Design of Experiments (DOE) May Prove Useful.: 2/25/2017 Ronald Morgan Shewchuk 1

Operational Excellence
Design of Experiments
Introduction
• In previous presentations we reviewed the technique of response surface
regression analysis to evaluate historical data and develop a modeling equation for
an output variable which we want to optimize.
• Historical data is great insofar as it is “free”, that is, the data has already been
generated as part of routine production operations.
• Historical data, however, is often compiled over a long period of time by multiple
different personnel leading to uncertainty in the data.
• This uncertainty in the data manifests itself in uncertainty in the analysis,
conclusions and recommendations.
• In cases where response surface regression analysis of historical data fails to
identify correlations with adjusted R2 values in excess of 85%, the technique of
Design of Experiments (DOE) may prove useful.
• Design of Experiments is a set of controlled experiments, conducted in randomized
order.
• The number of experiments required is dependent upon the DOE design which we
select.
2/25/2017 Ronald Morgan Shewchuk 1
Definitions
• Experiments are costly, especially if they are conducted in the production plant
rather than in the pilot plant or laboratory, so we want to select a DOE design
which minimizes the number of trials conducted without compromising the
integrity of the data analysis, and without producing discrepant product.
• There are some common terms used in Design of Experiments which are defined
below.
Factor: A controlled or uncontrolled input variable.
Level: A specific value or setting for a factor.
Response Variable: An output which is measured or observed.
Effect: The change in the response variable that occurs as experimental conditions
change.
Interaction: Synergistic effect which occurs when the effect of one factor on the
response variable depends on the setting of another factor(s).

Definitions
Two-way Interactions: Second order effects on the response variable resulting from
the interaction of two factors (eg AB, AC, BD, etc).
Three-way Interactions: Third order effects on the response variable resulting from
the interaction of three factors (eg ABC, ACD, BCD, etc).
Repetition: Running several samples during one experimental setup.
Replication: Duplicating the entire experiment in a time sequence with different

setups between each run.
Randomization: Technique used to randomize the order of the experimental runs or

the assignment of experimental units to the different factor-level
combinations.
Resolution: The degree to which the design of the experiment can differentiate
levels of interactions.

Definitions
Residual: The difference between an observed value and the predicted value of the
modeling equation.
Run: A single setup in a DOE from which data is gathered. For example, a three-
factor full factorial DOE with two levels will have 23 = 8 runs.
Trial: Used interchangeably with Run.
Treatment Combination: Used interchangeably with Run.
Orthogonal Design: An experimental design is said to be orthogonal if each factor is

tested in such a way that it can be evaluated independently of
the other factors.
Aliasing: Occurs when two factors or interaction terms are set at identical levels
throughout the experiment.
Confounding: Two factors are considered to be confounded when their test profiles
contain the same pattern of test settings making it impossible to
evaluate the two factors independently.
Taguchi Loss Function
• We have learned, during our review of Cause and Effect Diagrams, that any process
will have input variables which may be categorized as
 Controllable (C) – variables which must be held constant and require standard
operating procedures to ensure consistency
 Noise (N) – variables which are not controlled and thus introduce variation
into the process
 Experimental (X) – key process variables which must be tested to identify
their optimal settings.
• These variables act upon the process to influence the response variables which
measure process and/or product performance.
• This may be visualized as in Figure 9.1.

Figure 9.1 Process Input/Output with Variable Categories
Controllable Variables (C)
Experimental Response
Variables (X) Process Variables (Y)
Noise Variables (N)

• We have also learned, during our review of Statistical Process Control, the
importance of centering the process and reducing variation to maximize process
capability.
• Genichi Taguchi, a Japanese scientist, also recognized this importance and
furthermore theorized that there is a quadratic relationship between the financial
loss of the process and the distance the process is off target.
• This relationship is represented by the Taguchi Loss Function described in Eqn 9.1
and graphically depicted in Figure 9.2.
• The financial loss typically results from inspection costs, scrap, rework, increased
cycle time, increased inventories, design changes, reduced customer satisfaction,
reduced market share, etc.

L = k(y – T)2 Eqn 9.1
where L = monetary loss

y = response variable
T = target value of response variable
k = monetary constant
Figure 9.2 Taguchi Loss Function

Target
Monetary Loss (L)
L = k(y – T)2
LSL Response Variable (y) USL

Choosing and Experimental Design
• The steps involved in conducting a Design of Experiments are summarized in Fig 9.3.
• The type of experimental design selected will depend upon your objectives.
• Screening DOE designs are used to identify the key process input variables (KPIV)
that influence the process mean or variation.
• Modeling DOE designs build predictive equations for your output response variable
as a function of the key process input variables.
• Optimizing DOE designs locate the sweet spot of the process within the modeling
equation which optimizes the absolute value of the output response variable while
minimizing variation due to input noise variables.
• As with any decision process, there are trade-offs.
• Screening DOE’s are subject to variable confounding and missing variable
interaction effects but require fewer runs which results in lower experimental cost.
• Modeling DOE’s provide increased knowledge of the process by preventing
confounding and accounting for all variable interactions but require many runs
since all factor combinations must be tested.
Figure 9.3 Steps for Conducting a Design of Experiments
Design of Experiments Steps
Planning Phase
1. State the problem
2. Define the objectives
3. Select the output response variables
4. Select the input factors to be explored
5. Select the factor levels
6. Select the DOE design
7. Determine the sample size
8. Determine the number of replicates
9. Define the experimental plan (ie procedures, operators, measurement system, etc)
Execution Phase
10. Conduct the experiment
11. Collect the data
Analysis Phase
12. Identify significant factors and interactions
13. Fit and finalize the modeling equation
14. Validate results
15. Evaluate conclusions for impact on the current process and downstream customers
16. Conduct cost-benefit analysis of implementing conclusions
17. Consider next-generation DOE to further optimize the process

Choosing and Experimental Design
• Optimizing DOE’s provide a high level of process knowledge but require a large
number of replicates to ensure that the true sweet spot of the process has been
located. These design cost-benefits may be visualized as in Figure 9.4.
• A common mistake of novice experimenters is to select a comprehensive DOE
design with multiple factors, levels and replicates.
• The seven factor, three level, three replicate DOE is bound to scare off the most
open-minded Operations Manager.
• If your process has multiple input variables and you don’t know which variables are
important, it is best to begin with a screening DOE design.
• Once you reduce the factor set your team can conduct a modeling DOE to develop a
predictive equation for the output response variable.
• This predictive equation can then be subsequently used in response surface designs
to optimize the settings of the reduced factor set.
• If your process is well defined and/or you want to explore the effects of only a
handful of input variables then a modeling DOE design is probably a good starting
point. The DOE design decision tree is shown in Figure 9.5.
Figure 9.4 Considerations in Selecting an Experimental Design
DOE Objective Experimental Design Type

High (6-15) Low Low
Screening • Resolution III Fractional Factorial
• Resolution IV Fractional Factorial
• Plackett-Burman
Key Process Input Variables

•
Knowledge
Taguchi
Cost
Modeling • Full Factorial
• Resolution V Fractional Factorial
• Central Composite
• Box-Behnken
Optimizing • Response Surface Methodology

Low (2-5) High High

Figure 9.5 Decision Tree for Choosing an Experimental Design
Need for DOE

Identified
Define Problem and

Objectives
Define Metrics for

Response Variable
3 Variables Only
# Levels for Type of
Each Factor? Factors?
2 Variables and Attributes
# Factors
# Factors (K)? # Factors (K)?
(K)?
K 4 K=5 6K8 9  K  11 K 3 4K7 6K7 K5

12 Run Plackett- Central
16 Run
Full Factorial Half-Fraction Burman or Full Factorial Taguchi L18 Composite or
Fractional
Taguchi L12 Screening Box-Behnken
Factorial
Screening

Resolution
• Experimenters typically use the term resolution to describe the discriminating
power of a selected design.
• The resolution, R of a 2-level fractional factorial design is equivalent to the shortest
interaction term in the defining relation.
• The resolution of a 2k-q fractional factorial design where k is the number of input
factors and q is the fraction magnitude (q=1 for ½ fraction, q=2 for ¼ fraction, q=3
for ⅛ fraction) will depend on the number of input factors, the fraction magnitude
and the number of runs conducted.
• These influences are summarized in the Minitab resolution table of Figure 9.6.
• The higher the resolution of the design, the higher the discriminating power of the
design.
• A RII design has main effects aliased with other main effects. Consequently, it is not
a recommended experimental approach.
• RIII designs do not alias main effects with each other but do alias main effects with
2-way interactions. Thus, RIII designs are typically used in screening DOE’s to reduce
the input factor set number.
Figure 9.6 Minitab 2-Level Fractional Factorial Design Resolution Table

Resolution
• RIV designs do not alias main effects with 2-way interactions but do alias 2-way
interactions with other 2-way interactions.
• RIV designs are typically used for building modeling equations where resource
limitations preclude the use of an RV design.
• RV designs do not alias main effects with each other or with 2-way interactions.
• 2-way interactions are not aliased with other 2-way interactions.
• Main effects are aliased with 4-way interactions (which are rare) and 2-way
interactions are aliased with 3-way interactions.
• In general, RV designs are well suited to building modeling equations which are
devoid of significant interaction issues.
• Resolution attributes are summarized in Figure 9.7.
• You may have noticed the term Full along the leading diagonal of the resolution
table in Figure 9.6.
• This stands for Full Factorial. Full Factorial designs do not contain aliasing,
consequently their resolution is typically referred to as Full Factorial.
Figure 9.7 2-Level Design Resolution Attributes
RV
Main effects aliased with
4-way interact ions (rare).
2-way interact ions aliased
with 3-way interact ions.
Reco mmended for
modeling DOE’s.
RIV
Main effects aliased with 3-way interactions. 2-way
interactions aliased with other 2-way interact ions.
Reco mmended for modeling DOE’s with resource
limitations.
RIII
Main effects aliased with 2-way interactions.
Reco mmended for screening DOE’s
RII
Main effects aliased with other main effects.
Not reco mmended.

Coding and Uncoding Input Variables
• Mathematical analysis of DOE data requires that the experimental design be
created in coded input variables.
• This coding avoids the complications caused by different variable units and scales
through standardizing the inputs.
• Let’s say a microbiologist wanted to evaluate the effect of three factors on a
targeted cell culture growth – temperature, nutrient concentration and incubation
time.
• The low test setting for each factor is typically designated as –1, the high test
setting +1, and the center point (if the experimental design is three-level) is
designated as 0.
• This may be graphically visualized as in Figure 9.8.
• Conversion from uncoded to coded input variables may be accomplished by Eqn 9.2
and conversion back from coded to uncoded input variables may be accomplished
by Eqn 9.3.

Figure 9.8 Relationship Between Coded and Uncoded Input Variables
Uncoded Input Variables Coded Input Variables

Factor A B C A B C
nutrient incubation nutrient incubation
Description temperature concentration time temperature concentration time
Units C wt % hours dimensionless dimensionless dimensionless
Low 25 0.1 96 -1 -1 -1
High 35 0.2 192 1 1 1
Center Point 30 0.15 144 0 0 0
A - Temperature B - Nutrient Conc. C - Incubation Time

1 1 1
Coded Units
Coded Units
Coded Units
0 0 0
-1 -1 -1
25 30 35 0.1 0.15 0.2 96 144 192
Uncoded Units Uncoded Units Uncoded Units

Coding and Uncoding Input Variables
2(UC –UCCpt)
C= Eqn 9.2
(UCH –UCL)
where C = Coded Input Variable
UCH = High Value of Uncoded Input Variable
UCL = Low Value of Uncoded Input Variable
UC = Uncoded Input Variable
UCCpt = Center Point Value of Uncoded Input Variable
UC = ½C(UCH –UCL) + UCCpt Eqn 9.3

Full Factorial Designs
• Let us begin our journey into designed experiments by considering a three factor,
two level, two replicates DOE as described in Case Study XII.
Case Study XII: Full Factorial DOE Analysis of Adhesive Shear Strength
Raul Sanchez, the Production Manager of a large Automotive Parts and Assembly manufacturer in Veracruz, has just received a
disturbing call from the Quality Control Manager. The lap shear strength measurements of the last lot of AB4356 subassembly parts
have indicated a low shear strength average and a high standard deviation. This has resulted in a Cpk below 1.0 which prevents the
Quality Control Manager from certifying the lot and releasing the shipment. Raul has been expecting this call. He has been monitoring
the SPC charts for this quality characteristic for the last several weeks and has noticed a downward trend with increased variation.
The AB4356 subassembly includes a Buna N rubber strap fixtured to an Acrylonitrile Butadiene Styrene (ABS) housing with a
cyanoacrylate adhesive. Raul meets with his production team and they prepare a Cause and Effect Diagram of the possible sources of
low shear strength. There are many potential causes, but the group decides to focus on three factors – temperature, humidity and
surface roughness of the ABS substrate. Temperature and humidity are noise factors (the plant is not climate controlled). The substrate
surface roughness can be increased or decreased within certain limits depending on choice of supplier. The group opts for a three
factor, two level, two replicates Full Factorial DOE design to avoid confounding and the potential to miss interaction effects. The steps
for creating the experimental design are captured in the screen shots of Figure 9.9.
The group reviews historical production records and selects the low and high test conditions for the DOE based upon the measured
minimum and maximum values for the three factors over the last six months. The low and high values are summarized below.
Low High
Temperature (C) 21 30
Relative Humidity (%) 39 87
ABS Surface Roughness Ra (m) 0.29 1.05
The Quality Control Manager graciously agrees to allocate the resources of the environmental control chamber for the required four
days of testing and to perform the 24hr Lap Shear Strength testing per ISO 4587. The shear strength results are entered into the design
sheet and the DOE analysis is conducted as in Figure 9.10.
Figure 9.9 Steps for Creating a Full Factorial Experimental Design
Open a new worksheet. Click on Stat → DOE  Factorial  Create Factorial Design on the top menu.

Click the radio button for 2-level factorial (default generators) in the dialogue box and select 3 for the Number of factors. Click Designs.

Select Full Factorial Design in the dialogue box. Number of center points per block = 0. Number of replicates for corner points = 2.
Number of blocks = 1. Click OK. Then Click Factors.
Enter Temp for the name of Factor A, RH for Factor B and Ra for Factor C in the dialogue box. Leave the Low and High values in their coded
variable format. Click OK. Then Click OK one more time.
The session window indicates that you have created a full factorial design with three factors and sixteen runs. Click Window → Worksheet
on the top menu to display the randomized DOE template.
Enter Shear Strength for the name of column eight. Enter the measured shear strength results for each experiment in the appropriate cells
of the design sheet.
Figure 9.10 Steps for Analyzing a Full Factorial Experimental Design
Click on Stat → DOE  Factorial  Analyze Factorial Design on the top menu.

Select C8 Shear Strength for the Response variable in the dialogue box. Click Graphs.

Select Normal and Pareto for Effects Plots in the dialogue box. Click OK. Then Click OK one more time.

Pareto Chart of the Standardized Effects

(response is Shear Strength, Alpha = 0.05)
2.31
Factor Name
A Temp
B B RH
C Ra
A
Term
AB
AC
BC
ABC
0 2 4 6 8 10 12 14 16 18
Standardized Effect
The Pareto Chart of the Standardized Effects of Shear Strength indicates that humidity has the greatest impact on shear strength followed
by a minor effect of surface roughness. The red vertical line at Standardized Effect 2.31 is the threshold H0 value above which we would
reject the null hypothesis that there are no significant effects at an alpha level of 0.05. Click Window → Effects Plot for Shear Strength on
the top menu.
The Normal Plot of the Standardized Effects of Shear Strength indicates that B Relative Humidity and C Ra are significant factors. The
further the points are away from the blue normal line, the more significant the factor. Click Window → Session on the top menu.

The session window displays the ANOVA analysis results. Factors with P-values less than 0.05 are considered significant. Humidity is the
most important factor with a minor contribution from surface roughness. Temperature is not a significant factor. There are no significant
factor interactions.
Click on Stat → DOE  Factorial  Factorial Plots on the top menu.

Click on Main Effects Plot in the dialogue box. Click Setup.

Select C8 Shear Strength for Responses in the dialogue box. Include A: Temp, B: RH and C: Ra for Factors to Include in Plots. Click OK.
Then Click OK one more time.
Main Effects Plot for Shear Strength

Data Means
Temp RH
18
16
14
12
10
Mean
-1 1 -1 1
Ra
18
16
14
12
10
-1 1
The greater the slope of the line in the Main Effects Plot for Shear Strength the greater that factor’s influence on shear strength. The plot
indicates that the mean shear strength is maximized at high humidity.

Case Study XII: Full Factorial DOE Analysis of Adhesive Shear Strength
Output Interpretation
Raul has identified that the primary driver of lap shear strength is a noise variable which is outside his control. He now has the data
and analysis results to support a capital expense proposal to convert one of the small storage rooms into a humidity-controlled staging
room. Raul is optimistic that his boss will support the proposal since she is a chemist and will recognize that the DOE results are
supported by the reaction chemistry of the adhesive. Cyanoacrylate adhesives are catalyzed by water. If she refuses, Raul will have to
explore other adhesive alternatives which are insensitive to ambient humidity. Raul, employing the skills of a seasoned chess player,
surmises that he could probably use a screening DOE to make this selection with one of the input factors being adhesive type.
Plackett-Burman Screening Designs

• The Plackett-Burman designs were developed by R.L. Plackett and J.P. Burman in
1946 while working for the British Ministry of Supply.
• These designs permit the evaluation of multiple factors simultaneously in order to
identify the vital few from the trivial many.
• Plackett-Burman designs are of resolution III, meaning that main effects are not
aliased with one another but may be aliased with two-way interactions.
• They are an effective design approach for screening a large number of factors while
minimizing the number experiments conducted.

Plackett-Burman Screening Designs
• Consider the case where you have ten factors to be evaluated for impact on a
quality characteristic. A full factorial DOE with two levels and two replicates would
require 210 · 2 = 2,048 experiments.
• A Plackett-Burman screening DOE would require only 24 experiments.
• Let us apply the technique of a screening DOE and analysis in Case Study XIII.
Case Study XIII: Screening DOE Analysis of Drug Delivery Factors

Shanti Chopra is a researcher with an upstart pharmaceutical company. He has just been assigned to the SPES1564 development
program, a revolutionary drug intended to reduce the mortality rate caused by pancreatic cancer. Shanti’s first assignment is to
develop an effective drug delivery system for SPES1564 which will target pancreatic tumors. Shanti has many ideas, but he must
choose wisely since validation testing in mice typically takes fourteen days. He decides to begin with the ten factors identified below,
utilizing two levels and two replicates.
Peptide Coupler A Ligand

Peptide Coupler B Block Copolymer Molecular Weight
Peptide Coupler C Micelle Size
Peptide Coupler D Aptamer A
pH Aptamer B
Shanti will track the % reduction in pancreatic tumor size in orthotopically-implanted mice via fluorescence imaging. The steps in
creating the 12 Run Plackett-Burman screening DOE are captured in Figure 9.11. Experimental results are entered into the design
sheet and the DOE analysis conducted as in Figure 9.12.

Figure 9.11 Steps for Creating a Plackett-Burman Screening Experimental Design

Click the radio button for Plackett-Burman Design in the dialogue box and select 10 for the Number of factors. Click Designs.

Select 12 for the Number of runs in the dialogue box. Enter 2 for the Number of replicates. Click OK. Then Click Factors.

Enter the names of the ten factors in the dialogue box. The data type should be indicated as Numeric for all ten factors. Leave the values
for Low and High as the coded values –1 and 1 respectively. Click OK. Then click Options.
Uncheck the selection for Randomize runs just for this case in the dialogue box. This will facilitate our data entry into the design
worksheet. Click OK. Then click OK one more time.
The worksheet is populated with the factor settings for the 12 runs with two replicates.

Scroll to the right of the design sheet and label the first open column % Reduction Tumor Sz.

Conduct the experiments in randomized order and enter the % reduction in tumor size measurements in the response variable column.

Figure 9.12 Steps for Analyzing a Plackett-Burman Experimental Design

Select C15 % Reduction Tumor Sz for the Response variable in the dialogue box. Click Graphs.

Select Normal and Pareto for Effects Plots in the dialogue box. Click OK. Then Click OK one more time.

The Pareto Chart of the Standardized Effects of % Reduction in Tumor Size indicates that Peptide Coupler C, pH, Aptamer A and Micelle
Size have the greatest impact on tumor size. The red vertical line at Standardized Effect 2.16 is the threshold H0 value above which we
would reject the null hypothesis that there are no significant effects at an alpha level of 0.05. Click Window → Effects Plot for % Reduction
Tumor Sz on the top menu.
The Normal Plot of the Standardized Effects of % Reduction in Tumor Size indicates that Peptide Coupler C, pH, Aptamer A and Micelle Size
are significant factors. The further the points are away from the blue normal line, the more significant the factor. Click Window → Session
on the top menu.

The session window displays the ANOVA analysis results. Factors with P-values less than 0.05 are considered significant. Notice that
factor interactions are absent. Plackett-Burman designs do not have the discriminating power to identify factor interactions.
Click on Stat → DOE  Factorial  Factorial Plots on the top menu.

Click on Main Effects Plot in the dialogue box. Click Setup.

Select C15 % Reduction Tumor Sz for Responses in the dialogue box. Click on >> to include all factors in the plots. Click OK. Then Click OK
one more time.
The greater the slope of the line in the Main Effects Plot the greater that factor’s influence on tumor size reduction. The plot indicates that
tumor size reduction is maximized with high concentration of Peptide Coupler C, high concentration of Aptamer A, low pH, and small
micelle size. Shanti has effectively reduced his factor set from ten to four. He can now proceed to a modeling DOE with increased
discriminating power.
Central Composite Modeling Designs
• Central Composite designs were developed by G.E. Box and K.B. Wilson in 1951.
• Consequently, they are sometimes referred to as Box-Wilson designs.
• These designs are the most effective and efficient second order modeling
approaches where factors are purely quantitative.
• The design includes a factorial portion, a center point portion and an axial portion.
• The factorial portion consists of 2k runs, where k is the number of factors.
• The number of center points required to maintain orthogonality may be calculated
from the formula recommended by Peter John (7) nc = 4(nF + 1) – 2k where nF is
the number of runs in the 2-level factorial portion of the design.
• This formula tends to result in a large number of center points.
• You may cut back the number, recognizing that the primary purpose of the center
points is to get an estimate of the pure experimental error.
• The number of axial points will typically equal 2k.

Central Composite Modeling Designs
• Alpha,  is a parameter of Central Composite designs representing the axial point
distance from the center of the design.
• It may be calculated from the relation  = [nF]¼.
• The factorial portion of the design may be built for any resolution, thus providing a
balance between discriminating power and the number of runs conducted.
• Central Composite designs can be run sequentially to save resources.
• For example, the factorial and center point portions of the design can be tested
first.
• A linear model can then be built from the two-level portion to predict the center
point results.
• If the linear model is not validated at the center points then the axial points can be
added to complete the quadratic model.
• Let us apply the technique of a modeling design in Case Study XIV to extend the fine
work that Shanti has completed in the previous case study.

Case Study XIV: Modeling DOE Analysis of Drug Delivery Factors
Shanti Chopra, a researcher with an upstart pharmaceutical company, has been assigned to develop an effective drug delivery
system for SPES1564 which will target pancreatic tumors. His previous screening DOE has identified four important factors. Shanti
would like to identify a modeling equation to permit further optimization through Response Surface Methodology. Since his factors
are all quantitative he elects to use a Central Composite design (CCD) with four factors, three levels and three replicates.
nF = 24 = 16.  = [16]¼ = 2. nc = 4(16 + 1) – 2(4) = 12. This is too many center points so Shanti elects to cut back to three, to be
consistent with the number of replicates for each trial. The levels of the four factors to be tested are summarized below.
(-) (-1) (0) (+1) (+) Unit

Peptide Coupler C 12 18 24 30 36 g/ml
pH 3.2 3.8 4.4 5.0 5.6 dimensionless
Micelle Size 60 110 160 210 260 nm
Aptamer A 50 62.5 75 87.5 100 g/ml
Shanti will track the % reduction in pancreatic tumor size over fourteen days in orthotopically-implanted mice via fluorescence
imaging as his response variable. The steps in creating the Central Composite DOE are captured in Figure 9.13. Experimental
results are entered into the design sheet and the DOE analysis conducted as in Figure 9.14.

Figure 9.13 Steps for Creating a Central Composite Experimental Design
Open a new worksheet. Click on Stat → DOE  Response Surface  Create Response Surface Design on the top menu.

Select the radio toggle button for Central composite in the dialogue box. Select the Number of factors to be 4. Click Designs.

Select Full Design with one block in the dialogue box. Select the radio button for Custom Number of Center Points. Enter 3 for Cube block.
Leave the value of Alpha at its default value of 2.000. Enter 3 for the Number of replicates. Click OK. Then click Factors.
Select the radio button for Cube points and enter the names of the four factors in the dialogue box. Leave the values for Low and High as
the coded values –1 and 1 respectively. Click OK. Then click Options.
The worksheet is populated with the factor settings for the 27 runs with 3 replicates.

Scroll to the right of the design sheet and label the first open column % Reduction Tumor Sz.

Conduct the experiments in randomized order and enter the % reduction in tumor size measurements in the appropriate cell of the
response variable column.
Figure 9.14 Steps for Analyzing a Central Composite Experimental Design
Click on Stat → DOE  Response Surface  Analyze Response Surface Design on the top menu.

Select C9 % Reduction Tumor Sz for the Response variable in the dialogue box. Click OK.

The session window displays the response surface regression analysis results. Factors with P-values less than 0.05 are considered
significant. This means that pH, Micelle Size, Aptamer A and Peptide Coupler C squared are important factors. All other quadratic terms
and factor interactions are not significant.
Let’s proceed to simplify the regression model. Click on Stat → DOE  Response Surface  Analyze Response Surface Design on the top
menu.
Click on Terms in the dialogue box.

Clear all selected terms from the dialogue box by clicking <<. Reselect A: Peptide Coupler C, B: pH, C: Micelle Size, D: Aptamer A and AA
which stands for the A factor squared. Notice that we had to include the A term since AA was significant to avoid violation of hierarchy
rule. Click OK. Then click OK one more time.
The session window displays the reduced regression model analysis results. The reduced model has an adjusted R 2 of 91.58% which
means that it explains 91.58% of the variation in reduction in tumor size. The modeling equation with coded coefficients is shown in
Eqn 9.4.
Response Surface Methodology
^
Y = 58.304 – 1.733B – 2.517C + 5.136D – 7.745A2 – 0.079A Eqn 9.4
• Shanti now has a modeling equation which will form the basis of finding the local
optimum within the design space via the technique of Response Surface
Methodology.
• Response Surface Methodology is an iterative process by which experiments are
conducted along the pathway of steepest ascent (ie the direction of greatest
improvement in the response variable) in order to identify the factor settings which
optimize the response variable.
• This may be visualized in Figure 9.15.
• Response Surface Methodology allows us to see the contours of improvement so
that we may select factor settings that are well centered within the response
variable plateau.
• This leads to robust process operation which is resistant to noise variables as
opposed to running the process in an unstable region, akin to skateboarding on a
handrail.
Figure 9.15 Response Surface Methodology Pathway of Steepest Ascent
DOE 3
DOE 4
DOE 2 Response
Variable
DOE 1
Factor B
Factor A
• Consider the surface plots of Figure 9.16 for Shanti’s reduced regression model of
Case Study XIV.
• These have been generated in Minitab by selecting Stat  DOE  Response
Surface → Surface Plots on the top menu.

Response Surface Methodology
• Shanti has included four factors in his modeling equation, consequently there are
six two-factor surface plots and hence, six pathways of steepest ascent for the
response variable.
• But which pathway should we take?
• If Shanti’s modeling equation was first order, that is, of the form
Y-hat = C1 + C2x1 + C3x2 + C4x3 …+ Ck+1xk we could use the analytical approach as
outlined in Figure 9.17 to answer this question.
• But Shanti’s modeling equation includes the quadratic term A2 and its form does
not permit solution for the maxima using partial derivatives and simultaneous
equations.
• Thus, we must use the procedure indicated in Figure 9.18.
• Let us apply these steps in Case Study XV to locate the optimum factor settings for
Shanti Chopra’s targeted pancreatic cancer drug development.

Figure 9.16 Surface Plots for Case Study XIV Factors
Surface Plot of % Redn Tumor Sz vs pH, Peptide Coupler C

Hold Values
Micelle Size 0
Aptamer A 0
60
50
% Re dn Tumo r Sz
40
2
30
0 pH
-2
0 -2
2
Pe ptide Co uple r C

Surface Plot of % Redn Tumor Sz vs Micelle Size, Peptide Coupler C

Hold Values
pH 0
Aptamer A 0
60
% Re dn Tumor Sz
40
2
20 0
Micelle Size
-2
0 -2
2
Pe ptide Co upler C

Surface Plot of % Redn Tumor Sz vs Aptamer A, Peptide Coupler C

Hold Values
pH 0
Micelle Size 0
60
% Re dn Tumo r Sz
40
2
20
0
Apta me r A
-2
0 -2
2
Peptide Co uple r C

Surface Plot of % Redn Tumor Sz vs Micelle Size, pH

Hold Values
Peptide Coupler C 0
Aptamer A 0
65
% Redn Tumo r Sz60
55 2
50 0
Mice lle Size
-2
0 -2
pH 2

Surface Plot of % Redn Tumor Sz vs Aptamer A, pH

Hold Values
Peptide Coupler C 0
Micelle Size 0
70
% Redn Tumo r Sz60
2
50
0
Apta mer A
-2
0 -2
pH 2

Surface Plot of % Redn Tumor Sz vs Aptamer A, Micelle Size

Hold Values
Peptide Coupler C 0
pH 0
70
% Redn Tumo r Sz60
50 2
40 0
Apta mer A
-2
0 -2
2
Micelle Size

Figure 9.17 Optimization via Response Surface Methodology – 1st Order Modeling Equations
Response Surface Methodology Steps - 1st Order Modeling Equations
1. Conduct Screening DOE to identify main effects.

2. Conduct Modeling DOE to identify interactions and develop modeling equation.
3. Calculate path of steepest ascent for response variable.
4. eg) coded modeling equation Y-hat = Const + AcoeffA + BcoeffB + CcoeffC
5. Select one factor and iterate by one coded unit eg) A = 1
6. Calculate the associated step size in the other factors eg) B = Bcoeff/Acoeff * A and C =
Ccoeff/Acoeff * A
7. Create an iteration table with coded and uncoded values of factors. Use Eqn 9.3 to convert
coded factors to uncoded factor settings.
8. Conduct experiments at each iteration factor setting. Record the measured output response in
the iteration table.
9. Identify the optimum output response in the iteration table.
10. Conduct a Full Factorial DOE centered at the output response optimum identified in step 9.
11. Identify optimized modeling equation from Full Factorial DOE multiple response regression
analysis.
12. Identify factor settings which maximize the predicted value of the optimized modeling
equation for the output response variable.
13. Conduct confirmatory runs at the optimized process settings.
14. Establish upper and lower specification limits for each input variable to maintain the output
response variable in the optimum plateau.
15. Monitor output response variable via Statistical Process Control techniques.
16. Consider process improvements which will further reduce input factor variation.
17. Consider process improvements which will further reduce the effect of ambient noise
variables.

Figure 9.18 Optimization via Response Surface Methodology – 2nd Order Modeling Equations
Response Surface Methodology Steps - 2nd Order Modeling Equations
1. Open the Minitab file with the reduced regression model.

2. Click Stat → DOE → Response Surface → Contour/Surface Plots.
3. Generate the surface plot of Y-hat for the two factors in the modeling equation with
the largest absolute value coefficients.
4. Fix the other factors as constants at their coded values which will maximize Y-hat
within the modeling equation.
5. Conduct a Full Factorial DOE centered at the output response optimum identified in step 4.
6. Vary the fixed factors of step 4 such that their high or low value is taken one coded unit out of
the original design space of the modeling DOE.
7. Identify the pathway of steepest ascent for the fixed factors and output response optimum.
8. Repeat Full Factorial DOE centered at the output response optimum identified in step 7.
9. Vary the fixed factors such that their high or low value is taken one coded unit out of the
existing design space of the full factorial DOE.
10. Identify the values of the factors which optimize the output response variable.
11. Iterate steps 8 through 10 until the desired output response outcome is achieved.
12. Identify optimized modeling equation from Full Factorial DOE multiple response regression
analysis.
13. Hold factors at settings which maximize the predicted value of the optimized modeling
equation for the output response variable.
14. Conduct confirmatory runs at the optimized process settings.
15. Establish upper and lower specification limits for each input variable to maintain the output
response variable in the optimum plateau.
16. Monitor output response variable via Statistical Process Control techniques.
17. Consider process improvements which will further reduce input factor variation.
18. Consider process improvements which will further reduce the effect of ambient noise
variables.

Case Study XV: Optimization of Drug Delivery Factors by Response Surface Methodology
Shanti Chopra, a researcher with a pharmaceutical company, has been assigned to develop an effective drug delivery system
for SPES1564 which will target pancreatic tumors. His previous screening DOE has identified four important factors and his
modeling DOE has identified a quadratic relationship with the concentration of Peptide Coupler C. Shanti would like to use
the technique of Response Surface Methodology to determine the values of Peptide Coupler C concentration (A), pH (B),
Micelle Size (C) and Aptamer A concentration (D) which maximize the % reduction in pancreatic tumor size over fourteen days
in orthotopically-implanted mice.
Shanti’s previous DOE using a Central Composite Design has resulted in the following modeling equation.
Y-hat = 58.304 – 1.733B – 2.517C + 5.136D – 7.745A2 – 0.079A
Factors A2 and D have the largest absolute value coefficients. Y-hat is maximized if factors B and C are each set to the coded
values of –2 (their lower extremity of the CCD). The resulting surface plot is shown in Figure 9.19 with a theoretical maximum
reduction in tumor size of 77%.

Figure 9.19 Surface Plot Generation from Central Composite Design Modeling Equation
Open the Minitab file which contains the reduced regression modeling equation identified by Central Composite Design. Click on Stat →
DOE  Response Surface  Contour/Surface Plot on the top menu.
Check Surface plot in the dialogue box. Click Setup.

Click the radio button for Select a pair of factors for a single plot in the dialogue box. Choose A: Peptide Coupler C for the X Axis and D:
Aptamer A for the Y Axis. Choose coded units. Click Settings.
Enter -2 for pH and -2 for Micelle Size. Click OK. Then click OK two more times.

The Surface Plot is generated for the predicted value of % Reduction in Tumor Size for Peptide Coupler C vs Aptamer A.

Click on Stat → DOE → Response Surface → Response Optimizer on the top menu.

Select C9 % Reduction Tumor Sz for the response variable to optimize in the dialogue box. Click Setup.

Select Maximize for the Goal of the response optimizer in the dialogue box. Enter 0 for the lower limit and 100 for the target. Click OK.
Then click Options.
Enter starting values of 0, -2, -2 and 2 for Peptide Coupler C, pH, Micelle Size and Aptamer A respectively in the dialogue box. Click OK.
Then click OK one more time.
The optimization plot indicates a predicted maximum Reduction in Tumor Size of 77.0762%. Shanti is now ready to conduct a 22 full
factorial DOE to identify the pathway of steepest ascent for factors B and C. The steps for creating the DOE template are outlined in Figure
9.20.
Figure 9.20 Steps for Generating a 22 Full Factorial Design – Climbing DOE Number One

Click the radio button for 2-level factorial design in the dialogue box. Select 2 Factors. Click Designs.

Enter 3 for the number of replicates for corner points. Click OK. Then click Factors.

Enter pH for the name of factor A and Micelle Size for the name of factor B. Both factor data types are numeric. Click OK. Then click
Options.
The worksheet is populated with the factor settings for the 4 runs with 3 replicates.

Shanti can now proceed to run the first climbing DOE at the factor levels summarized below. Remember that our starting
point is 0, -2, -2, 2 for Peptide Coupler C concentration, pH, Micelle Size and Aptamer A concentration respectively. We will be
striking our ice pick into virgin territory for pH and Micelle Size in an attempt to incrementally climb the % reduction in tumor
size mountain.
(-1) (+1) (Constant) Unit

Peptide Coupler C 24 g/ml
pH 2.6 3.2 dimensionless
Micelle Size 10 60 nm
Aptamer A 100 g/ml
Experimental results are entered into the design sheet and the DOE analysis conducted as in Figure 9.21.

Figure 9.21 Steps for Analyzing 22 Full Factorial Climbing DOE Number One
Enter % Reduction Tumor Sz as the name for column 7.

Conduct the experiments in randomized order and enter the % reduction in tumor size measurements in the appropriate cell of the
response variable column.


The session window summarizes the regression analysis and ANOVA results for the Y-hat model.

The % reduction in tumor size may be predicted from the following equation.
Y-hat = 73.042 – 3.992B + 4.108C + 0.875BC
Y-hat will be maximized at coded values of -1 and +1 for pH (B) and Micelle Size (C) respectively. We have moved pH in the
right direction but we have moved micelle size in the wrong direction. That is, % reduction in tumor size has suffered by
reducing micelle size from the baseline level of 60 nm.
If we substitute -1 for B and +1 for C in the above equation, the predicted maximum reduction in tumor size is 80.267%. Our
new anchor point on the DOE mountain in the original coded units is 0, -3, -2, 2 for Peptide Coupler C concentration, pH,
Micelle Size and Aptamer A concentration respectively.
Shanti can now proceed to his second climbing DOE at the factor levels summarized below
(-1) (+1) (Constant) Unit

pH 2.0 2.6 dimensionless
Micelle Size 60 110 nm
Experimental results are entered into the design sheet and the DOE analysis conducted as in Figure 9.22.

Figure 9.22 Steps for Analyzing 22 Full Factorial Climbing DOE Number Two
Create the 2 factor, 3 replicate full factorial DOE template. Conduct the experiments in randomized order and enter the % Reduction in
Tumor Size measurements in the appropriate cells of the design sheet.


The session window summarizes the regression analysis and ANOVA results for the Y-hat model.

The % reduction in tumor size may be predicted from the following equation.
Y-hat = 73.883 + 11.083B + 3.783C + 1.517BC
Y-hat will be maximized at coded values of +1 and +1 for pH (B) and Micelle Size (C) respectively. We have moved pH in the
wrong direction but we have moved micelle size in the right direction. That is, % reduction in tumor size is maximized if we
had left the pH at the baseline level of 2.6 as identified in climbing DOE number one.
The predicted maximum reduction in tumor size is 90.266%. Our new anchor point on the DOE mountain in the original
coded units is 0, -3, -1, 2 for Peptide Coupler C concentration, pH, Micelle Size and Aptamer A concentration respectively.
It has taken one month to climb the response surface of this product development and move the response variable from the
benchmark level of 77% pancreatic tumor size reduction to 90%. Shanti is satisfied with the outcome and can now proceed to
conduct confirmatory runs (step 14 in Figure 9.18) at the optimized factor levels summarized below.
Level Unit
pH 2.6 dimensionless
Micelle Size 110 nm
• This case demonstrates the power of Response Surface Methodology to identify

factor settings which optimize the output response variable.
• It is well suited to product development and commissioning new processes.
• For existing processes, especially those producing at capacity to meet market
demand, the technique of Evolutionary Operation is better suited.
References
1. Anderson, Mark J. and Whitcomb, Patrick J., DOE Simplified – Practical Tools for Effective Experimentation, Productivity Press,
New York, NY, 2000
2. Barker, Thomas B., Quality by Experimental Design, Marcel Dekker, New York, NY, 1994
3. Barnett, E. Harvey, Introduction to Evolutionary Operation, Industrial and Engineering Chemistry, Vol 52, No 6, 1960, 500-503
4. Box, George E.P., Evolutionary Operation: A Method for Increasing Industrial Productivity, Applied Statistics, 1957, 81-101
5. Box, George E.P. and Draper, Norman R., Evolutionary Operation: A Statistical Method for Process Improvement, John Wiley &
Sons, New York, NY, 1969
6. Francis, Febe et al, Use of Response Surface Methodology for Optimizing Process Parameters for the Production of -amylase by
Aspergillus Oryzae, Biochemical Engineering Journal, Vol. 15, 2003, 107-115
7. John, Peter W.M., Statistical Design and Analysis of Experiments, Macmillan Publishing Co., New York, NY, 1971
8. Montgomery, Douglas C., Introduction to Statistical Quality Control, 5th Edition, John Wiley & Sons, New York, NY, 2005
9. Myers, Raymond H., Montgomery, Douglas C., and Anderson-Cook, Christine M., Response Surface Methodology, 3rd edition,
John Wiley & Sons, Inc., Hoboken, NJ, 2009
10. Plackett, R.L. and Burman, J.P., The Design of Optimum Multifactorial Experiments, Biometrika, Vol. 33, 1946, 305-325
11. Schmidt, Stephen R., Launsby, Robert G., Understanding Industrial Designed Experiments – Blending the Best of the Best
Designed Experiment Techniques, 4th edition, Air Academy Press, Colorado Springs, CO, 1998

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Operational Excellence

Factor: A controlled or uncontrolled input variable.

Level: A specific value or setting for a factor.

Response Variable: An output which is measured or observed.

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Repetition: Running several samples during one experimental setup.

Replication: Duplicating the entire experiment in a time sequence with different

Randomization: Technique used to randomize the order of the experimental runs or

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Trial: Used interchangeably with Run.

Treatment Combination: Used interchangeably with Run.

Orthogonal Design: An experimental design is said to be orthogonal if each factor is

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Controllable Variables (C)

Noise Variables (N)

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where L = monetary loss

Figure 9.2 Taguchi Loss Function

Monetary Loss (L)

LSL Response Variable (y) USL

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Design of Experiments Steps

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DOE Objective Experimental Design Type

Key Process Input Variables

Optimizing • Response Surface Methodology

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Need for DOE

Define Problem and

Define Metrics for

2 Variables and Attributes

K 4 K=5 6K8 9  K  11 K 3 4K7 6K7 K5

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Uncoded Input Variables Coded Input Variables

A - Temperature B - Nutrient Conc. C - Incubation Time

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UC = ½C(UCH –UCL) + UCCpt Eqn 9.3

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Pareto Chart of the Standardized Effects

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Click on Stat → DOE  Factorial  Factorial Plots on the top menu.

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Click on Main Effects Plot in the dialogue box. Click Setup.

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Main Effects Plot for Shear Strength

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Plackett-Burman Screening Designs

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Case Study XIII: Screening DOE Analysis of Drug Delivery Factors

Peptide Coupler A Ligand

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