Designofexperimentdevelopmentofdesignspacebyshivangchaudhary 140907151827 Phpapp01

DESIGN OF EXPERIMENTS (DoE) &
DEVELOPMENT OF DESIGN SPACE

FOR PHARMACEUTICAL PRODUCT DEVELOPMENT AS PER QbD
Designed & Developed by
Formulation Engineer (QbD/PAT System Developer & Implementer)

MS (Pharmaceutics)- National Institute of Pharmaceutical Education & Research (NIPER), INDIA
PGD (Patents Law)- National academy of Legal Studies & Research (NALSAR), INDIA
facebook.com/QbD.PAT.Pharmaceutical.Development
https://in.linkedin.com/in/shivangchaudhary
+91 -9904474045, +91-7567297579
Copyrighted by Shivang Chaudhary
shivaniper@gmail.com
Created & Copyrighted by Shivang Chaudhary
iNSIDES
DoE Definition & Comparison
DoE/ QbD Road Map
Factorial Designs
Response Surface Designs
Mixture Designs
Created & Copyrighted by Shivang Chaudhary Verification of DoE Results
DoE Summary guide

TRADITIONAL DESIGNING
Vs
Traditional Experimentation Design of Experiments
(OFAT/Minimal) (DoE/QbD)
Study one factor at a time (OFAT), Study multiple factors at once as a systematic
holding all other factors constant series of parallel experiments simultaneously
Serial experimentation is uneconomical in Parallel experiments is economical in terms of

terms of time, money, and energy & also time, money and efforts to get maximize
unfavorable & unpredictable Information with minimum runs
Complete fulfillment of the true optimal Purposeful changes are made to input factors to
product or robust process can never be identify causes for significant changes in the
guaranteed due to the presence of output responses & determining the
multiplication/ interactions of factors, i.e. the relationship between factors of that to achieve
effect of one or more factors on others, which an optimized product/ robust process.
can not be covered by OFAT
Accounts for Interactions between factors
Estimate each factor effect independent of the

existence of other factor effect by multiplication

WHAT IS DoE?
A SYSTEMATIC SERIES OF EXPERIMENTS,

In which PURPOSEFUL CHANGES ARE MADE TO INPUT FACTORS TO IDENTIFY CAUSES FOR
SIGNIFICANT CHANGES IN THE OUTPUT RESPONSES &
DETERMINING THE RELATIONSHIP BETWEEN FACTORS & RESPONSES to evaluate all the potential
factors simultaneously, systematically and speedily ;
WITH COMPLETE UNDERSTANDING OF THE PROCESS

to assist in better PRODUCT DEVELOPMENT & subsequent PROCESS SCALE-UP
with pretending the finished product quality & performance.
Different Different
Machine Discrete Operator
Variables
1 1
Controlled Inputs
(Responses)
(Factors)
Outputs
2 2
Product
Process
3 3
k r
Continuous
Variables
Temperature Humidity
DoE / QbD ROAD MAP
Definition of Determination of
Quality Risk
Assessment of DoE PAT Implementatn of
QTPP CQAs & Development of & Development of CONTROLS

CMAs & CPPs Design Space Feedback Control system
DEFINE OBJECTIVE IDENTIFY RESPONSES IDENTIFY FACTORS TO BE STUDIED

OF EXPERIMENT TO BE MEASURED SCREENING L=2 & ITS LEVELS TO INDUCE A MEASURABLE
SIGNIFICANT CHANGE TO THE RESPONSE
ASSESSMENT OF INDIVIDUAL
PLACKETTE 2 LEVEL 2 LEVEL FULL LINEAR
BURMAN FRACTIONAL FACTORIAL EFFECTS & INTERACTION
FACTORIAL
7 F 32 F3 HALF NORMAL EFFECT PLOT
4F6
PARETO BAR CHART
OPTIMIZATION L3 1D MAIN EFFECT PLOT
2D INTERACTION PLOT
OPTIMIZE SCRRENED OUT
CRITICAL FORMULATION &/OR FACTORIAL RESPONSE MIXTURE
PROCESSING PARAMETERS DESIGN SURFACE DESIGN
METHODOLOGY
ASSESSMENT OF
QUADRATIC OR CUBIC 3 LEVELFULL SIMPLEX
F=2 CENTRAL 2 F 6 2F4
CURVATURE IN RESPONSE FACTORIAL LATTICE
SURFACE MAP COMPOSITE
DESIGN
ADDITIONAL CENTER POINTS 2 LEVEL SIMPLEX
FRACTIONAL 3F5
2D CONTOUR PLOT CENTROID
F3 FACTORIAL BOX 3F5
3D RESPONSE SURFACE WITH CENTER BEHNKEN CONSTRAINED
4D CUBE PLOT POINTS DESIGN MIXTURE 2F6
ANOVA FOR TESTING OF SIGNIFICANCE OF SELECTED POLYNOMIAL MODEL EXPRESSING DIAGNOSTIC PLOTS FOR
RELATIONSHIP BETWEEN FACTORS & RESPONSES WITH LEAST SQUARE REGRESSION RESIDUAL (Obs-Pred) ANALYSIS
DEVELOPMENT OF OVERLAY PLOTS (DESIGN SPACE) FOR FINDING OUT OPTIMIZED RANGES OF CRITICAL FACTORS WHERE ALL THE SPECIFICATIONS OF ALL THE
DESIRED RESPONSES SIMULTANEOUSLY Meet, KNOWN AS A SWEET SPOT. WORKING WITHIN DESIGN SPACE IS NOT CONSIDERED AS A CHANGE. MOVEMENT OUT
OF THE DESIGN SPACE IS CONSIDERED TO BE A CHANGE & WOULD NORMALLY INITIATE A REGULATORY POST APPROVAL CHANGES
VERIFICATION
VERIFICATION OF EXPERIMENTAL RESULTS BY TAKING ADDITIONAL AT LEAST
3 CHECK POINT BATCHES IN THE SAME RANGE OF DESIGN SPACE & ANALYZE R2 OF OBSERVED Vs PREDICTED VALUES PLOT
CONTROL
SPACE
VERIFICATION
DESIGN SPACE
USE FACTORIAL DESIGN TO GET CLOSE TO THE PEAK ;
THEN RSM TO CLIMB IT. .. .
OPTIMIZATION 3/5 LEVEL CCD or BBD RSM DESIGN/

Simplex Lattice or Centroid type MIXTURE DESIGNS
REGION OF INTEREST
2 LEVEL Plackette Burman or

Fractional FACTORIAL DESIGNS SCREENING
REGION OF OPERABILITY (KNOWLEDGE SPACE)
IDENTIFICATION
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACTORIAL MIXTURE
PLACKETTE CONSTRAINED
BURMAN MIXTURE
2 LEVEL 3 LEVEL SIMPLEX SIMPLEX

FACTORIAL FACTORIAL LATTICE CENTROID
FULL 32 FULL
FACTORIAL FACTORIAL
23 FULL 23 FULL 33 FULL

FACTORIAL FACTORIAL FACTORIAL
FRACTIONAL
FACTORIAL
24-1 24-1 +3CP
FRACTIONAL FRACTIONAL
FACTORIAL FACTORIAL
RESPONSE SURFACE
CENTRAL BOX
COMPOSITE BEHNKEN
CIRCUMSCRIBED
22FP+ 4SP + 5CP 23FP+ 6SP + 6CP 23-1FFP+ 6SP + 6CP

CIRCUMSCRIBED CIRCUMSCRIBED CIRCUMSCRIBED
CCD CCD CCD
FACE CENTERED
INSCRIBED

FACTORIAL
RESPONSE
MIXTURE
SURFACE
TYPES APPLICATIONS
Used primarily TO REFINE A PROCESS by SCREENING OF CRITICAL

FACTORS & TO STUDY THE INTERACTIONS between the factors by
VARYING THE LEVELS OF ALL FACTORS AT THE SAME TIME instead OFAT
PLACKETTE BURMAN DESIGN

Efficient screening designs involving numerous factors (>6) in the study, when only
MAIN EFFECTS ARE CONCERNED OF INTEREST, assuming all other interactions negligible
A. FULL FACTORIAL DESIGNS

Measure responses at ALL COMBINATIONS of the
factor levels.
Number of Runs: LF . As the number of factors in a 2-level
factorial design increases, the number of RUNS INCREASES
quickly. i.e. 26 = 64 Runs for 6 Factors.
B. FRACTIONAL FACTORIAL DESIGNS
Uses a "FRACTION" of a full factorial design, so some of the
main effects and 2-way interactions are confounded and
cannot be separated
Number of Runs: LF-f
A good choice when RESOURCES ARE LIMITED or the
NUMBER OF FACTORS IN THE DESIGN IS LARGE because
they use FEWER RUNS than the full factorial .
FACTORIAL
RESPONSE
MIXTURE
SURFACE
OFAT FULL FACTORIAL
Vs 2 Level FULL FACTORIAL

2 Level OFAT Design
For 2 FACTORS Design For 2 FACTORS
2 FACTORS Comparative
Efficiency
=6/4 = 1.5
6 RUNS 4 RUNS
2 Level OFAT Design 2 Level FULL FACTORIAL

For 3 FACTORS Design For 3 FACTORS
3 FACTORS Comparative
Efficiency
=16/8 = 2
16 RUNS 8 RUNS

FACTORIAL
RESPONSE
MIXTURE
SURFACE
LINEAR MODEL forLINEAR

2F MODEL for 3F
+1 (High Level)
The order of polynomial MODEL(simplified mathematical relationship
between factors & response assisting in calculations & predictions) for any
design depends on the expected response behavior.
1. FIRST Order (LINEAR) terms modeling SLOPEs of a FLAT PLANE
2. SECOND Order (QUADRATIC) terms modeling CURVATUREs of an eclipse.
3. THIRD Order (CUBIC) terms: modeling Inflected ASSYMETRY like S curve
-1 (Low Level)
A Linear model with two factors, X1 and X2, can be written as

Y = 0 + 1X1 + 2X2 + 12X1X2 + experimental error
RESPONSE
MAIN MAIN 2F INTERACTION
EFFECT EFFECT TERM
Modeling of varying SLOPs of a FLAT PLANE

of the Response Surface
Evaluate Values OF MAIN EFFECTS &

two factor INTERACTIONs

FACTORIAL
RESPONSE
MIXTURE
SURFACE
LINEAR MODEL forLINEAR

2F MODEL for 3F

For a more complicated example, a linear model with three factors X1, X2, X3 and one response,
Y, would look like (if all possible terms were included in the model)
Y = 0 + 1X1 + 2X2 + 3X3 + 12X1X2 + 13X1X3 + 23X2X3 + 123X1X2X3 +

experimental error
RESPONSE MAIN 2 WAY 2 WAY 2 WAY 3 WAY
MAIN MAIN
EFFECT EFFECT EFFECT INTERACTION INTERACTION INTERACTION INTERACTION
TERM TERM TERM TERM
Modeling of varying SLOPs of a FLAT PLANE

of the Response Surface
Evaluate Values OF MAIN EFFECTS & two factor

INTERACTIONs & three factor INTERACTIONs

FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL 3 LEVEL

BURMANFACTORIAL
FACTORIAL
NO. OF NO. OF
LEVELS PB design in 12 runs for an experiment RUNS
containing up to (12-1=) 11 factors
2 4F
High +1 X1 X2 X3 X4 X5 X6 X7 X8 X9 X10 X11 DESIGN

POINTS
Low -1 1 +1 +1 +1 +1 +1 +1 +1 +1 +1 +1 +1
dp= number of Design
2 -1 +1 -1 +1 +1 +1 -1 -1 -1 +1 -1 Points estimates 1st order
3 -1 -1 +1 -1 +1 +1 +1 -1 -1 -1 +1 Linear Main Effects
(-1/+1 levels)
4 +1 -1 -1 +1 -1 +1 +1 +1 -1 -1 -1
5 -1 +1 -1 -1 +1 -1 +1 +1 +1 -1 -1
6 -1 -1 +1 -1 -1 +1 -1 +1 +1 +1 -1
7 -1 -1 -1 +1 -1 -1 +1 -1 +1 +1 +1
8 +1 -1 -1 -1 +1 -1 -1 +1 -1 +1 +1
9 +1 +1 -1 -1 -1 +1 -1 -1 +1 -1 +1
10 +1 +1 +1 -1 -1 -1 +1 -1 -1 +1 -1
11 -1 +1 +1 +1 -1 -1 -1 +1 -1 -1 +1
12 +1 -1 +1 +1 +1 -1 -1 -1 +1 -1 -1
APPLICATION ECONOMICAL SCREENING DESIGN for NUMEROUS FACTORS,

WHEN ONLY MAIN EFFECTS ARE CONCERNED OF INTEREST,
assuming all other interactions negligible

STUDY 1
FACTORIAL
RESPONSE
MIXTURE
SURFACE

CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
SCREENING OF CPPs OF FLUID BED

TOP SPRAY GRANULATION PROCESS
FOR SOLID ORAL DOSAGE FORMS DEVELOPMENT AS PER QbD
K OUTLET TEMPERATURE NO. OF FACTORS 11
J FILTER CLEANING FREQUENCY NO. OF LEVELS 2
I FILTER BAG PORE SIZE
H NO OF SPRAYING HEADS
G BINDER SPRAYING RATE
EXPERIMENTAL DESIGN
F ATOMIZATION AIR PRESSURE SELECTED
E GUN TO BED DISTANCE PLACKETTE BURMAN DESIGN
D PRODUCT TEMPERATURE TOTAL NO OF 12

EXPERIMENTAL RUNS
C (NO OF TRIALS)
BOWL CAPACITY
B INLET TEMPERATURE
A FLUIDIZATION AIR VELOCITY

STUDY 1
FACTORIAL
RESPONSE
MIXTURE
SURFACE

CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
OBJECTIVE To Screen Out Critical Processing Parameters of Fluid Bed Top Spray Granulation Process.
FACTORS TO BE STUDIED
Factors (Variables) Coded Levels & Actual Levels

-1 +1
A BINDER SPRAYING RATE (gm/min) 2 8
B ATOMIZATION AIR PRESSURE (bar) 1 3
C FLUIDIZATION AIR VELOCITY (cfm) 50 100
D INLET TEMPERATURE (C) 45 55
E PRODUCT TEMPERATURE (C) 25 35
F OUTLET TEMPERATURE (C) 35 45
G GUN TO BED DISTANCE (inches) 10 20
H NO OF SPRAYING HEADS 1 3
I FILTER BAG POROSITY (um) 20 40
J FILTER BAG CLEANING FREQUENCY (CPM) 2 10
K BOWL OCCUPANCY (%) 40 60
RESPONSES TO BE MEASURED
Responses (Effects) Goals for Individual Responses

Y1 %FINES To achieve minimum fines after granulation i.e. NMT 10%
Y2 % AGGLOMERATES To achieve minimum agglomerates after granulation i.e. NMT 10%
SCREENING OF CRITICAL PROCESSING PARAMETERS OF

FLUID BED TOP SPRAY GRANULATION PROCESS Created & Copyrighted by Shivang Chaudhary
STUDY 1
FACTORIAL
RESPONSE
MIXTURE
SURFACE

CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
PPs CQAs

STUDY 1
FACTORIAL
RESPONSE
MIXTURE
SURFACE

CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
SIGNIFICANT EFFECTS: MODEL TERMS
NEGLIGIBLE TERMS: ERROR ESTIMATES
%Agglomerates = +8.42 +5.58A -1.58B %Fines = +11.42 -5.25A +1.58B
Thus, LIQUID SPRAYING RATE (A) & ATOMIZATION AIR PRESSURE (B) are the most critical factors those
required to control the ultimate particle size during fluid bed granulation

STUDY 1
FACTORIAL
RESPONSE
MIXTURE
SURFACE

CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
Ho THERE IS NO SIGNIFICANT EFFECT OF SELECTED PROCESSING PARMETERS (PP) ON RESPONSE (CQA)
ANOVA Response 1: AGGLOMERATES ANOVA Response 2: FINES
F Value = Significant Signal Conclude that there is

Test For Comparing MODEL VARIANCE Negligible Noise only a 0.01% chance that
(SIGNAL=Predicted value) A "Model F-Value"
with RESIDUAL VARIANCE this large could
(NOISE=(Observed-Predicted value)) F Value= (MS Model/ MS Residuals) >1 occur due to noise.
F values i.e. MS Model/ MS Residuals for both the factors i.e. SR & AP were found to be far greater than 1
confirming SHARP STRONG SIGNAL (Main effect) compared to other NOISE (residual or error term)
p-value = Probability of Reject Ho& Conclude that there is a

Falsely Detecting the Significant Effect Accept Ha significant effect of
(also called as a A & B Processing
Level of Significance ()) p Value = < 0.05 for CI= 95% Parameters on CQA
p Value<0.05 at 95%CI for SR & AP, ensuring RIGHT DETECTION OF SIGNIFICANT EFFECTS of both factors on
response & giving 95% confidence that 99% population will meet the same specification within predefined targets

FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
BURMANFACTORIAL
FACTORIAL
NO. OF NO. OF NO. OF
LEVELS FACTORS 3 RUNS
2 Design points are at the Alternate Corner of Cube LF-f = 23-1 = 4
FACTORIAL
POINTS
fp= number of cube

points estimates 1st order
High Linear Main Effects & 2FI
(-1/+1 levels)
When the number of

factors is 4 or greater, a
full factorial design
requires a large number
of runs and is not very
efficient.
For example, 25 = 32
experiments for 6 factors
Low
APPLICATION A BETTER CHOICE FOR SCREENING OF 4 OR MORE FACTORS in which only an

ADEQUATELY CHOSEN FRACTION OF THE FULL FACTORIAL COMBINATIONS required for
the complete factorial experiment is selected to be run. In general, a fraction such as ,
, of full factorial. etc. of the runs has been picked up for fractional factorial
Here the ability to evaluate the effect of 3FI has to be sacrificed
STUDY 2
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
SCREENING OF CPPs OF HIGH

SHEAR WET GRANULATION PROCESS
NO. OF FACTORS 4
BINDER SOLUTION ADDITION TIME NO. OF LEVELS 2

D
EXPERIMENTAL DESIGN SELECTED
C KNEADING (MIXING & GRANULATION) TIME
FRACTIONAL FACTORIAL DESIGN
B CHOPPER (GRANULATOR) SPEED
A IMPELLER (MIXER) SPEED
TOTAL NO OF 24-1
EXPERIMENTAL RUNS
=8
(NO OF TRIALS)
Created & Copyrighted

Created by Shivang
& Copyrighted Chaudhary
by Shivang Chaudhary
STUDY 2
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
OBJECTIVE To Screen Out Critical Processing Parameters of High Shear Wet Granulation Process.
Factors (Variables) Levels of Factors studied

-1 +1
A BINDER ADDITION TIME (min) 1 2
B IMPELLER-MIXER SPEED (RPM) 50 100
C CHOPPER-GRANULATOR SPEED (RPM) 1000 3000
D KNEADING TIME (min) 3 5

Y1 %FINES To achieve minimum fines after granulation i.e. NMT 10%
Y2 % AGGLOMERATES To achieve minimum agglomerates after granulation i.e. NMT 10%
SCREENING OF CPPs OF HIGH SHEAR WET GRANULATION

PROCESS FOR SOLID ORAL DOSAGE FORM Created & Copyrighted by Shivang Chaudhary
STUDY 2
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
CPPs CQAs

STUDY 2
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
%Fines = +10.63 -2.13B +1.38C -4.38D %Agglomerates = +9.63 +2.62B -1.38C +4.88D
Thus, IMPPELER & CHOPPER SPEED & KNEADING time are the most critical factors
those required to control the ultimate particle size during fluid bed granulation

PROCESS FOR SOLID ORAL DOSAGE FORM Created & Copyrighted
Created by Shivang
STUDY 2
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OFTESTING
OF OFOF
OF FACTORS
EXPERIMMENTS
RESPONSE
EFFECTS
SIGNIFICANCE
Ho There Is No Significant Effect Of Selected Processing Parameters (PP) On Response (CQA)
ANOVA Response 1: FINES ANOVA Response 2: AGGLOMERATES
F Value = Significant Signal Conclude that there is

Test For Comparing MODEL VARIANCE Negligible Noise only a 0.01% chance that
(SIGNAL=Predicted value) A "Model F-Value"
with RESIDUAL VARIANCE this large could
(NOISE=(Observed-Predicted value)) F Value= (MS Model/ MS Residuals) >1 occur due to noise.
F values i.e. MS Model/ MS Residuals for both the factors i.e. speed & time were found to be far greater than 1 confirming
SHARP SIGNAL (Main effect) compared to other NOISE (residual or error term)
p-value = Probability of Reject Ho& Conclude that there is a

Falsely Detecting the Significant Effect Accept Ha significant effect of
(also called as a A & B Processing
Level of Significance ()) p Value = < 0.05 for CI= 95% Parameters on CQA
p Value<0.05 at 95%CI, for speed & time, ensuring RIGHT DETECTION OF SIGNIFICANT EFFECTS of both the factors on
desired granule size & giving 95% confidence that 99% population will meet the same specification within predefined targets

STUDY 3
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES
SCREENING & OPTIMIZATION OF CPPs OF

WURSTER COATING DRUG LAYERING PROCESS
FOR MULTIUNIT PARTICULATES SYSTEM DEVELOPMENT FOR SOLID ORALS AS PER QbD
NO. OF FACTORS 4
NO. OF LEVELS 3
4 PRODUCT TEMPERATURE

WITH ADD. CENTER POINTS
ATOMIZATION PRESSURE 3
ADD. CENTER POINTS 3

2 SPRAY RATE
TOTAL NO OF 24-1
EXPERIMENTAL RUNS
+3
(NO OF TRIALS)
= 11
AIR VOLUME 1

STUDY 3
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES
OBJECTIVE To Screen Out & Optimize CPPs of Wurster Coating Drug Layering Process.

-1 Center Point +1
A Air Volume (cfm) 80 cfm 100 cfm 120 cfm
B Spraying Rate (gm/min) 25 gm/min 35 gm/min 45 gm/min
C Atomization Pressure (bar) 1.2 bar 1.6 bar 2.0 bar
D Product Temperature (C) 42C 46C 50C
Responses (Effects) Goal for Individual Responses

Y1 Fines (%w/w) Fines should NMT 5%w/w
Y2 Agglomerates (%w/w) Agglomerates should NMT 5%w/w
Y3 Assay by HPLC (%) To achieve the assay of the product from 95% to 105%

WURSTER COATING DRUG LAYERING PROCESS Created & Copyrighted by Shivang Chaudhary
STUDY 3
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES
CPPs CQAs

STUDY 3
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES
%Assay=+98.00-0.67A-1.52D-0.55AD
SIGNIFICANT EFFECTS:
MODEL TERMS
%Fines=+2.59+0.79A+1.94D+0.59AD %Agglomerates=+4.49-1.71A+1.04B-2.71D

STUDY 3
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES

Y1 Fines (%w/w) Fines should NMT 5%w/w
Y2 Agglomerates (%w/w) Agglomerates should NMT 5%w/w
Y3 Assay by HPLC (%) To achieve the assay of the product within 95% to 105%

STUDY 4
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES

ROLLER COMPACTION DRY GRANULATION PROCESS
NO. OF FACTORS 4
NO. OF LEVELS 3
1 ROLLER PRESSURE

WITH ADD. CENTER POINTS
ROLLER GAP 2
3 MILLING SPEED
MILL ORIFICE SIZE 4 TOTAL NO OF 24-1

EXPERIMENTAL RUNS
+3
(NO OF TRIALS)
= 11

STUDY 4
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES
OBJECTIVE To Evaluate Effects of Critical Processing Parameters of Roller Compaction Dry Granulation .

-1 0 +1
A Roller Pressure (bar) 20 50 80
B Roller Gap (mm) 1.2 1.8 2.4
C Mill Speed (rpm) 20 60 100
D Mill Orifice Screen Size (mm) 0.6 1.0 1.4

Y1 Ribbon Density (g/cc) To achieve granule density from 1 to 1.2 g/cc
Y2 Granule D50 (um) To achieve mean particle size in the range from 400 to 800 um
Y3 Granule Flowability (ffc) To achieve the desired ffc more than 6
Y4 Tablet Hardness (Kp) To achieve tablet hardness more than 9.0 kP
Y5 Tablet CU (%RSD) To minimize % RSD in CU i.e. NMT 5%

ROLLER COMPACTION DRY GRANULATION PROCESS Created & Copyrighted by Shivang Chaudhary
STUDY 4
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES
CPPs CQAs

STUDY 4
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES
Ribbon Density =+1.11+0.14A-0.033B

Granule d50 =+639.50+1.00B-7.50C+4.50AC
+ 114.50BC-3.00CD+338.00ABC+150.00BCD SIGNIFICANT EFFECTS: Granule Flow ability=
MODEL TERMS +7.42+1.62A-0.53B+1.09D
Hardness Tablet CU
@10kN = =+3.14
+11.51 -0.89A
-2.29A +0.29B
+0.74B -0.61D

STUDY 4
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FRACTIONAL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
ANALYSIS
SCANNING
OF
OPTIMIZATION
OF &
OF FACTORS
EXPERIMMENTS
RESPONSE
TESTING
OF RANGES

Y1 Ribbon Density (g/cc) To achieve granule density from 1 to 1.2 g/cc
Y2 Granule d50 (um) To achieve mean particle size from 400 to 800 um
Y3 Granule Flowability (ffc) To achieve the desired ffc more than 6
Y4 Tablet Hardness (kp) To achieve tablet hardness more than 9.0 kP
Y5 Tablet CU (%RSD) To minimize % RSD in CU i.e. NMT 5%

FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
BURMANFACTORIAL
FACTORIAL
2 Design points are at the Corner of Square LF = 22 = 4
FACTORIAL
POINTS
High fp= number of

factorial/cube points
estimates 1st order Linear
Main Effects & 2FI
(-1/+1 levels)
run X1 X2
1 -1 -1
2 1 -1
3 -1 1
4 1 1
Low
APPLICATION Efficient screening design for 3 or less factors &

when ONLY MAIN EFFECTS & INTERACTION ARE OF INTEREST,
assuming all curvature effects negligible

STUDY 5
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS
EFFECT EVALUATION OF FORMUALATION VARIABLES

FOR SUSTAINED RELEASE ENCAPSULATED DOSAGE FORM
FOR HARD GELATIN CAPSULE DEVELOPMENT AS PER QbD
2 POLYMER CONTENT
1 API PARTICLE SIZE
RISKS
INADEQUATE OR EXCESS DRUG RELEASE WITH RESPECT TO TIME
DRUG PLAMA LEVEL BELOW MINIMUM EFFECTIVE CONC. OR ABOVE MAXIMUM SAFE CONC.
EFFICACY OR SAFETY COMPROMISED

STUDY 5
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS
OBJECTIVE To Evaluate Effects of Critical Formulation Variables of Sustained Release Composition for
Encapsulation into Hard Gelatin Capsule
NO. OF FACTORS 2
NO. OF LEVELS 2

POLYMER CONTENT
22 FULL FACTORIAL DESIGN
TOTAL NO OF 22
EXPERIMENTAL RUNS
=4
(NO OF TRIALS)
B
A API PARTICLE SIZE

-1 +1
A API Particle Size (microns) 10 25
B Polymer Content (%w/w) 20 30
EFFECT EVALUATION OF CRITICALFORMULATION VARIABLES

OF SUSTAINED RELEASE HARD GELATIN CAPSULE Created & Copyrighted by Shivang Chaudhary
STUDY 5
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS
CMAs CQAs
Factor X1: API Particle Factor X2: Polymer x1*x2 Response Y1:
Run Order code Size D90 (in microns) Content (in %w/w) [coded level] %Drug Released
[coded level] [coded level] within 12 hours
1 1 10 [-1] 20 [-1] [+1] 96
2 a 25 [+1] 20 [-1] [-1] 75
3 b 10 [-1] 30 [+1] [-1] 84
4 ab 25 [+1] 30 [+1] [+1] 67
ab + a b + 1 ab + b a + 1 ab + 1 a + b 1 + a + b + ab
1 = 2 = 12 = 0 =
2n 2n 2n 2n 2n 2n 2n
67:76 84:96 67:84 75:96 67:96 75:84 96 + 75 + 84 + 67
1 = 2 = 1 = 0 =
4 4 4 4 4 4 4
1 = 35.50 45.00 2 = 37.75 42.75 12 = 40.75 39.75 0 = +.
1 = 9.50 2 = 5.00 12 = +1.00
PREDICTION EFFECT EQUATION OF EACH FACTOR & THEIR INTERACTIONS

ON INDIVIDUAL RESPONSE BY LINEAR MODEL
%Drug Release Within 12 Hours = Y = 0 + 1X1 + 2X2 + 12X1X2

=+80.50 -9.50A -5.00B +1.00AB
STUDY 5
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS

Y1 %Drug Release within 12 hours To achieve NLT 85% drug release within 12 hours

FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
BURMANFACTORIAL
FACTORIAL
2 Design points are at the Corner of Cube LF = 23 = 8
FACTORIAL
POINTS
fp= number of cube

High Linear Main Effects & 2FI
(-1/+1 levels)
run X1 X2 X3
1 -1 -1 -1
2 1 -1 -1
3 -1 1 -1
4 1 1 -1
5 -1 -1 1
6 1 -1 1
7 -1 1 1
8 1 1 1
Low
APPLICATION Efficient screening design for 3 or less factors &

when ONLY MAIN EFFECTS & INTERACTION ARE OF INTEREST,
assuming all curvature effects negligible

STUDY 6
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS
EFFECT EVALUATION OF CRITICAL FORMULATION

VARIABLES OF METERED DOSE INHALER
FOR SUSPENSION AEROSOL DEVELOPMENT AS PER QbD
C PROPELLANT CONTENT
B SUSPENDING AGENT
A API PARTICLE SIZE
RISKS
INADEQUATE DRUG RELEASE PER SINGLE ACTUATION
EFFICACY COMPROMISED

STUDY 6
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS
OBJECTIVE To Evaluate the Effects of Critical Formulation Variables of

Metered Dose Inhaler (Suspension Aerosols))
NO. OF FACTORS 3
NO. OF LEVELS 2

PROPELLANT
TOTAL NO OF 23
EXPERIMENTAL RUNS
=8
(NO OF TRIALS)
C
A API PARTICLE SIZE

-1 +1
A API PARTICLE SIZE (microns) 1 10
B SUSPENDING AGENT (%w/w) 0.10 0.80
C PROPELLANT (%w/w) 70 90
EFFECT EVALUATION OF CRITICALFORMULATION VARIABLES OF

METERED DOSE INHALER (SUSPENSION AEROSOLS) Created & Copyrighted by Shivang Chaudhary
STUDY 6
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS
CMAs CQA

NET CONTENT OF DRUG PER DISCHARGE FROM MDI= +89.20 -8.18A +3.13B +1.67C +1.45AB
+0.55AC -0.45BC + 0.025ABC
EFFECT EVALUATION OF CRITICALFORMULATION VARIABLES OF

METERED DOSE INHALER (SUSPENSION AEROSOLS) Created & Copyrighted by Shivang Chaudhary
STUDY 6
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
EVALUATION OF
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL FACTORS

Y1 %Net Content Per Discharge From MDI To achieve NLT 90% drug discharge per single actuation
NET CONTENT OF DRUG PER DISCHARGE FROM MDI= +89.20 -8.18A +3.13B +1.67C +1.45AB

OF METERED DOSE INHALER (SUSPENSION AEROSOLS) Created & Copyrighted by Shivang Chaudhary
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
BURMAN FACTORIAL
FACTORIAL WITH CP
LF + cp + rp=
2 Design points are at the Corner of Cube
23 + 1+3= 12
FACTORIAL
POINTS
fp= number of cube

Linear Main Effects & 2FI
High (-1/+1 levels)
CENTER
POINTS
cp = number of center
points gives an
INDICATION OF
CURVATURE
REPLICATE
POINTS
Low rp= Replicating the

center points gives an
ESTIMATION OF
PURE ERROR.
APPLICATION Difference between the average of the center points & the average of the factorial design
points; gives an INDICATION OF CURVATURE [SS (curvature) = SS (A2) + SS (B2) + SS (C2),
an aliased combination of all 3 quadratic terms, as center point is the mid level of all
3 factors.] ; while replicating the center points gives an ESTIMATION OF PURE ERROR.
Factorial design can be augmented with axial points to create a central composite RSM
to estimate quadratic terms individually i.e. A2, B2, C2
STUDY 7
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING OF
ANALYSIS
OPTIMIZATION
OF OF OF
EVALUATION
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL
CRITICAL FACTORS
FACTORS
OPTIMIZATION OF PRESERVATIVE SYSTEM FOR

IN USE STABILITY OF MULTIDOSE STERILES
FOR INJECTION/ EYE/EAR/ NASAL DROPS DEVELOPMENT AS PER QbD
C BUFFERING AGENT
B ANTIOXIDANT
A ANTIMICROBIAL
RISKS
INADEQUATE ANTIMICROBIAL CONC. INADEQUATE ANTIOXIDANT CONC
MICROBIAL LOAD IN-USE OXIDATION IMPURITIES
SAFETY COMPROMISED

STUDY 7
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING OF
ANALYSIS
OPTIMIZATION
OF OF OF
EVALUATION
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL
CRITICAL FACTORS
FACTORS
OBJECTIVE To Optimize Preservative System for In Use Stability Of

Multi-dose Sterile Product (Injection, Eye/Ear Drops)
NO. OF FACTORS 3
NO. OF LEVELS 2
23 FULL FACTORIAL DESIGN WITH

BUFFERING AGENT
ADD. CENTER POINTS
TOTAL NO OF 23 + 3
EXPERIMENTAL RUNS
C
= 11
(NO OF TRIALS)
A ANTIMICROBIAL

-1 Center point (0) +1
A Antimicrobial (%W/W) 0.005 0.010 0.015
B Antioxidant (%W/W) 0.050 0.100 0.150
C Buffering Agent (%W/W) 0.800 1.400 2.000

IN USE STABIILITY OF MULTIDOSE STERILE PRODUCT Created & Copyrighted by Shivang Chaudhary
STUDY 7
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING OF
ANALYSIS
OPTIMIZATION
OF OF OF
EVALUATION
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL
CRITICAL FACTORS
FACTORS
CMAs CQAs
By looking at the difference between average of the center points & the average of the factorial design points, you can get an indication of curvature.
If the factorial model fits, then these averages should be equal, within statistical error. A peak or valley in the middle will be caught by this check.

REDUCTION in Microbial Load after 14 days =+99.42 +0.35A +0.075B +0.15C -0.050AB -0.075AC +0.025ABC
OXIDIZED Impurities after 14 days=+0.46 -0.035A -0.18B -0.052C +7.50E-003AB +5.00E-003AC + 0.010BC -2.50E-003ABC

STUDY 7
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING
TESTSOF
ANALYSIS
OPTIMIZATION
FOROF
FITNESS OF
OF FACTORS
EXPERIMMENTS
RESPONSE
OF CRITICAL
LINEAR FACTORS
MODEL
ANALYSIS of CURVATURE= Significant Curvature Linear model

FCurvature = (y factorial - y center)2/ [1/Nfactorial + 1/Ncenter] (peak/ valley in the middle should be augmented with
by comparing the average of the factorials points of response surface). ADDITIONAL more runs
to the average of the center points for CENTER POINTS via design
SS (curvature) = SS (A2) + SS (B2) + SS (C2) is an tools to estimate quadratic
p curvature = < 0.01 at 95%CI
aliased combination of all 3 quadratic terms, as terms individually
center point is the mid level of all 3 factors. F >1 i.e. A2, B2, C2.
curvature
Variation of the replicated design points about their

ANALYSIS of Lack of FIT= Insignificant means is about the same as the variation of the means
FLOF= MS Lack of Fit/ MS Pure Error = Lack of Fit from the fitted line in the response surface.
[Difference between mean vs predicted value] / [Difference So selected REDUCED LINEAR
between replicates & their mean value] plof Value = > 0.10 at 95%CI MODEL WITH 2FI & 3FI terms can be
SS residual = SS lack of fit +SS pure error used as a predictor of the response.
SS lof= SS of the means about fitted model No need for ADDITIONAL REPLICATED
SSpe=SS of the replicates about their mean Flof Value < 1 experiment to estimate pure error
REDUCED LINEAR MODEL

REDUCTION in Microbial Load after 14 days =+99.42 +0.35A +0.075B +0.15C -0.050AB -0.075AC +0.00BC +0.025ABC
OXIDIZED Impurities after 14 days=+0.46 -0.035A -0.18B -0.052C

STUDY 7
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE 3 LEVEL
2 LEVEL FULL
CASE
BURMAN FACTORIAL
FACTORIAL WITH CP
IDENTIFICATION
DESIGNING OF
ANALYSIS
OPTIMIZATION
OF OF OF
EVALUATION
OF FACTORS
EXPERIMMENTS
RESPONSE
CRITICAL
CRITICAL FACTORS
FACTORS
Responses (Effects) 5 Goals for Individual Responses

Y1 Reduction in Microbial Load after 14D in use To achieve NLT 99.5% reduction in microbial load
Y2 %Oxidized Impurities after 14D in use To minimize the level of oxidized impurities NMT 0.5%
Factors (Variables) Knowledge Space Design Space Control Space

A Antimicrobial (%W/W) 0.005-0.015 0.010-0.015 0.012-0.015
B Antioxidant (%W/W) 0.050-0.150 0.080-0.150 0.010-0.150
C Buffering Agent (%W/W) 0.800-2.000 0.800-2.000 0.800-2.000

FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
BURMANFACTORIAL
FACTORIAL
3 Design points are at the Corner of Square, LF = 3 2 = 9

Center of Square edges & Overall center of Square
FACTORIAL
POINTS
High
fp= number of factorial
Linear Main Effects, 2FI
(-1/+1 levels) & curvature
in the model
run X1 X2
Medium 1 0 0
2 1 0
3 2 0
4 0 1
5 1 1
6 2 1
7 0 2
Low 8 1 2
9 2 2
APPLICATION To MODEL POSSIBLE CURVATURE IN THE RESPONSE FUNCTION

to facilitates investigation of a quadratic relationship between the response
and each of the factors

STUDY 8
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE
OPTIMIZATION OF CRITICAL FORMULATION

VARIABLES OF SOFT GELATIN CAPSULE
FOR SOFT GELATIN CAPSULE DEVELOPMENT AS PER QbD
2 GLYCERINE : DRY GELATIN RATIO
1 WATER : DRY GELATIN RATIO
RISKS
LONGER DISINTEGRATION TIME
DRUG RELEASE SUSTAINED
ACTION DELAYED

STUDY 8
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE
OBJECTIVE To Optimize Critical Formulation Variables of Soft Gelatin Capsule Shell
NO. OF FACTORS 2
NO. OF LEVELS 3
EXPERIMENTAL DESIGN
WATER : GLYCERINE
SELECTED

B
TOTAL NO OF 32 FP
EXPERIMENTAL RUNS =9
(NO OF TRIALS)
A WATER : GELATIN

0 1 2
A Water: Dry Gelatin Ratio 0.70 1.00 1.30
B Glycerine: Dry Gelatin Ratio 0.30 1.05 1.80
OPTIMIZATION OF CRITICAL FORMULATION VARIABLES OF

SOFT GELATIN CAPSULE DOSAGE FORM Created & Copyrighted by Shivang Chaudhary
STUDY 8
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE
CMAs CQA
PREDICTION EFFECT EQUATION OF EACH FACTOR, THEIR INTERACTIONS & CURVATURES

ON INDIVIDUAL RESPONSE BY QUADRATIC MODEL
DISINTEGRATION TIME=+11.22 -7.67A +4.83B -0.50AB +3.67A2 +1.17B2

SOFT GELATIN CAPSULE DOSAGE FORM Created & Copyrighted by Shivang Chaudhary
STUDY 8
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE
DISINTEGRATION TIME Goals for Individual Responses

Y1 Disintegration Time To achieve disintegration of soft gelatin capsule within 10 minutes

A Water: Dry Gelatin Ratio 0.70-1.30 0.90-1.30 1.00-1.20
B Glycerine: Dry Gelatin Ratio 0.30-1.80 0.30-1.45 0.75-1.25

SOFT GELATIN CAPSULE DOSAGE FORM Created & Copyrighted
Created by Shivang
STUDY 9
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE
OPTIMIZATION OF CRITICAL PROCESSING

PARAMETERS OF DRY MIXING PROCESS
FOR SOLID ORAL DOSAGE FORM DEVELOPMENT AS PER QbD
2 BLENDING TIME
1 BLENDING SPEED
RISKS
INAPPROPRIATE BLENDING SPEED &/OR TIME
BLEND UNIFORMITY COMPROMISED
CONTENT UNIFORMITY COMPROMISED

STUDY 9
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE
OBJECTIVE To Optimize Critical Processing Parameters of Dry Mixing Process
NO. OF FACTORS 2
NO. OF LEVELS 3
EXPERIMENTAL DESIGN
SELECTED
BLENDING TIME

B
TOTAL NO OF 32 FP
EXPERIMENTAL RUNS =9
(NO OF TRIALS)
A BLENDING SPEED

0 1 2
A Blending Speed (in RPM) 8 10 12
B Blending Time (in minutes) 5 10 15
OPTIMIZATION OF CRITICAL PROCESSING VARIABLES OF

DRY MIXING/ BLENDING PROCESS Created & Copyrighted by Shivang Chaudhary
STUDY 9
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE
CPPs CQAs

Average Assay of Blend Uniformity =+99.61 +0.78A+2.32B-0.95AB-1.52A2-2.22B2
RSD Of Blend Uniformity=+1.94-0.47A-1.45B+0.53AB+1.13A2+1.98B2

STUDY 9
FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
CASE
BURMANFACTORIAL
FACTORIAL
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSE
DESIGN SPACE

Y1 Avg. Assay of BU (%) To achieve average assay of BU in the range from 98 to 102%
Y2 RSD of BU(%) To achieve minimum variability in BU i.e. NMT2.0%
By Overlaying contour maps from each responses on top of each other, RSM was used to find out the IDEAL WINDOW
of operability-Design Space per proven acceptable ranges & Edges of Failure with respect to individual goals

A Blending Speed (RPM) 8.0-12.0 9.15-11.35 9.5-11.0
B Blending Time (minutes) 5.0-15.0 10.0-13.5 10.0-12.0

FACTORIAL
RESPONSE
MIXTURE
SURFACE
PLACKETTE2 LEVEL
3 LEVEL FULL
BURMANFACTORIAL
FACTORIAL
3 Design points are at the Corner of Cube, LF = 33 = 27

Center of cube edges faces & Overall center of cube
FACTORIAL
POINTS
High
fp= number of factorial
Linear,2FI (-1/+1 levels) &
curvature in the model
Here, No. of factors=

Medium
3
So, 33=27 Experiments

are required
It can be proved to be
costly & time consuming,
Low So better to choose other
alternative for
optimization of 3 factors
APPLICATION The model and treatment runs for a 3 factor, 3-level design can be expressed as
Yijk = + Ai + Bj + ABij + Ck + ACik + BCjk + ABCijk +Sijk
In such cases, main effects have 2 degrees of freedom, two-factor interactions have
22 = 4 degrees of freedom and k-factor interactions have 2k degrees of freedom.
FACTORIAL
RESPONSE
MIXTURE
SURFACE
TYPES APPLICATIONS
Used to REFINE models to OPTIMIZE FACTORS after

screening of critical factors using factorial designs; especially
if you suspect CURVATURE in the response surface.
Two main types of response surface designs:

A. CENTRAL COMPOSITE DESIGN (CCD)
can fit a full quadratic model.
Levels: 5 [highest, `high medium lower `lowest' or
- ,`-1' 0 and `+1', + ]
Design Points: start with factorial points and add "star" points
to estimate curvature. If the distance from the center to a
factorial point is 1, then the distance from the center of the
design space to a star point is with | |= [2k]1/4 >= 1.
No of Experimental Runs: 2fp + 2SP + CP
B. BOX-BEHNKEN DESIGN (BBD)

Levels: 3 levels per factor, unlike CCD
Design Points: at the mid points of edges of the
process space and at the center
fewer design points than CCD, so more economical
Provides strong coefficient estimates near the center of
the design space (where the presumed optimum is), but
weaker at the corners of the cube (where there were
not any design points).

FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACTORIAL RESPONSE SURFACE
Vs Vs
3 Level FULL FACTORIAL 5 Level CENTRAL 3 Level BOX BEHNKEN
Design For 3 FACTORS COMPOSITE For 3 FACTORS Design For 3 Factors
Comparative Comparativ
Efficiency e Efficiency
27 RUNS 20 RUNS 15 RUNS
=27/20 =20/15 =
=1.35 1.33

FACTORIAL
RESPONSE
MIXTURE
SURFACE
QUADRATIC MODEL FULL CUBIC MODEL

+1 (High between factors & response assisting in calculations & predictions) for any
Level) design depends on the expected response behavior.
A second-order (quadratic) model (typically used in response surface DOE's

O (Center with suspected curvature) does not include the three-way interaction term but
points) adds three more terms to the linear model, namely (11X12 + 22X22 + 33X32 )
-1 (Low
Level)
2 FACTOR 2 FACTOR 2 FACTOR
INTERCTION INTERCTION INTERCTION
MAIN MAIN MAIN TERM TERM
TERM
RESPONSE EFFECT EFFECT EFFECT
Y = 0 + 1X1 + 2X2 + 3X3 + 12X1X2 + 13X1X3 + 23X2X3

+ 11X12 + 22X22 + 33X32 + experimental error
QUADRATIC QUADRATIC QUADRATIC
TERM TERM TERM
Modeling of CURVATURE in
the Response Surface
Appropriately Fit ECLIPSE REGION

of Response Surface.
FACTORIAL
RESPONSE
MIXTURE
SURFACE
QUADRATIC MODEL FULL CUBIC MODEL

RESPONSE Y=
MAIN EFFECTS 0 + 1X1 + 2X2 + 3X3
INTERACTION +12X1X2 + 13X1X3 + 23X2X3

TERMS
+123X1X2X3
QUADRATIC
TERMS +11X12 + 22X22 + 33X32
Modeling of ASSYMETRY in +112X12X2 + 113X12X3 + 122X1X22

the Response Surface CUBIC
TERMS +133X1X32 + 223X22X3 + 233X2X32
Appropriately Fit S shaped
region of Response Surface. +111X13 + 222X23 + 333X33
Accurately give ADEQUATE VIEW OF +experimental error
ASSYMETRIC RESPONSE SURFACE

FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
COMPOSITE BEHNKEN
CCC CCF CCI
Alpha value > 1 = 1 < 1

Star points are at some distance from Limits specified for factor settings are
the center based on the properties true limits, the CCI design uses the
Star points are at the center of each
Star desired for the design and the number factor settings as the Star points and
face of the factorial square or cubical
Points of factors in the design, establish new creates a factorial or fractional
face, so = 1
extremes for the low and high settings factorial design within those limits
for all factors
For 2 factors, the design points For 2 factors, the design points
describe a star's circle circumscribed describe a factorial square within
Design around the factorial square. factorial points are at the corner of star's circle.
Points For 3 factors, the CCC design points each square or cubical face For 3 factors, the CCI design points
describe a star's sphere circumscribed describe a factorials cube within
around the factorial cube. star's sphere.
Rotatability Rotatable Design Non Rotatable Design Rotatable Design
Levels requires 5 levels of each factor requires 3 levels of each factor requires 5 levels of each factor
Process Space explore largest process space explore optimum process space explore smallest process space
A Scaled Down CCC design with each
Design Augmenting an existing factorial or resolution V fractional factorial design
factor level of the CCC design divided
Augmentation with star points can produce this design
by to generate the CCI design.

FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CENTRAL COMPOSITE BEHNKEN
5 Factorial SQUARE Within Star CIRCLE 2fp + 2sp + cp

FACTORIAL
POINTS
Highest
fp= number of
High
estimates 1st order Linear
Main Effects & 2FI
(-1/+1 levels)
STAR
POINTS
Medium
sp = number of star/axial
points estimates 2nd order
quadratic effects-
curvature (+/- levels)
Low CENTER
POINTS
Lowest cp= number of center

points estimates pure
error & tie blocks
together (0 level).
APPLICATION A TIME & COST EFFECTIVE BETTER ALTERNATIVE TO 3 LEVEL FFD

FOR 2 or MORE THAN 2 FACTORS where Region of Operability is greater
than Region of Interest to accommodate axial runs FOR OPTIMIZATION OF
THE OPERATING RANGES OF CRITICAL FACTORS.
STUDY 10
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
OPTIMIZATION OF CPPs OF
TABLET COMPRESSION PROCESS
FOR TABLET DEVELOPMENT AS PER QbD
A COMPRESSION FORCE
B TURRET SPEED
RISKS
LOWER HARDNESS WEIGHT VARIATION INADEQUATE DISINTEGRATION
HIGH FRIABILITY CONTENT NONUNIFORMITY INADEQUATE DISSOLUTION
QUALITY COMPROMISED SAFETY COMPROMISED EFFICACY COMPROMISED

STUDY 10
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CPPs of Tablet Compression Process
NO. OF FACTORS 2
NO. OF LEVELS 5
EXPERIMENTAL DESIGN
SELECTED
CIRCUMSCRIBED CENTRAL
COMPOSITE RSM FOR 2 FACTORS
TURRET SPEED

B
TOTAL NO OF 4 fp
EXPERIMENTAL RUNS +4 sp
(NO OF TRIALS) +5 cp
=13
A COMPRESSON FORCE

- -1 0 +1 +
A COMPRESSION FORCE (kN) 1.17 2.00 4.00 6.00 6.83
B TURRET SPEED (RPM) 3.79 10.00 25.00 40.00 46.21
OPTIMIZATION OF CRITICAL PROCESSING PARAMETERS OF

TABLET COMPRESSION PROCESS Created & Copyrighted by Shivang Chaudhary
STUDY 10
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
CPPs CQAs

FRIABILITY =+0.15 DRUG DISSOLVED IN 30 MIN =+97.20 CONTENT UNIFORMITY =+4.15

-0.066A -8.37A -0.088A
+0.026B +0.16B +1.45B
-7.500E-003AB -1.75AB -0.08AB
+0.028A2 -5.73A2 +0.13A2
+0.021B2 -1.48B2 +0.73B2

STUDY 10
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE

Y2 Friability To achieve tablet friability NMT 0.2%w/w
Y4 Dissolution Drug release should NLT 90% in 30 minutes
Y6 Content uniformity Acceptance Value should in CU test should NMT 5.0
By Overlaying contour maps from each responses on top of each other, RSM was used to find out the IDEAL WINDOW
of Operability-Design Space per proven acceptable ranges & Edges of Failure with respect to individual goals

A Compression Force (kn) 2.0-6.0 3.0-5.0 3.5-4.5
B Turret Speed (RPM) 10-40 10-30 15-25
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
5 Factorial CUBE within Star SPHERE 2fp + 2sp + cp

FACTORIAL
POINTS
Highest
fp= number of
High estimates 1st order Linear
Main Effects, 2FI & 3FI
(-1/+1 levels)
STAR
POINTS
sp = number of star/axial
Medium points estimates 2nd order
quadratic effects-
curvature (+/- levels)
CENTER
POINTS
Low
cp= number of center
Lowest error & tie blocks
together (0 level).
APPLICATION A TIME & COST EFFECTIVE BETTER ALTERNATIVE TO 3 LEVEL FFD

FOR 2 or MORE THAN 2 FACTORS where Region of Operability is greater
than Region of Interest to accommodate axial runs FOR OPTIMIZATION OF
THE OPERATING RANGES OF CRITICAL FACTORS.
STUDY 11
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
OPTIMIZATION OF CPPs OF FLUID BED

TOP SPRAY GRANULATION PROCESS
FOR SOLID ORAL DOSAGE FORM DEVELOPMENT AS PER QbD
A BINDER SPRAYING RATE
B ATOMIZATION AIR PRESSURE
C FLUIDIZATION AIR VELOCITY
RISKS
HIGHER %FINES HIGHER %AGGLOMERATES
SOFT GRANULES HARD GRANULES
LOWER HARDNESS INADEQUATE DISINTEGRATION
HIGH FRIABILITY INADEQUATE DISSOLUTION
QUALITY COMPROMISED EFFICACY COMPROMISED

STUDY 11
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CPPs of Fluid Bed Granulation Process
NO. OF FACTORS 3
NO. OF LEVELS 5
EXPERIMENTAL DESIGN
SELECTED
FLUIDIZATION AIR VELOCITY
COMPOSITE RSM for 3 factors
TOTAL NO OF 8 fp
C
EXPERIMENTAL RUNS +6 sp
=20
A BINDER SPRAYING RATE

- -1 0 +1 +
A Binder Spraying Rate (gm/min) 1.64gm/min 3 gm/min 5 gm/min 7 gm/min 8.36gm/min
B Atomization Pressure (bar) 0.32bar 1 bar 2 bar 3 bar 3.68bar
C Fluidization Air Velocity (cfm) 32.96cfm 50 cfm 75 cfm 100 cfm 117.04cfm
OPTIMIZATION OF CPPs OF FLUID BED TOP SPRAY

GRANULATION FOR SOLID ORALS Created & Copyrighted by Shivang Chaudhary
STUDY 11
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
CPPs CQAs

Agglomerates (%w/w) = +2.21+1.61A-0.34B-0.20C-0.16AB-0.14AC Fines (%w/w) = +2.00-0.25A+1.78B+0.35C-

+0.038BC+0.65A2 +0.14B2+0.082C2 0.012AB+0.013AC+0.16BC+0.22A2+0.59B2+0.22C2
%Process Efficiency (%) = +97.18+1.76A+0.52B-5.83C+0.50AB+0.50AC-0.50BC-1.92A2-1.39B2-3.69C2

GRANULATION FOR SOLID ORALS Created & Copyrighted
Created by Shivang
STUDY 11
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE

Y1 Agglomerates (%w/w) Agglomerates should NMT 2.5%w/w
Y2 Fines (%w/w) Fines should NMT 2.5%w/w
Y3 Process Efficiency (%) To achieve the maximum process efficiency (%yield) NLT 95%w/w

A Spraying Rate (gm/min) 3-7 3.50-5.50 4.00-5.00
B Atomization Pressure (bar) 1-3 1.25-2.25 1.50-2.00
C Fluidization Air Velocity (cfm) 50-100 55-75 60-70

GRANULATION FOR SOLID ORALS Created & Copyrighted
Created by Shivang
STUDY 12
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
OPTIMIZATION OF CPPs OF SOFT GELATIN

CAPSULE ENCAPSULATION PROCESS
FOR SOFT GELATIN CAPSULE DEVELOPMENT AS PER QbD
1 MELTING/ HEATING
TEMPERATURE
GELATIN
2 LAYER
THICKNESS
ROTARY
3 DIE
SPEED
RISKS
IMPROPER MACHINE SPEED THICKENED SOFTGEL LAYER HIGHER TEMPERATURE
WEIGHT VARIATION INADEQUATE DRUG RELEASE IN-PROCESS IMPURITIES
QUALITY COMPROMISED EFFICACY COMPROMISED PATIENT SAFETY COMPROMISED

STUDY 12
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CPPs of Encapsulation Process for Soft Gelatin Capsule
NO. OF FACTORS 3
NO. OF LEVELS 5
EXPERIMENTAL DESIGN
SELECTED
ROTARY DIE SPEED
COMPOSITE RSM WITH

FRACTIONAL FACTORIAL
(SCALE DOWN CCD)

C
TOTAL NO OF 4 ffp
EXPERIMENTAL RUNS + 6sp
(NO OF TRIALS) + 5cp
MELTING TEMPERATURE
=15
A

- -1 0 +1 +
A Melting/ Heating Temperature (C) 52.9 55.0 60.0 65.0 67.1
B Gelatin Layer Thickness (mm) 0.46 0.50 0.60 0.70 0.74
C Rotary Die Speed (RPM) 1.59 2.00 3.00 4.00 4.41
SOFTGEL CAPSULE ENCAPSULATION PROCESS Created & Copyrighted
Created by Shivang
STUDY 12
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
CPP CQAs

WEIGHT VARIATION =++1.29-0.035A+0.11B+0.71C -0.043AB+0.46AC +0.015BC+0.17A2 +0.22B2+0.79C2
DISSOLUTION AT 30 MINS=+97.96-1.06A-4.60B-0.35C-0.85AB-0.60AC-2.56BC-1.69A2-6.69B2-1.69C2
%TOTAL IMPURITIES =+1.50+0.95A+0.14B-0.14C-0.041AB-8.579E-003AC+0.25BC+0.32A2+0.044B2-6.481E-003C2
SOFTGEL CAPSULE ENCAPSULATION PROCESS Created & Copyrighted
Created by Shivang
STUDY 12
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CIRCUMSCRIBED BOX
CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
Y1 Weight variation (%) Weight variation should not be more than i.e. NMT 1.5%RSD
Y2 Drug Dissolved at 30 min %Drug dissolved should not be less than 95%
Y3 Total Impurities (%) Total Impurities should not be increased more than 1.5%w/w

A Melting/ Heating Temperature (C) 53-67 55-60 56-60
B Gelatin Layer Thickness (mm) 0.46-0.74 0.54-0.62 0.55-0.60
C Rotary Die Speed (RPM) 1.6-4.4 2.75-3.25 2.80-3.20
SOFTGEL CAPSULE ENCAPSULATION PROCESS Created & Copyrighted by Shivang Chaudhary
STUDY 13
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
DRY HEAT STERILIZATION PROCESS
FOR NON-AQUEOUS PARENTERAL DEPOT DOSAGE FORM
DEVELOPMENT AS PER QbD
B EXPOSURE TIME
A STERILIZATION TEMPERATURE
RISKS
INADEQUATE EXPOSURE HIGH TEMPERATURE
MICROBIAL LOAD INPROCESS IMPURITIES
SAFETY COMPROMISED

STUDY 13
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CPPs of Dry Heat Sterilization Process for Non-Aqueous Parenteral Depots
NO. OF FACTORS 2
NO. OF LEVELS 3
EXPERIMENTAL DESIGN
SELECTED
FACE CENTERED CENTRAL

EXPOSURE TIME

B
TOTAL NO OF 4 fp
EXPERIMENTAL RUNS +4 cp
=13
A STERILIZATION TEMPERATURE

-1 0 +1
A Sterilization Temp (C) 120C 150C 180C
B Exposure Time (min) 30 min 60 min 90 min
OPTIMIZATION OF CPPs OF DRY HEAT

STERILIZATION PROCESS FOR PARENTERALS Created & Copyrighted by Shivang Chaudhary
STUDY 13
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
design ANALYSIS
of DEVELOPMENT
OF OF
OF FACTORS
experimments
RESPONSES
DESIGN SPACE
CPPs CQAs

%REDUCTION IN MICROBIAL LOAD=+99.82+0.50A+0.25B-0.20AB-0.37A2-0.026B2
% DEGRADATION (TOTAL IMPURITIES) =+1.30+0.52A+0.27B+0.095AB+0.33A2+0.15B2

STUDY 13
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
design ANALYSIS
of DEVELOPMENT
OF OF
OF FACTORS
experimments
RESPONSES
DESIGN SPACE

Y1 % REDUCTION IN MICROBIAL LOAD Should Not Less Than 99.9% (3Log reduction)
Y2 % DEGRADATION (TOTAL IMPURITIES) Should Not More Than 1.5%

A Sterilization temp (c) 120-180 145-165 150-160
B Exposure Time (min) 30-90 45-80 50-80

STUDY 14
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OPTIMIZATION OF CPPs OF SUBLIMATION PHASE

(1 DRYING) OF LYOPHILILIZATION PROCESS
FOR DEVELOPMENT OF FREEZE DRIED RECONSTITUTED DOSAGE FORM AS PER QbD
B CHAMBER PRESSURE
A SHELF TEMPERATURE
RISKS
PRODUCT TEMPERATURE DURING PRIMARY DRYING TOTAL DURATION OF PRIMARY DRYING
EXCEEDS CRITICAL TEMPERATURE EXCEEDS MAXIMUM TIME TO ACCOMMODATE THE

(Tcol FOR AMORPHOUS/ Teut FOR CRYSTALLINE) PLANTS DEMANDS FOR PRODUCT SUPPLY
CAKE APPEARANE COMPROMISED (COLLAPSE/MELT) MFG COST OF THE D PRODUCT INCREASED
QUALITY COMPROMISED PATIENT ACCEPTANCE COMPROMISED

STUDY 14
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CPPs of Sublimation Phase (Primary Drying Step) of Freeze Drying Process for
Reconstituted Powders
NO. OF FACTORS 2
NO. OF LEVELS 3
EXPERIMENTAL DESIGN
SELECTED
CHAMBER PRESSURE


B
TOTAL NO OF 4FP
EXPERIMENTAL RUNS +4SP
(NO OF TRIALS) +5CP
SHELF TEMPERATURE
=13
A

-1 0 +1
A Shelf Temperature (C) -10C +5C +20C
B Chamber Pressure (Pa) 10 Pa (o.1mbar) 15 Pa 20 Pa (0.2mbar)
OPTIMIZATION OF CPPs OF FREEZE DRYING PROCESS

FOR RECONSTITUTED POWDERS Created & Copyrighted by Shivang Chaudhary
STUDY 14
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
design of
ANALYSIS
DEVELOPMENT
OF OF
OF FACTORS
experimments
RESPONSES
DESIGN SPACE
CPPs CQAs

Product Temperature=-16.21+7.00A+1.50B+0.000AB-0.28A2+0.22B2
Total Drying Time =+39.86-27.33A-7.83B+4.00AB+0.48A2+1.98B2

STUDY 14
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
design of
ANALYSIS
DEVELOPMENT
OF OF
OF FACTORS
experimments
RESPONSES
DESIGN SPACE

Y1 Product should be maintained below critical product temperature i.e. -12C
Temperature to prevent collapse of the structure to get the desired cake appearance
Y2 Primary should be less than 48 hours (2day) to control processing cost &
Drying Time ultimately to control product price for high patient acceptance

A Shelf Temperature (C) -10C - +20C -2.5 - +17.5C 0C- +15C
B Chamber Pressure (Pa) 10-20 10-20 10-20Pa (0.1-0.2mbar)

STUDY 15
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
OPTIMIZATION OF CMAs & CPPs OF

HIGH SHEAR WET GRANULATION PROCESS
A BINDER
B DISINTEGRANT
C KNEADING TIME
RISKS
SOFT GRANULES HARD GRANULES
LOWER HARDNESS INADEQUATE DISINTEGRATION
HIGH FRIABILITY INADEQUATE DISSOLUTION
QUALITY COMPROMISED EFFICACY COMPROMISED

STUDY 15
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CMAs & CPPs of Wet Granulation Process
NO. OF FACTORS 3
NO. OF LEVELS 3

COMPOSITE DESIGN
KNEADING TIME
TOTAL NO OF 8fp
EXPERIMENTAL RUNS + 6sp
C
(NO OF TRIALS) + 6cp

=20
A BINDER
Factors (Variables) Levels of Factors Studied

- = -1 0 + = +1
A Binder (%w/w) 4% 7% 10%
B Disintegrant (%w/w) 1% 3% 5%
C Kneading Time (min) 2 min 4 min 6 min
OPTIMIZATION OF CMAs & CPP OF HIGH SHEAR

WET GRANULATION PROCESS FOR SOLID ORALS Created & Copyrighted by Shivang Chaudhary
STUDY 15
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGNING OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
CMAs CPP CQAs

HARDNESS =+75.16+25.00A-2.40B+8.00C-1.00AB-2.25AC- FRIABILITY=+0.11-0.071A+6.000E-003B-0.025C +0.000AB+

1.25BC-4.91A2+0.091B2-0.91C2 7.500E-003AC+0.000BC+0.024A2-1.364E-003B2+3.636E-003C2
DISINTEGRATION TIME=+8.21+2.30A-2.90B+1.00C- DRUG DISSOLVED=+94.83-7.90A+3.70B-4.70C+

0.62AB+0.13AC-0.37BC-0.27A2+3.73B2+0.23C2 0.88AB+2.38AC+0.38BC-6.82A2-1.82B2-3.82C2

STUDY 15
FACTORIAL
RESPONSE
MIXTURE
SURFACE
FACE CENTERED BOX

CASE
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE

Y1 Hardness (n) To achieve tablet hardness in the range from 65 to 85N
Y2 Friability (%) To achieve minimum friability i.e. NMT 0.15%
Y3 Disintegration (min) To achieve tablet DT within 10 minutes
Y4 Dissolution (%) To achieve maximum dissolution in 30 minutes i.e. NLT 90%

A Binder (%) 4-10 5.75-7.75 6.00-7..50
B Disintegrant (%) 1-5 2.50-5.00 3.00-4.00
c Kneading Time (min) 2-6 2.50-5.50 2.50-4.50

FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
COMPOSITE BEHNKEN
3 Design Points are at the MIDPOINTS of edges of the 12 MP+3CP=15

process space & at the CENTER
MID POINTS
MP= number of Mid

High Linear Main Effects, 2FI ,
3FI (-1/+1 levels) & 2nd
order Quadratic terms
CENTER
POINTS
Medium CP= number of center

error & tie blocks
together (0 level).
F CCD BBD
Low 2 13 (5 CP) -
3 20 (6 CP) 15
4 30 (6 CP) 27
5 33 (ff) or 52 (FF) 46
6 54 (fF or 91 (FF) 54
APPLICATION An ECONOMIC ALTERNATE CHOICE OF CCD for fitting quadratic models that requires 3
levels of each factor, where Region of Interest & Region of Operability nearly the same.
Provides strong coefficient estimates near the center of the design space (where the
presumed optimum is), but weaker at the corners of the cube (where
there weren't any design points). Created & Copyrighted by Shivang Chaudhary
STUDY 16
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE

SUSPENSION HOMOGENIZATION PROCESS
FOR LIQUID ORAL DOSAGE FORM DEVELOPMENT AS PER QbD
C STIRRING TIME
B SURFACTANT
A HYDROCOLLOID
RISKS
INADEQUATE VISCOSITY INADEQUATE ZETA POTENTIAL HIGH RATE OF SEDIMENTATION
CONTENT UNIFORMITY COMPROMISED

STUDY 16
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CMAs & CPPs of Liquid Suspension Dosage Form
NO. OF FACTORS 3
NO. OF LEVELS 3
BOX BEHNKEN DESIGN

STIRRING TIME
TOTAL NO OF 12MP
EXPERIMENTAL RUNS + 3CP
(NO OF TRIALS) =15
C
A HYDROCOLLOID

-1 0 +1
A HYDROCOLLOID (%) 20%w/w 30%w/w 40%w/w
B SURFACTANT (%) 0.50%w/w 1.00%w/w 1.50%w/w
C STIRRING TIME (min) 30min 45min 60min

SUSPENSION HOMOGEMIZATION Created & Copyrighted by Shivang Chaudhary
STUDY 16
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
CMAs CPP CQAs

Sedimentation Volume Ratio =+0.037-0.013A-0.068B- Zeta Potential =-42.00-1.75A-19.38B-6.63C+2.25AB-

0.033C+0.010 AB+0.010AC+0.015BC+0.042A2+0.13B2+0.047C2 1.25AC+7.00BC-1.75A2+5.00B2-2.50C2
Viscosity=+45.00+1.88A+16.13B+6.00C+0.75AB+0.50AC Content Uniformity=+1.73-0.075A-0.14B-0.24C-

+0.000BC+0.38A2+0.38B2-1.38C2 0.025AB+0.075AC+0.050BC+0.28A2+0.46B2+0.51C2

STUDY 16
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE

Y1 Sedimentation Volume Ratio To achieve the minimum SVR i.e. NMT 0.1
Y2 Zeta Potential (mV) To achieve zeta potential of suspension in the range of -40 to -50 mv
Y3 Viscosity (cps) To achieve viscosity in the range of 40 to 50 cps
Y4 Content Uniformity (AV) To achieve minimum acceptance value in CU i.e. NMT 2.0

A HYDROCOLLOID (%) 20.0-40.0 27.5-32.5 28.0-32.0
B SURFACTANT (%) 0.50-1.50 0.60-1.40 0.75-1.25
C STIRRING TIME (min) 30-60 37-53 40-50
STUDY 17
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE

HARD GELATIN ENCAPSULATION PROCESS
FOR HARD GELATIN CAPSULE DEVELOPMENT AS PER QbD
A GLIDANT
B ANTIADHERANT
C FILLING RATE
RISKS
INAPPROPRIATE FLOW PROPERTY & FILLING RATE INADEQUATE DISINTEGRATION
WEIGHT VARIATION & CONTENT NON UNIFORMITY INADEQUATE DISSOLUTION

STUDY 17
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize CMAs & CPPs of Hard Gelatin Capsule Encapsulation.
NO. OF FACTORS 3
NO. OF LEVELS 3
BOX BEHNKEN DESIGN

FILLING RATE
TOTAL NO OF 12 +
EXPERIMENTAL RUNS 3CP
(NO OF TRIALS)
C
=15
A GLIDANT

-1 0 +1
A Glidant (%w/w) 0.10%w/w 0.25%w/w 0.40%w/w
B Lubricant (%w/w) 0.50%w/w 1.25%w/w 2.00%w/w
C Filling Rate (SPM) 50SPM 65SPM 80SPM

HARD GELATIN CAPSULE ENCAPSULATION Created & Copyrighted by Shivang Chaudhary
STUDY 17
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE
CMAs CPP CQAs

Weight Variation =+1.53-0.21A-0.11B+0.37C- Content Uniformity=+3.03-0.35A-0.16B+0.74C-0.025AB-

0.025AC-0.025BC+0.28A2+0.18B2+0.91C2 0.075AC+0.61A2+0.43B2+1.83C2
Disintegration Time =+3.23-0.21A+0.82B-0.16C- %Drug Dissolved in 30 minutes =+95.67+2.00A-

0.17AB-0.050AC-0.075BC+0.66A2+1.03B2+0.058C2 4.25B+1.50C+1.00AB-0.50AC+0.50BC-4.58A2-7.08B2-0.083C2

STUDY 17
FACTORIAL
RESPONSE
MIXTURE
SURFACE
CENTRAL BOX
CASE
COMPOSITE BEHNKEN
IDENTIFICATION
DESIGN OF
ANALYSIS
DEVELOPMENT
OF OF
OFEXPERIMMENTS
FACTORS RESPONSES
DESIGN SPACE

Y1 Weight Variation Relative Standard Deviation in WV test should NMT 2.0%
Y2 Content Uniformity Acceptance Value in CU test should NMT 4.0
Y3 Disintegration To achieve complete disintegration (no residue) within 5 minutes
Y Dissolution To achieve at least 95% drug release within 30 minutes

A Glidant (%) 0.10-0.50 0.18-0.36 0.20-0.30
B Anti-adheant (%) 0.50-2.00 0.70-1.30 0.80-1.20
C Filling Rate (SPM) 50-80 58-72 60-70

FACTORIAL
RESPONSEMIXTURE
SURFACE
TYPES APPLICATIONS
A special class of response surface experiments in which the

1. Factors are components of a mixture & the components must
total to a constant i.e. 1 (100%).
2. Response is a function of proportion of components.
A. SIMPLEX LATTICE
Mixture design for 2 to 24 components where all components must have
the same range & there are no constraints on the design space.
In a {q, m} design, the proportions assumed by each q component take
the m+1 equally spaced leveled values from 0 to 1
Number of design points in the {q, m } simplex-lattice is
(q+m-1)! /(m!(q-1)!).
B. SIMPLEX CENTROID
Mixture design for 3 to 8 components where all components must have
the same range & there are no constraints on the design space.
Design points chosen are the pure blends, binary blends, tertiary blends,
and so on the overall centroid. It cannot be used to estimate the full
cubic model, but can be used to estimate a special cubic model known
as scheffe model. In the q-component, the number of distinct points is 2q 1.
C. CONSTRAINED MIXTURE
Upper and/or lower bound constraints may be present for each components of the mixture. In mixture
designs when there are constraints on the component proportions, these are often upper and/or lower
bound constraints in the form of Li xi Ui, i = 1, 2,..., q, where
Li is the lower bound for the ith component and
Ui the upper bound for the ith component.
FACTORIAL
RESPONSEMIXTURE
SURFACE
FACTORIAL MIXTURE
Vs
2 Level FULL FACTORIAL 2 Level MIXTURE Design
Design For 2 FACTORS For 2 FACTORS
2 FACTORS
A+B =1
In a 2 Component mixture, once we know the percentage of one ingredient, the percentage of other component is set by the constraint. So 2 factor
space is no longer 2-dimensional as it is in a factorial design space, but a 1-dimensional line containing all possible combinations of X1 & X2.
Along this line the proportion of X1+X2 is 1.
2 Level FULL FACTORIAL 2 Level MIXTURE Design

Design For 3 FACTORS For 3 FACTORS
3 FACTORS
A+B+C =1
For 3 Component mixture, the factorial cube reduces to a 2-dimensional equilateral triangle of all combinations of the 3-components.
Only points on the triangle are now feasible.
FACTORIAL
RESPONSEMIXTURE
SURFACE
LINEAR MODEL SCHEFFE POLYNOMIAL
NO. OF
COMPONENTS 2
1st ORDER
LINEAR MODEL
Y = 0 + 1 x1 + 2 x2
REDUCED 1st ORDER
SCHEFFE POLYNOMIAL
Y = 0 + 1 x1 + 2 x2
Here, Model Intercept Beta nought- 0
is a Mean Response when both components , x1 & x2 are zero, which cant exist
in Mixtures, because In 2 component Mixture, Constraints: x1 + x2 =1
Thus, Replacing 0 by 0 (x1+x2),
Y= 0 (x1+x2) + 1X1 + 2x2
Y= (0 + 1) x1 + (0 + 2)x2
Replacing (0 + 1) by new linear coefficient 1 & (0 + 2) by new 2 ;
Y= 1x1 + 2x2
Reduced Polynomial Scheffe Model depend on the number of components symbolized by

letter q; characterized by LACK OF INTERCEPT & lack of squared or cubed terms
FACTORIAL
RESPONSEMIXTURE
SURFACE
QUADRATIC MODEL SCHEFFE POLYNOMIAL
NO. OF
COMPONENTS 2
2nd ORDER
QUADRATIC MODEL
Y = 0 + 1x1 + 2x2 + 12x1x2 +11x12+ 22x22
REDUCED 2nd ORDER

SCHEFFE POLYNOMIAL
Y = 0 + 1x1 + 2x2 + 12x1x2 +11x12+ 22x22

Here, Model Intercept Beta nought- 0
is a Mean Response when both components , x1 & x2 are zero, which cant exist
in Mixtures, because In 2 component Mixture, Constraints: x1 + x2 =1
Thus, Replacing 0 by 0 (x1+x2), x12 by x1(1-x2), x22 by x2(1-x1)
Y= 0 (x1+x2) + 1X1 + 2x2 + 11(x1(1-x1))+ 22(x2(1-x1))
Y= (0 + 1+ 11) x1 + (0 + 2+ 22)x2 + (12- 11- 22)x1x2
Replacing 0 + 1+ 11 by 1 ; 0 + 2+ 22 by new 2; 12- 11- 22 by 12
Y= 1x1 + 2x2+ 12x1x2
letter q; characterized by LACK OF INTERCEPT & LACK OF SQUARED terms
FACTORIAL
RESPONSEMIXTURE
SURFACE
FULL CUBIC MODEL SCHEFFE POLYNOMIAL
NO. OF
COMPONENTS 3
REDUCED 1st ORDER
LINEAR MODEL

=
=1
REDUCED 2nd ORDER
QUADRATIC MODEL Linear (1st Order) Quadratic (2nd Order) Full Cubic (3rd Order)
q q
= i=1 iXi + i<j j=2 ijXiXj
REDUCED 3RD ORDER

SPECIAL CUBIC MODEL
q q q
= i=1 iXi + i<j j=2 ijXiXj + i<j j<k k=3 ijkXiXjXk
3RD ORDER
FULL CUBIC MODEL
q q q q
= i=1 iXi + i<j j=2 ijXiXj + i<j j=2 ijXiXj Xi Xj + i<j j<k k=3 ijkXiXjXk

letter q; characterized by LACK OF INTERCEPT & LACK OF SQUARED & CUBE terms
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
LATTICECENTROIDMIXTURE
LEVELS COMPONENTS 3 RUNS
(q+m-1)! /
m+1 =2+1 =3 {q components, m degree} = {3,2}
(m!(q-1)!) = 6
CORNER
POINTS
1 Level
3 Corner points are the
pure components of
single individual assessing
the Main Effect
SIDE
POINTS
1/2 Level
3 Side points are
Binary Blends assessing
1st order Linear & 2nd
Quadratic effect & 2FI
0 Level
APPLICATION A special class of response surface experiments in which the

1. Factors are components of a mixture &
2. Components of the mixture must total to a constant i.e. 1 (100%).
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
(q+m-1)! /
(m!(q-1)!) = 10
CORNER
POINTS
1 Level
pure components of
the Main Effect
2/3 Level
SIDE
POINTS
6 Side points are

1/3 Level 1st order Linear & 2nd
CENTER
POINTS
0 Level 1 Mixture Points are

Ternary blend in face
center area assessing 3rd
order Cubic effect & 3FI

STUDY 18
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OPTIMIZATION OF SWEETENER FLAVOR & COLOR

RATIO IN LIQUID ORAL MIXTURES
FOR SOLUTION SUSPENSION EMULSION DOSAGE FORM
DEVELOPMENT AS PER QbD
3 COLORANT
2 FLAVOR
1 SWEETENER
RISK
UNACCEPTABLE TASTE OF LIQUID ORAL MIXTURE
PATIENT ACCEPTANCE
COMPROMISED

STUDY 18
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize Sweetener: Color: Flavor ratio of Liquid Oral Dosage Form
NO. OF COMPONENTS 3
EXPERIMENTAL DESIGN
SELECTED
SWEETENER
{3,3} SIMPLEX LATTICE MIXTURE
TOTAL NO OF 10
EXPERIMENTAL RUNS
(NO OF TRIALS)
A
A

1 2 3 4
A SWEETENER (%w/w) 0% 0.333 0.667 1%
B FLAVOR (%w/w) 0% 0.333 0.667 1%
C COLOR (%w/w) 0% 0.333 0.667 1%
OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN

LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM Created & Copyrighted by Shivang Chaudhary
STUDY 18
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
CMAs CQAs

PATIENT ACCEPTANCE SCORE =+8.14A+4.49B+4.13C+9.71AB+9.39AC+4.56BC)

[SIGNIFICANT TERMS: AB, AC, BC]

STUDY 18
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE

Y1 PATIENT ACCEPTANCE To achieve maximum Patient Acceptance Score as maximum as possible out of 10. &
SCORE NLT 9.0

A SWEETENER (%w/w) 0-1.00% 0.55-.0.75 0.60-0.70
B FLAVOR (%w/w) 0-1.00% 0.10-0.40 0.20-0.30
C COLOR (%w/w) 0-1.00% 0.00-0.20 0.05-0.15

FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
(q+m-1)! /
(m!(q-1)!) = 10
CORNER
POINTS
1 Level
pure components of
the Main Effect
SIDE
POINTS
1/2 Level
6 Side points are
1st order Linear & 2nd
CENTER
0 Level POINTS
0 Mixture Points are


FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
(q+m-1)! /
(m!(q-1)!) = 20
CORNER
POINTS
1 Level
pure components of
the Main Effect
2/3 Level
SIDE
POINTS
12 Side points are

1/3 Level 1st order Linear & 2nd
CENTER
POINTS
0 Level
4 Mixture Points are

FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
DESIGN NO. OF NO. OF

POINTS COMPONENTS 3 RUNS
In the q-component, the 2q-1=8-1=7

number of distinct points
is 2q 1. CORNER
POINTS
Design points
correspond to
q permutations of pure components of
(1, 0, 0, ..., 0) single individual assessing
for q single component the Main Effect
blend,
SIDE
POINTS
2
permutations of
(0.5,0 .5, 0, ..., 0) 3 Side points are
for all binary mixtures, Binary Blends assessing

1st order Linear & 2FI
3
permutations of & 2nd Quadratic effect
(1/3, 1/3, 1/3, 0, ..., 0)
for ternary, and so on, CENTROID
POINTS
with finally the overall
centroid point (1/q, 1/q, 1 Centroid assessing
..., 1/q) for 3rd order Special
q-nary mixture Cubic effect & 3FI
APPLICATION 7 runs for a 3 component simplex-centroid design of degree 2 are:

(1,0,0), (0,1,0), (0,0,1), (.5,.5,0), (.5,0,.5), (0,.5,.5), (1/3, 1/3, 1/3). This design differs from
a simplex-lattice design used for 3 to 8 mixture components. It cannot be used to
estimate the full cubic model, but can be used to estimate a special cubic model

STUDY 19
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OPTIMIZATION OF GLIDANT LUBRICANT

ANTIADHERANT RATIO IN SOLID ORAL MIXTURES
FOR TABLET/ CAPSULE DOSAGE FORM DEVELOPMENT AS PER QbD
1 GLIDANT
2 LUBRICANT
3 ANTIADHERANT
RISKS
INADEQUATE GLIDANT INADEQUATE ANTIADHERANT INADEQUATE LUBRICANT
POOR FLOW OF GRANULES ADHESION OF GRANULES TO EJECTOION OF COMPLETE

FROM HOPPER TO DIE PUNCES & DIES TABLET FROM DIE
WEIGHT VARIATION & STICKING CAN BE OBSERVED ON PICKING CAN BE OBSERVED ON

CONTENT NONUNIFORMITY TABLET PERIPHERALS TABLET SURFACE
QUALITY COMPROMISED

STUDY 19
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize Glidant: Lubricant: Anti-Adherant ratio of Solid Orals
NO. OF COMPONENTS 3
GLIDANT
SIMPLEX CENTROID
TOTAL NO OF 10
EXPERIMENTAL RUNS
(NO OF TRIALS)
TOTAL OF 3 2
COMPONENTS

Low High
A GLIDANT (%w/w) 0% 0.5%
B LUBRICANT (%w/w) 0.5% 1%
C ANTIADHERANT (%w/w) 1% 1.5%
OPTIMIZATION OF GLIDANT: LUBRICANT: ANTIADHERANT

RATIO IN SOLID ORAL DOSAGE FORM Created & Copyrighted by Shivang Chaudhary
STUDY 19
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
CMAs CQAs

ON INDIVIDUAL RESPONSE BY MIXED ORDER SPECIAL CUBIC MODEL
Angle of Repose = ++33.95A+40.95B+39.04C-2.22AB-18.04AC-0.037BC-25.41ABC

(MIX ORDER SPECIAL CUBIC MODEL)

STUDY 19
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE

Y1 Angle of Repose To achieve angle of repose in the range from 30 to 35 (GOOD Flow property)

A GLIDANT (%w/w) 0-0.5% 0.20-0.50 0.30-0.40
B LUBRICANT (%w/w) 0.5-1.0% 0.50-0.70 0.55-0.65
C ANTIADHERANT (%w/w) 1.0-1.5% 1.10-1.40 1.20-1.30

FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
DESIGN NO. OF NO. OF

POINTS COMPONENTS 4 RUNS
Design points
{q components, m degree} = {4,2} 2q-1=16-1=15
correspond to
q permutations of CORNER
(1, 0, 0, ..., 0) POINTS
for q single component
blend, 4 Corner points are the
pure components of
2
permutations of
(0.5,0 .5, 0, ..., 0) the Main Effect
for all binary mixtures,
SIDE
POINTS
3
permutations of
(1/3, 1/3, 1/3, 0, ..., 0) 3 Side points are
for ternary, and so on, Binary Blends assessing
1st order Linear & 2FI
with finally the overall & 2nd Quadratic effect
centroid point (1/q, 1/q,
..., 1/q) for CENTROID
q-nary mixture POINTS
5 Centroid assessing
3rd order Special
Cubic effect & 3FI
APPLICATION 15 runs for a 4 component simplex-centroid design of degree 2 are:

(1,0,0,0), (0,1,0,0), (0,0,1,0), (0,0,0,1), (.5,.5,0,0), (.5,0,.5,0) ..., (0,0,.5,.5),
(1/3,1/3,1/3,0), ...,(0,1/3,1/3,1/3), (1/4,1/4,1/4,1/4). This design differs from a simplex-
lattice design used for 3 to 8 mixture components. It cannot be used to estimate the full
cubic model, but can be used to estimate a special cubic model
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
NO. OF NO. OF ORIGINAL
LEVELS COMPONENTS 3 COMPONENT
xi* = (xi-Li) /
(1-L))
3 component mixture problem with constraints : 0.3 x1 0.4 x2 0.1 x3 xi = Li + (1 - L) xi*
Since the new region of the experiment is Constructing a design in the pseudo
still a simplex, it is possible to define a new components is accomplished by
set of components that take on the values specifying the design points in terms of
from 0 to 1 over the feasible region. This the xi* and then converting them to the
will make the design construction and the original component settings using:
model fitting easier over the constrained xi* = (xi-Li) / (1-L) So. xi-Li = (1 - L) xi*
region of interest. xi = Li + (1 - L) xi*
These new pseudo components 3-Component Simplex-Centroid
xi* = (xi-Li) / (1-L) where, Pseudo Original

L = = Li < 1 Components Components
X1 X2 X3 X1* X2* X3*
L = sum of all lower bounds.
1 0 0 0.5 0.4 0.1
0 1 0 0.3 0.6 0.1
0 0 1 0.3 0.4 0.3
0.5 0.5 0 0.4 0.5 0.1
0.5 0 0.5 0.4 0.4 0.2
0 0.5 0.5 0.3 0.5 0.2
0.3 0.3 0.3 0.3 0.4 0.1
33 33 33 66 66 66
3 3 3 7 7 6
In the example above, the pseudo components are x1* = x1-0.3 / 0.2; x2* = x2-0.4 / 0.2; x3* = x3-0.1 / 0.2
APPLICATION Specially applicable when there are constraints on the component proportions in the
mixture, these are often upper and/or lower bound constraints in the form
Li xi Ui, i = 1, 2,..., q, where,
Li is the lower bound for the i-th component &
Ui is the upper bound for the ith component
STUDY 20
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OPTIMIZATION OF OIL WATER EMULGENT

RATIO IN SEMISOLID MIXTURES
FOR EMULSION CREAM DEVELOPMENT AS PER QbD
1 OILY PHASE
2 AQUEOUS PHASE
3 EMULGENT
RISKS
SEPERATION OF OILY PHASE & AQUEOUS PHASE

DURING ROUTINE IN-USE STABILITY
PATIENT COMPLIANCE
COMPROMISED

STUDY 20
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
OBJECTIVE To Optimize of Oil: Water: Emulgent ratio in Liquid/ Semisolid Emulsion Dosage Form
NO. OF COMPONENTS 3
OIL
D-Optimal Constrained Mixture
ADD. REPLICATES 5
TOTAL NO OF 16
EXPERIMENTAL RUNS
(NO OF TRIALS)
Factors (Variables) Actual Levels Constrained Levels

A OIL (%w/w) 10-50% 20-40%
B WATER (%w/w) 30-70% 40-60%
C EMULGENT (%w/w) 0-40% 0-20%
OPTIMIZATION OF OIL:WATER:EMULGENT RATIO

IN LIQUID/ SEMISOLID EMULSION DOSAGE FORM Created & Copyrighted by Shivang Chaudhary
STUDY 20
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE
CMAs CQAs

ON INDIVIDUAL RESPONSE BY CUBIC MODEL
%CONTENT Uniformity=+88.33A+66.67B+55.82C+14.78AB+96.62AC+89.14BC
OPTIMIZATION OF OIL: WATER: EMULGENT RATIO

STUDY 20
FACTORIAL
RESPONSEMIXTURE
SURFACE
SIMPLEX SIMPLEX
CONSTRAINED
CASE
IDENTIFICATION
DESIGNING OF OF
ANALYSIS
DEVELOPMENT OF
OF FACTORS
EXPERIMMENTS
RESPONSES
DESIGN SPACE

Y1 %CONTENT Uniformity To achieve maximum content after uniform stirring & homogenization
i.e. NLT 90%

A OIL (%w/w) (20-50%)20-40% 25-35% 28-32%
B WATER (%w/w) (45-75%)45-75% 50-60% 55-60%
C EMULGENT (%w/w) (5-35%) 5-15% 8-16% 8-12%
OPTIMIZATION OF OIL:WATER:EMULGENT RATIO

HOW TO VERIFY RESULTS OF DOE ?
When the analysis of the experiment is complete,

one must VERIFY THAT THE PREDICTIONS ARE GOOD for VALIDATION PURPOSE OF
DESIGN & MODEL. These are called CONFIRMATION RUNS
A MINIMUM OF 3 CONFIRMATORY RUNS should be conducted

allowing an estimate of variability at BEST INDUSTRIAL setting to
have a quality product with stable manufacturing process
The OBSERVED RESULTS of these confirmatory runs will be

compared with PREDICTED RESULTS from ANOVA predicted
equation by means of CORRELATION COEFFICIENT
R2 should not be less than 0.9.
The CONFIRMATION RUNS should be conducted in an ENVIRONMENT AS SIMILAR AS POSSIBLE

to the original experiment.
Other EXTRANEOUS FACTORS that may change or affect the results of the confirmation runs are:
PERSON/OPERATOR ON THE EQUIPMENT, TEMPERATURE, HUMIDITY, MACHINE PARAMETERS,
QUALITU OF RAW MATERIALS
IF YOU DON'T FIND THE ANSWER AFTER CHECKING THE ABOVE 3 ITEMS, the MODEL MAY NOT
PREDICT VERY WELL IN THE REGION YOU DECIDED WAS "best".
You still learned from the experiment and you should use the information gained from this
experiment to design another follow-up experiment.

SUMMARY
DESIGNEFFECT
MODEL
MODEL
ANOVA
GUIDE SELECTION VALIDATION
SELECTION SELECTION
GRAPHS
VALIDATION
PBD FFD 2k FD Xk FD CCD BBD MD

Object of Experimentation
Screening
Optimization
Factor Type
Composition (Formulation)
Manufacturing (Processing)
Number of Factors
5f2
f6
Number of Levels
L=2
L3
Model proposed
Linear model
Interaction model
Quadratic model
Cubic model
Scheffe Mixture model
Where, FD: Factorial Design, FFD: Fractional Factorial Design, PBD: Plackette Burman Design,
CCD: Central Composite Design, BBD: Box-Behnken Design,
MD: simplex lattice & simplex centroid Mixture Design,

SUMMARY
DESIGNEFFECT
MODEL
MODEL
ANOVA
SELECTION SELECTION
GRAPHS
VALIDATION
During Selection of any Design for experimentation, OBJECTIVE (goal) of the experiment &
NUMBERS of the factors involved are the primary two most important factors to be considered
PLACKETTE BURMAN or FRACTIONAL WITH CP &
FRACTIONAL FACTORIAL FULL FACTORIAL
Res IV Factorial Designs are appropriate when: Res V Factorial Designs are appropriate when:
Numerous unknown factors are involved The goal is EVALUATION OF MAIN EFFECTS &
The goal is SCREENING of critical factors INTERACTIONS between factors (2 F 4)
Emphasis is on identifying important factor effects Have Sufficient time & resources for development
Time & Resources are limited Res V Fractional or Full Factorial Design can be augmented
If F>6 use Plackette Burman, if 4 F 6 then use fFD with axial star points to create CCD RSM for optimization.
RESPONSE SURFACE MIXTURE DESIGNS
DESIGNS (CCD or BBD) (SIMPLEX or CONSTRAINED)
RSM designs are appropriate when: Use MIXTURE Designs (SIMPLEX LATTICE or SIMPLEX
Vital factors are known & limited (2 F 5) CENTROID or CONSTRAINED MIXTURE) when:
The goal is OPTIMIZATION of critical factors Factors are components of a mixture
Emphasis is on the fitted surface representing true behavior Emphasizing ratios of ingredients in formulations
detect non-linear significant curvature in response surface Response is a function of proportions
Ranges of factors are defined (definite knowledge space) Ingredients must total to 1 (100%)
SUMMARY
DESIGNEFFECT
MODEL
MODEL
ANOVA
SELECTION SELECTION
GRAPHS
VALIDATION
, Effect Half Normal Probability plot reveals vital few from trivial many & Pareto bar chart puts all the effects in
perspective during Selection of Significant Main Effects from Non significant Errors
EFFECT HALF NORMAL REVEALS VITAL FEW SIGNIFICANT CRITICAL FACTORS OUT
PROBABILITY PLOT OF NONCRTICAL NONSIGNIFICANT TRIVIAL MANY
Normal probability plot indicates whether the residuals (noise

factors) follow a normal distribution, which will follow a straight
line. Half-Normal Probability Plot can be used to choose significant
effects. It follows the same principle as the full normal probability
plot, except the sign of the effect is ignored in plotting.
Thus, LARGE ABSOLUTE VALUES SHOW UP AS OUTLIERS AT
NOTICEABLE GAP FROM RIGHT TO LEFT IN THE UPPER RIGHT-HAND
SECTION OF THE GRAPH. A distinct inflection point or "dogleg"
indicates the transition between significant and insignificant effects.
PUTS EFFECTS IN PERSPECTIVE FOR EASY UNDERSTANDING

PARETO BAR CHART
OF RELATIVE IMPORTANCE OF FACTORS
The Pareto chart may be more comfortable viewing as the Pareto
Chart has the significant effects selected. There are two different t
limits plotted on the graph - based on the Bonferroni corrected t and
a standard t.
EFFECTS THAT ARE NOW ABOVE THE BONFERRONI LIMIT ARE
ALMOST CERTAINLY SIGNIFICANT. Effects that are now above the
T-Value Limit are possibly significant and should be added
if they are not already selected.
Use Stepwise Regression, Forward Selection or Backward Elimination on the basis of corresponding
Coefficient values to identify important variables; when selecting variables for inclusion in the model, follow the
HIEARCHY PRINCIPLE & keep all main effects that are part of significant higher order terms or interactions,
even if the main effect p-value is larger than you would like. Created & Copyrighted by Shivang Chaudhary
SUMMARY
DESIGNEFFECT
MODEL
MODEL
ANOVA
SELECTION SELECTION
GRAPHS
VALIDATION
The order of polynomial: MODEL (A mathematical relationship between factors & response assisting
in calculations & predictions) for any design depends on the expected response behavior.
LINEAR MODEL QUADRATIC MODEL
FIRST Order (LINEAR) terms modeling SLOPEs of a SECOND Order (QUADRATIC) terms modeling
STRAIGHT LINE or FLAT PLANE CURVATUREs of an ECLIPSE.
Used for SCREENING of Significant Factors for Used for OPTIMIZATION of Factors for development
Identification of Main Effects & Interactions of Design Space from Knowledge Space
CUBIC MODEL SCHEFFE MODEL
THIRD Order (CUBIC) terms: modeling Inflected Reduced Polynomial Scheffe Model characterized by
ASSYMETRY like S curve in response eclipse LACK of intercept & LACK of square & cube terms
During Selection of Model for Analysis of Response; ANOVA should be carried out thoroughly for
testing of SIGNIFICANCE of each MODEL TERMS (p<0.05), insignificant LACK OF FIT (p>0.1) with MODEL GRAPHS
SUMMARY
DESIGNEFFECT
MODEL VERIFICATIO
MODEL
MODEL
GUIDE SELECTION
SELECTION SELECTION GRAPHSN
DIAGNOSTICS
ANOVA should be carried out for testing of significance of selected MODEL with F-Value >>1 & p<0.05,
insignificant LACK OF FIT (p>0.10), adequate PRECISION > 4, R2 & R2 adjusted as NUMERICAL INDICATORS with
well behaved RESIDUALS analyzed by DIAGNOSTIC PLOTS as GRAPHICAL INDICATORS
ACTUAL VS RESIDUALS VS
PREDICTED PLOT RUN PLOT
Points should be Random

scatter with no pattern
Points should be Random

scatter along 45 line with
no increasing or
decreasing trend
Residuals are estimates of experimental error obtained by

subtracting the observed responses from
the predicted responses calculated from the chosen model.
Residual (Experimental Error) Noise= (Observed Responses) Actual Data (Predicted Responses) Model Value
RESIDUALS VS RESIDUAL VS
PREDICTED PLOT FACTOR PLOT
Points should be
Random scatter with no
megaphone =< pattern
Points should be split by

the zero line at either end
of the range- no obvious
main effects (up & down)
RESIDUAL ANALYSIS is necessary to confirm/validate that the MODEL ASSUMPTIONS for the ANOVA are met.
Thus model should predict values higher than actual & lower than actual with equal probability. In addition the
level of error should be independent of when the observation occurred in the study, or the size of the
observation being predicted, or even the factor setting involved in making the prediction Created & Copyrighted by Shivang Chaudhary
SUMMARY
DESIGNEFFECT
MODEL MODEL
MODEL
SELECTION SELECTION GRAPHS
DIAGNOSTICS
Model Graphs gives a clear picture of how the response will behave at different levels of factors
at a time through predicted response equation with individual coefficients
1D 2D
INTERACTION PLOT CONTOUR PLOT
Interaction occurs with 2 NON-PARALLEL CROSS LINES, 2D PLOT OF TWO INDEPENDENT FACTORS Vs one
indicating the effect of one factor depends on response factor to predict the response at different
the level of the other factor. levels of factors, while holding the magnitude of
response and other factors as constant.
3D RESPONSE 4D
SURFACE PLOT CUBE PLOT
3D SURFACE PLOT OF TWO INDEPENDENT FACTORS 4D PLOT OF THREE INDEPENDENT FACTORS

Vs one response factor to explore the effect of changing AT A TIME Vs one response factor at different levels
levels of factors on the response, while holding the of factors, while holding the magnitude of response
magnitude of response & other factors constant. and other factors as constant.
SUMMARY
DESIGNEFFECT
MODEL
DIAGNOSTIC
ANOVA
GUIDE SELECTION VERIFICATION
SELECTION SELECTION
PLOTS
VALIDATION
VERIFICATION is a confirmation of an DESIGN SPACE, which should be rugged & robust to normal variation
within a SWEET SPOT, where all the specifications for the individual responses (CQAs) met to the predefined targets
(QTPP) in OVERLAY PLOT, obtained by overlaying contour surfaces of individual responses with their respective goals.
BLENDING SPEED BLENDING TIME
8.0-12.0 5.0-15.0 Known Ranges of OPERABILITY

KNOWLEDEGE SPACE before Designing
9.0-11.5 10.0-12.5 Optimized Ranges of FEASIBILITY

DESIGN SPACE after Development
9.5-10.5 10.0-12.0 Planned Ranges of CONTROLLING

CONTROL SPACE during Commercialization
A MINIMUM OF 3 CONFIRMATORY RUNS should be conducted allowing an estimate of variability WITHIN

DESIGN SPACE to have a quality product &/or stable process. The OBSERVED RESULTS of these confirmatory runs
should be compared with PREDICTED RESULTS from ANOVA predicted equation
by means of CORRELATION COEFFICIENT R2 which should be not less than 0.9). Created & Copyrighted by Shivang Chaudhary
DESIGN IS A JOURNEY OF DISCOVERY
THANK YOU SO MUCH FROM
SHIVANG CHAUDHARY
Quality Risk Manager & Intellectual Property Sentinel- CIIE, IIM Ahmedabad
MS (Pharmaceutics)- National Institute of Pharmaceutical Education & Research (NIPER), INDIA
PGD (Patents Law)- National academy of Legal Studies & Research (NALSAR), INDIA
facebook.com/QbD.PAT.Pharmaceutical.Development
https://in.linkedin.com/in/shivangchaudhary
+91 -9904474045, +91-7567297579
Copyrighted by Shivang Chaudhary
shivaniper@gmail.com

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DESIGN OF EXPERIMENTS (DoE) &

DEVELOPMENT OF DESIGN SPACE

Designed & Developed by

Formulation Engineer (QbD/PAT System Developer & Implementer)

DoE Definition & Comparison

DoE/ QbD Road Map

Response Surface Designs

Created & Copyrighted by Shivang Chaudhary Verification of DoE Results

DoE Summary guide

Created & Copyrighted by Shivang Chaudhary

Serial experimentation is uneconomical in Parallel experiments is economical in terms of

Estimate each factor effect independent of the

Created & Copyrighted by Shivang Chaudhary

A SYSTEMATIC SERIES OF EXPERIMENTS,

WITH COMPLETE UNDERSTANDING OF THE PROCESS

QTPP CQAs & Development of & Development of CONTROLS

DEFINE OBJECTIVE IDENTIFY RESPONSES IDENTIFY FACTORS TO BE STUDIED

OPTIMIZATION L3 1D MAIN EFFECT PLOT

OPTIMIZATION 3/5 LEVEL CCD or BBD RSM DESIGN/

2 LEVEL Plackette Burman or

REGION OF OPERABILITY (KNOWLEDGE SPACE)

2 LEVEL 3 LEVEL SIMPLEX SIMPLEX

23 FULL 23 FULL 33 FULL

22FP+ 4SP + 5CP 23FP+ 6SP + 6CP 23-1FFP+ 6SP + 6CP

Created & Copyrighted by Shivang Chaudhary

Used primarily TO REFINE A PROCESS by SCREENING OF CRITICAL

PLACKETTE BURMAN DESIGN

A. FULL FACTORIAL DESIGNS

OFAT FULL FACTORIAL

Vs 2 Level FULL FACTORIAL

2 Level OFAT Design 2 Level FULL FACTORIAL

Created & Copyrighted by Shivang Chaudhary

LINEAR MODEL forLINEAR

A Linear model with two factors, X1 and X2, can be written as

Modeling of varying SLOPs of a FLAT PLANE

Evaluate Values OF MAIN EFFECTS &

Created & Copyrighted by Shivang Chaudhary

LINEAR MODEL forLINEAR

The order of polynomial MODEL(simplified mathematical relationship

Y = 0 + 1X1 + 2X2 + 3X3 + 12X1X2 + 13X1X3 + 23X2X3 + 123X1X2X3 +

Modeling of varying SLOPs of a FLAT PLANE

Evaluate Values OF MAIN EFFECTS & two factor

Created & Copyrighted by Shivang Chaudhary

PLACKETTE2 LEVEL 3 LEVEL

High +1 X1 X2 X3 X4 X5 X6 X7 X8 X9 X10 X11 DESIGN

APPLICATION ECONOMICAL SCREENING DESIGN for NUMEROUS FACTORS,

Created & Copyrighted by Shivang Chaudhary

PLACKETTE2 LEVEL 3 LEVEL

SCREENING OF CPPs OF FLUID BED

K OUTLET TEMPERATURE NO. OF FACTORS 11

J FILTER CLEANING FREQUENCY NO. OF LEVELS 2

I FILTER BAG PORE SIZE

G BINDER SPRAYING RATE

E GUN TO BED DISTANCE PLACKETTE BURMAN DESIGN

D PRODUCT TEMPERATURE TOTAL NO OF 12

A FLUIDIZATION AIR VELOCITY

Created & Copyrighted by Shivang Chaudhary

PLACKETTE2 LEVEL 3 LEVEL

Factors (Variables) Coded Levels & Actual Levels

Responses (Effects) Goals for Individual Responses

SCREENING OF CRITICAL PROCESSING PARAMETERS OF

PLACKETTE2 LEVEL 3 LEVEL

SCREENING OF CRITICAL PROCESSING PARAMETERS OF