex process-
es that is possible to study without complicated equations.
The ANN methodology has several advantages compared
to regression models, such as more flexibility concerned
with the number and type of experimental data, high pre-
dictive power, more accuracy, using all data, and not re-
quired to normalize data (Bezerra et al., 2008).
In Table 5, some studies regarding the application of RSM
combined with ANN for optimization of food processes
(mainly isolation studies) has been presented. For example,
Sinha et al. (2013) used RSM and ANN to develop predictive
models for simulation and optimization of the annatto dye
extraction process and they compared both modeling method-
ologies (RSM and ANN) statistically by R2, root mean square
error (RMSE), and AAD based on the validation data set.
Their results revealed that ANN had better prediction perfor-
mance than RSM.
In a study by Shahraki et al. (2014), they applied RSM
combined with genetic algorithms (GA) to optimize the fluid-
ized bed drying of sesame seeds and their results revealed that
GA can improve the equation coefficients obtained by RSM.
Application of RSM in Non-food Processes
In addition to food processes, RSM has been successfully
used to optimize non-food processes such as biochemical
and chemical engineering processes. Both BBD and CCD
designs have been used in different non-food process studies,
for example in capillary zone electrophoresis (BBD, Suresh
Objective of study Ref.
Development predictive models for simulation (Sinha et al., 2013)
and optimization of the dye extraction process
Optimizing of the linear gradient separation of 10 (Tran et al., 2007)
herbicides consisting of a mixture of acids,
bases, and neutrals employing a single ANN
for modeling the response surface
Sing experimental design conjunction with (Novotná et al., 2005)
artificial neural networks for optimization of
isocratic ion-pair separation of neuroprotective
peptides
Optimizing the solid-phase extraction employing (Spanilá et al., 2005)
central composition design and ANN
Comparing artificial neural networks for (Agatonovic-Kustrin et al.,
response surface modeling in HPLC with 1998)
multiple regression methods
Food Bioprocess Technol (2017) 10:413–433
Babu et al., 2004), microwave-assisted extraction of persistent
organochlorine pesticides (BBD, Gfrerer and Lankmayr,
2005), separation of β-blockers by ion-pair capillary electro-
phoresis (BBD, Servais et al., 2002), optimization of cadmium
determination by flame atomic absorption spectrometry
(BBD, Souza et al., 2005), biosensor development (CCD,
Zhang et al., 2011; Mirmoghtadaie et al., 2013), optimization
extraction of human antibodies (CCD, Rosa et al., 2007), and
optimization extraction of five 1,4-dihydropyridines calcium
channel antagonists from human plasma (CCD, Baranda et al.,
2005). A wide range of dependent and independent variables
have been investigated in these processes, which are based on
the case and target.
Conclusions
Nowadays, application of RSM in the optimization of differ-
ent food industry processes is common due to its advantages
compared with conventional methods. By reviewing the liter-
ature, it was shown that CCD was the most utilized second-
order experimental design for optimizing the food processes.
Also, the RSM approach was only usable for optimizing the
processes which can be depicted with a second-order polyno-
mial equation. Moreover, it is important to use some criteria
such as lack-of-fit and AAD to assay the suitability of fitting
the response surface models, in addition to R2. Finally, an
adaptive learning technique, which uses ANN merged with
RSM, can be helpful to model the dependence relation and it
has more accuracy in the prediction compared with traditional
RSM.
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