QUALITY BY DESIGN
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Mumbai, India
Date: May 2008
Slide 1 May 2008
QUALITY BY DESIGN
Dr Tom Sam
President
Industrial Pharmacy Section
International Pharmaceutical
Federation (FIP)
Slide 2 May 2008
QUALITY BY DESIGN
products
processes
Slide 3 May 2008
What is Quality?
Quality
Requirements
= need or
expectations
Target Product
Quality Profile
Patient
(or surrogate)
“Good pharmaceutical quality represents
an acceptably low risk of failing to achieve
the desired clinical attributes.”
Slide 4 May 2008
Which quality do we want
for our medicines ? 6σ
DPMO
1000000
Restaurant bills
(defectsper 100000
million
opportunities) 10000
Airlines baggagecheck in
1000
100
Egypt Air (5,8)
Air India(5,8)
Lufthansa (6,6)
10
1
0,1
Best-in-class
Quantas, SAS
0,01
2σ
3σ
4σ
5σ
6σ
7σ
Source: Motorola, Air Safety Online
Quelle: Motorola, Air SafetyOnline
Slide 5 May 2008
With which quality do we manufacture our
medicines: 6σ, 5σ, 4σ, 3σ, 2σ ?
DPMO
1000000
Restaurant bills
(defectsper 100000
million
opportunities) 10000
Airlines baggagecheck in
1000
100
Egypt Air (5,8)
Air India(5,8)
Lufthansa (6,6)
10
1
0,1
Best-in-class
Quantas, SAS
0,01
2σ
3σ
4σ
5σ
6σ
7σ
Source: Motorola, Air Safety Online
Quelle: Motorola, Air SafetyOnline
Slide 6 May 2008
How do we fill this quality gap
in the pharmaceutical industry?
Sigma ppm Defects
Current Mfg
Quality provided
to patients
2
3
4
5
6
308,537
66,807
6,210
233
3.4
Yield
69.2%
93.3%
99.4%
99.98%
99.99966%
Cost of Quality
25-35%
20-25%
12-18%
4-8%
1-3%
……by testing !!!!
Data from: Dr. Doug Dean & Frances Bruttin
PriceWaterhouseCoopers
Slide 7 May 2008
The quality mantra
“Quality can not be tested into
products; it has to be built in
by design”
Slide 8 May 2008
How can we modernize our industry?
 More knowledge of our products and processes,
allowing better design and more control
 Better management:
- introduction of quality risk management
- expansion of GMP to more extensive
pharmaceutical quality system
Slide 9 May 2008
Dr Ajaz Hussain
‘Pharmaceutical GMPs
for the 21st Century’
Slide 10 May 2008
Slide 11 May 2008
Knowledge based decisions
Need for regulatory oversight
The knowledge pyramid
First
Principles
Why?
MECHANISTIC
KNOWLEDGE
How?
Desired State
“CAUSAL" KNOWLEDGE
What “Causes” What?
CORRELATIVE KNOWLEDGE
What Is Correlated to What?
DESCRIPTIVE KNOWLEDGE:
What?
Current State
The New Quality Paradigm –
The Evolving Regulatory Framework
Product Life Cycle
Product
Design
Process
Design
Scale-up &
Transfer
Commercial
Manufacture
ICH Q8/Q8(R) - Pharmaceutical Development
PAT Guidance
ICH Q9 – Quality Risk Management
ICH Q10 – Pharmaceutical Quality Systems
Slide 12 May 2008
Product
Slide 13 May 2008
Definition: Quality by Design
Quality by Design is
 a systematic approach to
development
 that begins with predefined
objectives
 and emphasizes
- product and process
understanding
- and process control,
 based on sound science and
quality risk management.
Slide 14 May 2008
EMEA/CHMP/ICH/518819/2007
Quality by Design approach
can be used for
 Active
pharmaceutical
ingredients
 Materials incl
excipients
 Analytics
Slide 15 May 2008
 Simple dosage
forms
 Advanced drug
delivery systems
 Devices
 Combination
products (e.g.
theranostics)
Impact of QbD
 Companies re-organize their science
 Universities change their curriculum
 Health authorities change their assessment and
inspection
Slide 16 May 2008
QUALITY BY DESIGN
Step 1. Agree on the Target Product Profile
Step 2. Determine the Critical Quality Attributes (CQAs)
Step 3. Link the drug and excipient attributes and the
process parameters to the CQAs
Step 5. Define the Control Strategy
Step 6. Prepare QbD registration file
Step 7. Product lifecycle management and
continual improvement
Slide 17 May 2008
EMEA/CHMP/ICH/518819/2007
Step 4. Define the Design Space
What are the steps in a
Quality by Design approach?
2. CRITICAL
QUALITY
ATTRIBUTES
3. LINK
MAs AND PPs
TO CQAS
1. TARGET
PRODUCT
PROFILE
4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT
Slide 18 May 2008
5. ESTABLISH
CONTROL
STRATEGY
Step 1.
Agree on the Target Product Profile
Target Product Profile:
- a prospective and dynamic
summary of the quality
characteristics of a drug
product
- that ideally will be achieved to
ensure that the desired
quality, and hence the
safety and efficacy, of a drug
product is realised.
The TPP forms the basis of design
of the product.
Slide 19 May 2008
Consider:
 dosage form
 route of administration
 strength
 release / delivery of the drug
 pharmacokinetic characteristics
(e.g., dissolution; aerodynamic
performance)
 drug product quality criteria
(e.g., sterility, purity).
TPP for paediatric dosage form
TPP adult
Slide 20 May 2008
TPP paediatric (may
depend upon age group)
What are the steps in a
Quality by Design approach?
2. CRITICAL
QUALITY
ATTRIBUTES
3. LINK
MAs AND PPs
TO CQAS
1. TARGET
PRODUCT
PROFILE
4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT
Slide 21 May 2008
5. ESTABLISH
CONTROL
STRATEGY
CRITICAL QUALITY ATTRIBUTES
- definition
A critical quality attribute (CQA) is a
- physical, chemical, biological, or
microbiological property or characteristic
- that should be within an appropriate
limit, range, or distribution
- to ensure the desired product quality.
EMEA/CHMP/ICH/518819/2007
Slide 22 May 2008
Step 2. Determine the Critical Quality
Attributes (CQAs)
Drug product CQAs are used to guide the
product and process development.
 solid oral dosage
forms:
 typically those
aspects affecting
- product purity
- product potency
- product stability
- drug release.
Slide 23 May 2008
 other delivery systems:
 can additionally include
more product specific
aspects, such as
- aerodynamic
properties for inhaled
products
- sterility for parenterals,
- adhesive force for
transdermal patches.
Product-centric
Quality by Design
Excipient
Quality
Attributes
DRUG
PRODUCT
Formulation
Parameters
Chemical purity
Physical form
API
Purity
Raw Material quality
Formulation
Process Related
Particle size
API
Quality Attributes
Mechanical
Properties
Excipient
Compatibility
Slide 24 May 2008
What are the steps in a
Quality by Design approach?
2. CRITICAL
QUALITY
ATTRIBUTES
3. LINK
MAs AND PPs
TO CQAS
1. TARGET
PRODUCT
PROFILE
4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT
Slide 25 May 2008
5. ESTABLISH
CONTROL
STRATEGY
Step 3. Link the drug and excipient attributes
and the process parameters to the CQAs
I Chart
115
UCL=111.55
Individual Value
110
105
_
X=99.63
100
95
90
LCL=87.71
60
62
64
66
68
70
72
Observation
74
76
78
80
People
I Chart
115
UCL=112.65
Inputs to the process
control variability
of the Output
110
Individual Value
105
100
_
X=97.94
95
90
85
LCL=83.23
80
40
44
46
48
50
52
Observation
54
56
58
60
Equipment
I Chart
115
UCL=112.65
110
Individual Value
105
100
_
X=97.94
95
90
85
LCL=83.23
y = ƒ(x)
I Chart
80
40
42
44
46
48
50
52
Observation
54
56
58
60
115
Measurement
UCL=116.68
Individual Value
115
110
105
_
X=102.37
100
95
UCL=114.17
110
y
Individual Value
I Chart
120
105
_
X=99.95
100
95
90
LCL=88.05
20
22
24
26
28
30
32
Observation
34
36
38
40
90
Process
LCL=85.72
85
1
I Chart
115
11
21
31
41
51
61
Observation
71
81
91
UCL=111.55
110
Individual Value
I
N
P
U
T
S
(X)
42
105
_
X=99.63
100
95
90
OUTPUT
LCL=87.71
60
62
64
66
68
70
72
Observation
74
76
78
80
Materials
I Chart
UCL=111.17
110
Individual Value
105
_
X=98.76
100
95
90
LCL=86.35
85
80
82
84
86
88
90
92
Observation
94
96
98
100
Environment
Slide 26 May 2008
Source: Moheb Nasr, FDA
Mapping the Linkage
Inputs:
Outputs:
CQA1
M2
Material Attributes
Critical
CQA2 Quality
Attributes
CQA3
P1
P2
P3
Process
Parameters
Relationships:
CQA1 = function (M1)
CQA2 = function (P1, P3)
CQA3 = function (M1, M2, P1)
P2 might not be needed in the
establishment of design space
Slide 27 May 2008
Source: Moheb Nasr, FDA
M1
Experimental Approach for Identifying
Parameters
Design of Experiments (DOE) is an efficient method to determine
relevant parameters and interactions
2. Conduct randomized experiments
1. Choose experimental design
(e.g., full factorial, d-optimal)
3. Analyze Data
Determine significant factors
Slide 28 May 2008
Experiment
Factor A
Factor B
Factor C
1
+
-
-
2
-
+
-
3
+
+
+
4
+
-
+
ICH Q9 Quality Risk Management
Initiate Quality Risk
Management Process
Formal
Risk Management
Process
1. Risk
2.
Risk
Assessment
Control
Output / Result of the Quality
Risk Management Process
4.
Slide 29 May 2008
Risk Review
What are the steps in a
Quality by Design approach?
2. CRITICAL
QUALITY
ATTRIBUTES
3. LINK
MAs AND PPs
TO CQAS
1. TARGET
PRODUCT
PROFILE
4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT
Slide 30 May 2008
5. ESTABLISH
CONTROL
STRATEGY
Step 4. Define the Design Space
 The linkage between
- the process inputs (input variables and process
parameters) and
- the critical quality attributes
 can be described in the design space.
Slide 31 May 2008
Definition of Design Space
 The multidimensional combination
and interaction of input variables
(e.g. material attributes) and
process parameters that have been
demonstrated to provide assurance
of quality.
Roll pressure
 The material attributes and process parameters that
assure quality.
Gap width
Screen Size
Dataset - Run1-10a.M3
Observed vs. Predicted $Time [Last comp.] (Aligned)
300
200
100
0
-100
0
10
20
30
40
50
60
70
80
90
100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260
$Time (normalized)
SIMCA-P+ 11.5 - 05/02/2007 23:17:07
Slide 32 May 2008
What are the steps in a
Quality by Design approach?
2. CRITICAL
QUALITY
ATTRIBUTES
3. LINK
MAs AND PPs
TO CQAS
1. TARGET
PRODUCT
PROFILE
4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT
Slide 33 May 2008
5. ESTABLISH
CONTROL
STRATEGY
1a
Response surface plot of in-vitro release
as a function of two critical parameters
of the mixing and lamination process.
Slide 34 May 2008
Contour plot of
in-vitro release
EMEA/CHMP/ICH/518819/2007
Design Space
Design Space
Design Space
Knowledge
Space
Control Space
Slide 35 May 2008
Step 5. Define the Control Strategy
The control strategy should describe and justify how
 in-process controls and
 the controls of
- input materials
(drug substance and excipients),
- container closure system,
- intermediates and
 the controls of end products
contribute to the final product quality
Slide 36 May 2008
5. CONTROL STRATEGY
Elements of a control strategy can include, but are not limited to, the
following:
• Control of input material attributes (e.g., drug substance, adhesive
polymer, primary packaging materials) based on an understanding
of their impact on processability or product quality
• Product specification(s)
• Controls for unit operations that have an impact on downstream
processing or end-product quality (e.g., the impact of solvent on
degradation)
• In-process or real-time release in lieu of end-product testing
• A monitoring program (e.g., full product testing at regular intervals)
for verifying multivariate prediction models.
Slide 37 May 2008
What are the steps in a
Quality by Design approach?
2. CRITICAL
QUALITY
ATTRIBUTES
3. LINK
MAs AND PPs
TO CQAS
1. TARGET
PRODUCT
PROFILE
4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT
Slide 38 May 2008
5. ESTABLISH
CONTROL
STRATEGY
Step 7. Product lifecycle management
continual improvement
Minimal Approach
• Reactive
(i.e., problem solving
and corrective action)
Slide 39 May 2008
QbD
Approach
• Preventive
action
• Continual improvement
facilitated
Better processes will lead to products
with less variability
Now (GMP)
Variable
Input
Fixed
Process
Variable
Output
Drug
Product
PAT/QbD
Variable
Input
Slide 40 May 2008
Adapted
Process
Consistent
Output
The Revolution in Quality Thinking
Quality by Testing
and Inspection
Enhanced
• product knowledge
• process understanding
Quality by Design
quality assured by well designed product & process
Slide 41 May 2008