Case Studies in Quality by

Design with Design of

Experiments From
Pharmaceutical Technology
Lynn Torbeck
19 August 2008

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Overview
A little, very little, history
3 types of controlled experiments
Key literature and dates
Todays driving force behind QbD
Show me an example in my area of
interest
Case Studies from Pharm Tech

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19 August 2008 3
A Short Bit of History
Sir Ronald A. Fisher
Born 1890, England
Died 1962, Australia
Graduated college in 1913, math,
genetics
1919 joined Rothamsted Experimental
Station in Harpenden, England
The right person in the right place.
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Three Controlled Experiments
John S. Mill, System of Logic, 1843
1. Success / Failure
One run, no factors varied, one outcome, yes/no
Easy to design, easy to analyze
Lack of comparison, inefficient
2. OFAT, One-Factor-at-a-Time
We all learned this in school
Several runs, one factor varied, two outcomes
Easy to Design, has comparison of outcomes
Cant find interactions and is inefficient
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Fishers Experiments
Multiple runs, multiple factors varied
Multiple outcomes
Will find interactions
Is much more efficient
Comparison of outcomes

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Key Literature
1926, The Arrangements of Field
Experiments. Journal of the Ministry of
Agriculture of Great Britain. Fisher.
1935, The Design of Experiments,
Oliver & Boyd, London. Fisher.
1951, On the Experimental Attainment
of Optimum Conditions, Box and
Wilson. The original source for QbD !

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Todays Driving Force
FDA / PAT guidance
ICH Q8 Quality by Design
ICH Q8 _ Annex with DOE example
The freedom of Design Space
Ability to change within Design Space
Economics and cost savings
Product / Process Knowledge
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State of the Topic
While there is more to Quality by
Design than DOE, it seems to be the
part that most people have the most
trouble with.
Chemometrics is many times more
complicated than DOE but yet it seems
to be more readily accepted than DOE.

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Show Me an Example
Many people have taken a DOE class at
some time, but still have difficulty in
getting started.
The most common request is for
examples in specific areas.
Examples here show that it is not all
that difficult to get started.
QbD was being done before ICH Q8

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Six Steps to Designing
1. Do your homework
2. Define the measured responses (CQA)
3. Brainstorm factors (CPP)
4. Select 2-7 factors to be treatments
5. Select levels or values for treatments
6. Select a design

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A Short List of Designs
Number of Runs
4 8 8 9 12 16
Number 2 22 3*3, 32
of 3 23-1III 23
Factors 4 24-1IV PB9 24
5 25-2III PB8 PB9 25-1V
6 26-3III PB8 PB9 26-2IV
7 27-4III PB8 PB9 27-3IV
8 PB9 28-4IV
9 PB12
10 PB12
11 19 August 2008 PB12 12
Pharm Tech Yearbook, 1999
Functionality Testing of a Co-processed
Diluent Containing Lactose and
Microcrystalline Cellulose
Gohel, M., et all
Pre-formulation development of
excipients

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Objective
The objective of the present study was
to prepare the directly compressible
adjuvant by using a simpler process
that could be adopted by any
pharmaceutical company.
Product is a tablet

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Treatments
A: Ratio of lactose to MCC
75:25, 85:15
Binding Agent
Dextrin, HPMC
% binding agent
1.0%, 1.5%

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Held Constant
Stirring speed at 35 rpm
Stirring time at 90 minutes

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Agglomerate Responses
Bulk Density, Tapped Density
Angle of Repose, Flow Rate
Hausner ratio
Carrs Index
Friability Index
Moisture uptake

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Statistical Design
Three treatments
Each at two levels
Eight sets of conditions or runs
A 23 full factorial design

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Results
This is a complicated set of data with
many two factor interactions, but it can
be understood by looking at a
geometric presentation of the factors
and the responses for flow rate.
Ratio is on the horizontal, A, axis
Agent is on the vertical, B, axis
Percent is on the third, C, axis

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 Agent
B

HPMC
16.00 16.00

19.00 14.00

Ratio
Dextrin 14.80 18.00 A
75/25% 85/25%

1.0%

15.00 14.60

C Percent
1.5% 19 August 2008 20
Observations for Flow Rate
1. Within these bounds, flow is 14.0 to
19.0 g/s
2. Slowest is 85/15, HPMC, 1.5%.
3. Fastest is 75/25, HPMC, 1.5%
4. Fast is 85/15, Dextrin, 1.0%

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Pharm Tech, November 1999
This is a related example.
An Investigation of the Direct-
Compression Characteristics of Co-
processed Lactose-Microcrystalline
Cellulose Using Statistical Design.
Gohel, M., and Jogami, P.

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Pharm Tech, June, 1993
A bottle packaging example.
The Effect of Rayon Coiler on the
Dissolution of Hard-Shell Gelatin
Capsules.
Hartauer, K.; Bucko, J.; Cooke, G;
Mayer, R.; Schwier, J. and Sullivan, G.

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BioPharm, October 1997
Demonstrating Process Robustness for
Chromatographic Purification of a
Recombinant Protein.
Kelly, B.; Jennings, P.; Wright, R. and
Briasco, C.

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Objective
Control is achieved by setting
operating ranges for manipulated
process variables. Those ranges should
ensure that a process does not fail
within the multidimensional operating
space defined by those limits.
That is, the Design Space !

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Treatments
1. Load Mass 2.4 15.5
2. Load Conductivity 2.5 4.2
3. % Cleavage 63 75
4. Wash pH 9.4 9.6
5. Wash volume 9.7 11.6
6. Elution pH 9.4 9.6
7. Elution conductivity 8.6 14.4
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Responses
1. Recovery %
2. Purity %
3. rhIL-11 mass
4. Product pool volume
5. Elution pool concentration

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Statistical Design
Wash pH / Wash volume confounded
Elution pH / Elution conductivity
confounded
1. Five factors each at two levels
2. 16 runs will still find the two factor
interactions
3. Design is a 25-1 fractional factorial

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A:Elution pH B:Conductivity C:Cleavage D:Load Mass E:Wash pH Recovery % Purity %
-1 -1 -1 -1 1 112.6 96.3
1 -1 -1 -1 -1 90.7 96.9
-1 1 -1 -1 -1 104.9 97.1
1 1 -1 -1 1 72.8 97.3
-1 -1 1 -1 -1 99.6 96.1
1 -1 1 -1 1 84.2 97.1
-1 1 1 -1 1 98.4 97.3
1 1 1 -1 -1 104.2 97.8
-1 -1 -1 1 -1 104.3 91.8
1 -1 -1 1 1 79.0 94.9
-1 1 -1 1 1 94.8 96.6
1 1 -1 1 -1 93.7 96.0
-1 -1 1 1 1 95.5 94.4
1 -1 1 1 -1 88.5 93.9
-1 1 1 1 -1 78.7 96.5
1 1 1 19 August 2008
1 1 58.7 29 98.4
Design Space

Independent Dependent
Factor ? Response
Space Space

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Conceptual Design Space

Operation
Space Opt

Region of Interest

Region of operability
Uncertain space
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Statistical Design Space
The mathematically and statistically
defined combination of Factor Space
and Response Space that results in a
system, product or process that
consistently meets its quality
characteristics, SSQuIP, with a high
degree of assurance. LDT

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Analysis
Analysis is done by fitting a
mathematical model to the factors
(CPP) and the responses (CQA) that
includes the factor main effects and the
significant two factor interactions
The model is then used to find contour
plots for recovery and purity.

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Design-Expert Software Recovery
1.00
Recovery
112.6

58.7
0.50
X1 = A: Elution pH
X2 = B: Conductivity

Actual Factors B: Conductivity

C: Cleavage = -1.00 99.8417 95.4875 91.1333 86.7792
0.00
D: Load Mass = 0.00
E: Wash pH = 0.00

-0.50
104.196

-1.00
-1.00 -0.50 0.00 0.50 1.00

A: Elution pH
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Design-Expert Software Purity
1.00
Purity
98.4 96.6333

91.8
0.50
X1 = A: Elution pH
X2 = B: Conductivity 96.1792

Actual Factors B: Conductivity

C: Cleavage = -1.00
0.00
D: Load Mass = 0.00
E: Wash pH = 0.00 95.725

-0.50 95.2708

94.8167

-1.00
-1.00 -0.50 0.00 0.50 1.00

A: Elution pH
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Design-Expert Software
1.00
Overlay Plot
Overlay Plot

Recovery
Purity
0.50
X1 = A: Elution pH
X2 = B: Conductivity

Actual Factors B : C onductivity

C: Cleavage = -1.00 Recovery: 100 Recovery: 90
0.00
D: Load Mass = 0.00
E: Wash pH = 0.00

-0.50

-1.00
-1.00 -0.50 0.00 0.50 1.00

A: Elution pH
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Pharm Tech, February 1999
Blow-Fill-Seal Technology: Part II,
Design Optimization of a Particulate
Control System.
Price, J.

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Objectives
1. Optimize the particulate control
system
2. Find cause and effect relationships
3. Alter the system settings to improve
performance
4. Find interactions between factors

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Treatments
1. HEPA flow rate % 20 50 80
2. Damper % open 30 55 80
3. Chimney air ft/min 300 550 800
4. HEPA height in 0 0.375
5. Isolation plate Slotted Hole
6. Knife cut Double Single

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Response
Particulate level.
Three measurements at each of the 24
conditions

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Statistical Design
Six factors
Three at two levels
Three at three levels
16 combinations
8 center points
Design is a 26-2 fractional factorial
Design is resolution IV

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Analysis
Analysis of Variance, ANOVA, was used.
15 effects were included
5 were statistically significant
Damper
HEPA height
Knife cur
Isolation plate
HEPA flow * HEPA height OR {damper*knife cut}

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Conclusions
The study met the design objective of
minimizing the particulate levels while
the particulate control system operated
in the dynamic state. a more
thorough understanding of the cause
and effect relationships between the
critical input factors and the particulate
levels was obtained using the DOE.

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Pharm Tech, Analytical
Validation, 1999
Robustness Testing of an HPLC Method
Using Experimental Design.
Peters, P. and Paino, T.

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Objective
This article describes an experimental
design that challenged an analytical
method that assays two components in
a solid dosage drug product.
Confirm the robustness of an HPLC
method.

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Treatments
HPLC system A, B
HPLC column Y, X
Wavelength
A 270, 290
B 215, 235
Flow rate 0.7, 1.3

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Treatments
Injection volume 10, 30
Column temp Ambient, 30
Mobile phase
TFA 85, 75
MeCN 15, 25

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Responses
1. Resolution of component A and B
2. Theoretical plates for A and B
3. Tailing factor for A and B
4. %RSD of the peaks for A and B

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Statistical Design
7 factors each at two levels
Wavelength A and B are confounded
Mobile phase TFA and MeCN are
confounded
8 runs done in triplicate for 24 total
Design is a 27-4 fractional factorial
Design is resolution III.

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Analysis and Results
Visual inspection of an overlay of the 8
chromatograms shows that the method
is robust within the tolerance limits of
the parameters tested. They have
acceptable resolution and peak shape.

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Compare Chromatograms

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Pharm Tech, May 1998
A Systematic Formulation Optimization
Process for a Generic Pharmaceutical
Tablet.
Hwang, R.; Gemoules, M; Ramlose, D.
and Thomasson, C.

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Objective
optimizing an immediate release
tablet formulation for a generic
pharmaceutical product.
Develop a generic tablet with a
disintegration time of 6-12 minutes, 5
minute dissolution of 40-60% and 45
minute dissolution of greater than 90%.

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Treatments
API particle size small large
API % 5% 10%
Lactose MCC ratio 1:3 3:1
MCC particle size small large
MCC density low high

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Treatments
Disintegrant cornstarch, glycolate
Disintegrant % 1% 5%
Talc 0 5%
Mag Sterate 0.5% 1%

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Responses
Blend homogeneity
Compression force %RSD
Ejection force
Tablet weight %RSD
Tablet hardness

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Responses
Tablet friability
Tablet disintegration time
Tablet dissolution at 5 minutes
Tablet dissolution at 45 minutes

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Statistical Design
9 factors each at two levels
16 runs
Design is a 29-5 fractional factorial
Resolution III

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The best formulation:
API 7.14%
Fast-Flo lactose 60.74%
Avicel PH-302 30.37%
Talc 1%
Mag Stearate 0.75%

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Conclusion
The formulation was successfully
scaled up to a 120 kg batch size and
the manufacturability and product
quality were confirmed.
This study has demonstrated the
efficiency and effectiveness of using a
systematic formulation optimization
process
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Pharm Tech, March 1994
Evaluation of a Cartridge and a Bag
Filer System in Fluid-Bed Drying.
Bolyard, K. and McCurdy, V.

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Pharm Tech Europe, April 2000
Response Surface Methodology Applied
to Fluid Bed Granulation.
Wehrle, P. et all

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Pharm Tech
March 1992 and May 1992
A Compaction Study of Directly
Compressible Vitamin Preparations for
the Development of a Chewable Tablet,
Parts I and II.
Konkel, P. and Mielck, B.

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Pharm Tech, March 1994
Computer Assisted Experimental
Design in Pharmaceutical Formulation.
Dobberstein, R. et all.

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Pharm Tech, April 1998
A Unique Application of Extrusion for
the Preparation of Water Soluble
Tablets.
Murphy, M. and Hollenbeck, R.

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Pharm Tech, June 2000
Artificial Neural Network and Simplex
Optimization for Mixing of Aqueous
Coated Beads to Obtain Controlled
Release Formulations.
Vaithiyalingam, S. et all.

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Summary
Looked at 13 Case studies
Shown 3 types of analysis
Shown several areas of application
Illustrated how to get started
Shown that Q8 QbD has a precedent
DOE has been used for a long time

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Acknowledgements
The University of Adelaide Library is the
owner of the image of Sir R. A. Fisher.
Pharmaceutical Technology holds the
copyright for the journal articles used in
this presentation.
Opinions in this presentation are that of
Lynn Torbeck alone.

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