ISPE CCChQualityDesignSixSigmaAlliesPharmaDevPres

Quality by Design & Design For Six Sigma:
Allies in Pharmaceutical Development

ISPE Breakfast Seminar
Toronto: May 12, 2009
Montreal: May 13, 2009
Presented by: Murray Adams

Contact: murray.adams@rogers.com
1-905-796-8514
Operational Excellence Consulting Ltd.
Guidance Documents
ICH and FDA have published several guidance documents

on pharmaceutical development and validation
ICH Q8, Q8(R1), Q9, Q10
FDA Process Validation: General Principles and Practices
Common theme of systematic, science based approach to

obtaining enhanced process knowledge and managing risk
Focus for today: Q8(R1) Pharmaceutical Development
Quality by Design (QbD)
QbD alignment with Design For Six Sigma (DFSS) principles

Copyright Operational Excellence Consulting Ltd. 2009
QbD Key Concepts and Principles
Quality cannot be tested into products it must be built in
Enhanced scientific knowledge of products and processes

in development can be used to assure product quality
Critical Quality Attributes (CQA) and factors which affect

them must be well understood and controlled
Drug substance
Excipients
Intermediates
Drug product
QbD Key Concepts and Principles (Contd)
Risk assessment should be used throughout development

to guide and justify development decisions
Material and process parameters must be linked to CQAs

of the finished product
Design space used to define the acceptable limits for

operational parameters to assure the product quality
Control strategies implemented to manage risk

QbD and DFSS Alignment
Ensure quality on the basis of detailed process knowledge
Understanding the relationships between product/process

inputs and outputs
Design of Experiments (DoE) and/or historical regression analysis
Modeling designs produce prediction equations / transfer functions
Transfer functions can then be used to perform:
Expected Value Analysis (EVA a.k.a. Monte Carlo Simulation)
Robust design
Tolerance allocation studies (setting appropriate specifications)

Whats DoE ?
Purposefully changing settings of process inputs (Xs) in order to

observe the effect on process outputs (Ys or CQAs).
Changing multiple inputs to produce an equation which describes

the relationships between inputs, outputs and interactions
Transfer Functions
Inputs
X1
Outputs
e.g. Materials
Y1 = f1 (X1, X2, X3)
X2
X3
e.g. Parameters
e.g. Environmental
Y1
Process
Y2 = f2 (X1, X2, X3)
Y2
DOE Terminology
Inputs, Factors, Xs variables which if changed or

uncontrolled will affect one or more responses
Outputs, Responses, Ys metrics of interest (quality,

performance, cycle time, cost) which are affected by inputs
Interactions combination effect when the effect of one

factor depends upon the setting of another factor
Levels the number of settings evaluated for each factor
Experimental Run a trial conducted using a carefully

chosen combination of settings for each factor
Finding the Critical Few
Before conducting experiments we must identify the most

important factors affecting our process
Find the critical few among the trivial many
Prior knowledge, literature search, experience
Map the process at a relatively high level (8 12 steps)
Cause and Effect Analysis (a.k.a. Fishbone / Ishikawa diagram)
Risk assessment Failure Mode and Effects Analysis (FMEA)
Identify risk areas with materials and process parameters
Which factors and parameters must be controlled?

Cause & Effect Example

Method
Measurement
Machine
(X) Pre-compression
(X) Blend Time
(X) Main Compression
(C) Test method

(X) Lubrication Time
(C) SOP / PBR
(X) Compression Speed

(C) Punch Size / Shape
Dissolution
Rate
(C) Avicel Grade
(N) Relative Humidity
(N) Experience
(X) Mg Stearate Mesh
(C) Temperture
(C) Training
(X) API PSD
Manpower
Materials
C = Constant
N = Noise
X = Experimental
Factor
Environment
FMEA Example
1. Steps / Components
Product
Function /
or
Purpose
Process
Failure Mode
Failure Effects
S
E
V
Causes
Controls
D
E
T
R
P
N
Actions
6. List all causes

leading to failure
2. Whats the
intended function
or purpose?
Plans
P
S
P
O
P
D
p
r
p
n
10. Calculate RPN =

Sev * Occ * Det
7. Probability
of occurrence?
(1 to 5)
3. How could it
fail to do this?
4. What are the
consequences?
5. How bad
is it? (1 to 5)
O
C
C
8. What controls
are in place today?
9. Probability of
escaped detection
(1 to 5)
Calculate RPN, prioritize, assign corrective actions, calculate PRPN

FMEA Examples
Formulation Components
Formulation
Function
Component
Failure Mode
Failure Effects
S
E
V
Drug
Substance
Active
Poor bioavailability Reduced effectiveness
Ingredient too little release
Magnesium
Stearate
Lubricant Over lubricated
Poor bioavailability
(reduced effectiveness)
Under lubricated
Causes
O
C
C
Controls
Incorrect Particle
PSD Spec & test
3
Size Distribution
method
Wrong mesh
size - too small
5 Content too high
2 Content too low
D
E
T
R
P
N
- MSA on test method

60 - Confirm PSD spec
appropriate
Actions
- Spec
10 - Confirm spec
1
1
- Spec
- Spec
1
1
5
2
Causes
O
C
C
Poor bioavailability
Blended too
4
(reduced effectiveness)
much
Tablet picking
Plans
Fred,
May 25
- None
- None
Process Steps
Process
Step
Lubrication
Blending
Purpose
Lubricate
granules
Failure Mode
Over lubricated
Failure Effects
Under lubricated Picking
S
E
V
Controls
D
E
T
R
P
N
- Spec
- Timer on blender
24 - Confirm spec
12 - Confirm spec
2 Blended too little 2
Actions
Plans
10
Data Collection
The knowledge gained in a DoE is only as good as the data

we collect for the analysis.
Measurement System Analysis (MSA)
How big is the measurement error?
Accuracy, repeatability, reproducibility, P/Tol, P/Tot
Sampling plan
What kind of data are we collecting (continuous or discrete)?
How big a sample do we need?
Is the sample representative?
How are we going to collect the samples? (random, intervals, other)?
Is everyone collecting the samples in the same way?
What about PATs? (Process Analytical Technologies)

11
Snapshots vs. a Movie
Conventional analytical testing provides snapshots of quality attributes

at various points in time
Traditionally we test the finished product at the end of the process
Beginning
Middle
End
PATs can provide real time, or near real time, sequence of pictures
showing the evolution of the process
Allows continuous, real time quality assurance
Beginning Continuous Monitoring

End
12
Which process is yours?

Textbook
380
Sensor 1
360
Sensor 3
340
2
320
1/2
(Ws /m K)
Thermal Effusivity
400
300
Sensor 4
How much do we really know about

whats going on inside the blender?
280
260
240
220
200
0
12
15
18
21
24
27
30
Variable
Blend Time (minutes)
Thermal Effusivity vs Blend Time

410
5.0%
4.5%
400
Effusivity
390
*Tables, graphs and data reproduced

with permission from Patheon Inc. and
Mathis Instruments
3.5%
3.0%
380
2.5%
370
2.0%
1.5%
360
1.0%
350
0.5%
340
0.0%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Time (Minutes)
%RSD
Sensor B23
Sensor B18
Sensor B25
Mean
Overall Mean
13
%RSD (Across Sensors)
4.0%
Types of DoE Designs

Screening Designs
Modeling Designs
Typically 6 11 factors
Typically 2 5 factors
Many factors in few runs
Narrow the focus
Prediction equation
(Transfer function)
2 or 3 levels
Optimization, robust design,

tolerance allocation
2 or 3 levels
Examples
Examples
Taguchi L12 (or PB12)
Full / Fractional Factorial
Taguchi L18 (3 levels)
Central Composite Design
PB 20
Box Behnken
Fractional Factorials
14
L12 Design Matrix

Factor
B
Blend
Time
(Min)
Row #
1
2
3
4
5
6
7
8
9
10
11
12
5
5
5
5
5
5
15
15
15
15
15
15
Lubrication
Time (Min)
2
2
2
5
5
5
2
2
2
5
5
5
D
E
F
G
Mg
Pre-comp
Main Comp
Press
Stearate API PSD Force
Force (KN)
Speed
Mesh
(KN)
-1
2
5
30
2000
-1
2
5
40
5000
1
5
10
30
2000
-1
5
10
30
5000
1
2
10
40
2000
1
5
5
40
5000
1
5
5
30
5000
1
2
10
40
5000
-1
5
10
40
2000
1
2
5
30
2000
-1
5
5
40
2000
-1
2
10
30
5000
Dissolution
Y1
Y2
Y3
----
Y12
Y bar
Random Order = 4 ,11 ,5 ,1 ,3 ,2 ,9 ,7 ,12 ,6 ,8 ,10
Identify factors affecting response(s) average, variation, both or neither
Check up to 11 factors in 12 runs
High level information on main effects only
No information on interactions
Possible to monitor multiple responses

15
23 Full Factorial Example

Factor
A
API PSD
(d50)
Row #
1
2
3
4
5
6
7
8
B
Blend
Time
2
2
2
2
5
5
5
5
Dissolution
C
Main Comp
Force (KN)
10
10
15
15
10
10
15
15
Y1
Y2
Y3
.- - - -
Y12
Y bar S
30
40
30
40
30
40
30
40
Random Order = 7 ,4 ,3 ,2 ,5 ,8 ,1 ,6
Full Factorial designs produce prediction equation / transfer function

describing relationship between factors and the response(s)
Main effects of 3 factors, all 2 way interactions, 3 way interaction
Process optimization
Multiple response optimization

16
Transfer Functions
(a.k.a. Prediction Equations)
The transfer function is a equation which mathematically describes

the relationship between the process inputs and outputs
This empirical model is extremely valuable knowledge
Process optimization
Robust design
What if scenarios
Setting specifications
2 level designs
Y = b0 + b1X1 + b2X2 + b3X1X2
3 level designs
Y = b0 + b1X1 + b2X2 + b3X1X2 + b4X12+ b5X22
17
Design Space
Definition of Design Space according to ICH Q8:
The multidimensional combination and interaction of input variables

that have been demonstrated to provide assurance of quality.
Translation what combination(s) of input settings will meet the

specifications for the output(s)?
Multiple response optimization determines the optimum set of

conditions to meet specs of 2 or more outputs simultaneously
Weighting the outputs provides opportunity to allow for relative

importance in trade-off situations
18
Design Space Example
Consider two Outputs e.g. dissolution (Y1) and dosage uniformity (Y2)
There may be two inputs (X1 and X2) which are important to both outputs
Which combinations of X1 and X2 are acceptable?

Y 1 = dissolution
In spec
Y 2 = dosage uniformity
5.0
5.0
4.8
4.8
4.6
4.6
4.3
4.3
4.1
4.1
3.9
3.9
3.7
3.7
3.4
3.4
3.2
3.0
2.8
3.2
X2
3.0
2.8
2.6
2.6
2.3
2.3
2.1
2.1
1.9
1.9
1.7
1.7
1.4
1.4
1.2
1.2
1.0
20 23 26 28 31 34 37 39 42 45 48 51 53 56 59 62 64 67 70
Out of Spec
X2
1.0
20 23 26 28 31 34 37 39 42 45 48 51 53 56 59 62 64 67 70
X1
X1
19
Design Space Example (Contd)
Which combination(s) of X1 and X2 will meet both the dissolution

and dosage uniformity specifications?
Y 2 = dosage uniformity
Y 1 = dissolution
X2
X1
X2
X1
20
Expected Value Analysis

(a.k.a. Monte Carlo Simulation)
Unfortunately many inputs are not constants!
EVA applies the distribution of inputs to the transfer functions to

predict output distribution
X1
Y1 = b0 + b1X1 + b2X2 + b3X1X2
X2
X3
Y1
Process
Y2 = b7 + b4X1 + b5X2 + b6X1
Y2
21
Robust Design Studies
Helps to identify conditions which make the process tolerant of variation

of certain inputs which are difficult or costly to control
Process
Process
X
3
Initial settings produce outputs which are sometimes out of spec

Shifting input average settings may achieve the same average
response but reduce the output variation even though the variation of
the inputs remains the same
22
Tolerance Allocation
Determines the affect of input variation on the response.
How much would the process improve if we tightened the input spec?
Process
Process
X
3
Intuitively,
we think tightening input specs will improve the process, but..
Do all inputs have the same amount of influence?
Tighter specs often cost more money, so lets choose the best option
We might find that its possible to relax some specs with no ill effects!
23
Control Strategies
SOPs, PBRs, training programs help to ensure consistency
Policies, process limits, RM specs, testing, facilities, maintenance etc.
FMEA living document updated throughout product life cycle
Investigate problems and implement corrective actions
Effective transfer of process knowledge from development to

production (Tech Transfer)
Process Qualification confirm design is functional as predicted
Before commercial distribution begins, a manufacturer is expected to

have accumulated enough data and knowledge about the commercial
1.
production process to support post-approval distribution.
(1. Joseph C. Famulare; Deputy Director, Office of Compliance FDA/CDER)

24
Control Strategies (Contd)
Extensive testing (at least initially) to increase data base of

knowledge
Control charts alert us to abnormal conditions and trends
PATs can be used to monitor and control some critical process

steps in real time
On-going monitoring provides opportunity for process

improvement as more data is accumulated
Historical regression analysis
Annual product reviews
Change Control ensure data available to support modifications

25
Some Benefits of QbD & DFSS
Assures the quality of product and reliable delivery of its intended

performance
Identifies critical controls and potential areas of risk early in the

product life cycle (development)
reduces / eliminates need for significant post approval changes

minimizes cost of change
Helps to ensure efficient use of resources; both before and after

product launch
Enhanced product/process understanding provides opportunities

for more flexible regulatory approaches
risk-based regulatory decisions (reviews and inspections)

ease of process improvement within the approved design space
real-time QC / reduced end-product release testing
26
Q&A
Presented by: Murray Adams
Operational Excellence Consulting Ltd.
Email: murray.adams@rogers.com
Bus. Tel: 1-905-796-8514
27

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Quality by Design & Design For Six Sigma:

Allies in Pharmaceutical Development

Presented by: Murray Adams

Operational Excellence Consulting Ltd.

ICH and FDA have published several guidance documents

ICH Q8, Q8(R1), Q9, Q10

FDA Process Validation: General Principles and Practices

Common theme of systematic, science based approach to

Focus for today: Q8(R1) Pharmaceutical Development

Quality by Design (QbD)

QbD alignment with Design For Six Sigma (DFSS) principles

QbD Key Concepts and Principles

Quality cannot be tested into products it must be built in

Enhanced scientific knowledge of products and processes

Critical Quality Attributes (CQA) and factors which affect

Copyright Operational Excellence Consulting Ltd. 2009

QbD Key Concepts and Principles (Contd)

Risk assessment should be used throughout development

Material and process parameters must be linked to CQAs

Design space used to define the acceptable limits for

Control strategies implemented to manage risk

QbD and DFSS Alignment

Ensure quality on the basis of detailed process knowledge

Understanding the relationships between product/process

Design of Experiments (DoE) and/or historical regression analysis

Modeling designs produce prediction equations / transfer functions

Transfer functions can then be used to perform:

Expected Value Analysis (EVA a.k.a. Monte Carlo Simulation)

Tolerance allocation studies (setting appropriate specifications)

Purposefully changing settings of process inputs (Xs) in order to

Changing multiple inputs to produce an equation which describes

Y2 = f2 (X1, X2, X3)

Inputs, Factors, Xs variables which if changed or

Outputs, Responses, Ys metrics of interest (quality,

Interactions combination effect when the effect of one

Levels the number of settings evaluated for each factor

Experimental Run a trial conducted using a carefully

Finding the Critical Few

Before conducting experiments we must identify the most

Find the critical few among the trivial many

Prior knowledge, literature search, experience

Map the process at a relatively high level (8 12 steps)

Cause and Effect Analysis (a.k.a. Fishbone / Ishikawa diagram)

Risk assessment Failure Mode and Effects Analysis (FMEA)

Identify risk areas with materials and process parameters

Which factors and parameters must be controlled?

Cause & Effect Example

(X) Blend Time

(X) Main Compression

(C) Test method

(X) Compression Speed

(C) Avicel Grade

(N) Relative Humidity

Copyright Operational Excellence Consulting Ltd. 2009

6. List all causes

10. Calculate RPN =

Calculate RPN, prioritize, assign corrective actions, calculate PRPN

Lubricant Over lubricated

- MSA on test method

Under lubricated Picking

2 Blended too little 2

Copyright Operational Excellence Consulting Ltd. 2009

The knowledge gained in a DoE is only as good as the data