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
Target Product
= need or
Quality Profile
expectations

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 Airlines baggagecheck in
10000
opportunities)
1000

100 EgyptAir (5,8)

10 Air India(5,8)
Lufthansa (6,6)
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 Airlines baggagecheck in
opportunities)
10000
M fg
en t
ur r
C1000
100 EgyptAir (5,8)
10 Air India(5,8)
Lufthansa (6,6)
1 id ed
p ro v s
0,1 a lity tientBest-in-class
Q u o pa Quantas, SAS
0,01 t

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 Yield Cost of Quality
2 308,537 69.2% 25-35%
Current Mfg
3 66,807 93.3% 20-25%
4 6,210 99.4% 12-18%
Quality provided 5 233 99.98% 4-8%
to patients
6 3.4 99.99966% 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

 The knowledge pyramid
First
Principles
Knowledge based decisions Why?

MECHANISTIC
Desired State
Need for regulatory oversight

KNOWLEDGE
How?

“CAUSAL" KNOWLEDGE
What “Causes” What?

CORRELATIVE KNOWLEDGE Current State

What Is Correlated to What?

DESCRIPTIVE KNOWLEDGE:
What?

Slide 11 May 2008

 The New Quality Paradigm –
The Evolving Regulatory Framework
Product Life Cycle

Product Process Scale-up & Commercial

Design Design Transfer Manufacture Product

ICH Q8/Q8(R) - Pharmaceutical Development

PAT Guidance

ICH Q9 – Quality Risk Management

ICH Q10 – Pharmaceutical Quality Systems

Slide 12 May 2008

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.

EMEA/CHMP/ICH/518819/2007
Slide 14 May 2008
 Quality by Design approach
can be used for
 Simple dosage forms
 Active
pharmaceutical  Advanced drug
ingredients delivery systems
 Materials incl  Devices
excipients
 Combination
 Analytics products (e.g.
theranostics)

Slide 15 May 2008

 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 4. Define the Design Space

EMEA/CHMP/ICH/518819/2007
Step 5. Define the Control Strategy

Step 6. Prepare QbD registration file

Step 7. Product lifecycle management and

continual improvement

Slide 17 May 2008

 What are the steps in a
Quality by Design approach?
2. CRITICAL 3. LINK
QUALITY MAs AND PPs
ATTRIBUTES TO CQAS

1. TARGET 4. ESTABLISH
PRODUCT DESIGN
PROFILE SPACE

6. PRODUCT 5. ESTABLISH
LIFECYCLE CONTROL
MNGMNT STRATEGY

Slide 18 May 2008

 Step 1.
Agree on the Target Product Profile
Consider:
Target Product Profile:
- a prospective and dynamic  dosage form
summary of the quality
characteristics of a drug  route of administration
product
 strength
- that ideally will be achieved to
ensure that the desired  release / delivery of the drug
quality, and hence the
safety and efficacy, of a drug  pharmacokinetic characteristics
product is realised. (e.g., dissolution; aerodynamic
performance)
The TPP forms the basis of design
of the product.  drug product quality criteria
(e.g., sterility, purity).

Slide 19 May 2008

 TPP for paediatric dosage form

TPP adult TPP paediatric (may

depend upon age group)

Slide 20 May 2008

 What are the steps in a
Quality by Design approach?
2. CRITICAL 3. LINK
QUALITY MAs AND PPs
ATTRIBUTES TO CQAS

1. TARGET 4. ESTABLISH
PRODUCT DESIGN
PROFILE SPACE

6. PRODUCT 5. ESTABLISH
LIFECYCLE CONTROL
MNGMNT STRATEGY

Slide 21 May 2008

 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:  other delivery systems:

 typically those aspects  can additionally include

affecting more product specific
- product purity aspects, such as
- product potency - aerodynamic
- product stability properties for inhaled
- drug release. products
- sterility for parenterals,
- adhesive force for
transdermal patches.

Slide 23 May 2008

 Product-centric
Quality by Design

Excipient Chemical purity

Quality
Physical form
Attributes
API Raw Material quality
Purity

DRUG API
PRODUCT Quality Attributes

Formulation Particle size

Process Related Mechanical
Formulation
Properties
Parameters
Excipient
Compatibility

Slide 24 May 2008

 What are the steps in a
Quality by Design approach?
2. CRITICAL 3. LINK
QUALITY MAs AND PPs
ATTRIBUTES TO CQAS

1. TARGET 4. ESTABLISH
PRODUCT DESIGN
PROFILE SPACE

6. PRODUCT 5. ESTABLISH
LIFECYCLE CONTROL
MNGMNT STRATEGY

Slide 25 May 2008

Step 3. Link the drug and excipient attributes
and the process parameters to the CQAs
I Chart

s
115

UCL=111.55

e
110

Individual Value
105

u
_
100 X=99.63

s
95

s ib
90
LCL=87.71

r
60 62 64 66 68 70 72 74 76 78 80

e rs t
Observation

c At Inputs to the process

People

Pro mete
I Chart

y
115

t
UCL=112.65
110

li
105

Individual Value
100 _

a
X=97.94

ra
95

control variability
90

a u
85
LCL=83.23
80

Q
40 42 44 46 48 50 52 54 56 58 60

P
Observation

I Equipment
115
I Chart
of the Output
y = ƒ(x)
UCL=112.65

N
110

105
Individual Value

100 _
X=97.94
95

90

I Chart

P
85
LCL=83.23
80
40 42 44 46 48 50 52 54 56 58 60
Observation 115
UCL=114.17

Measurement 110

U
y
I Chart
105

Individual Value
120

UCL=116.68
115

T
110
100 X=99.95
Individual Value

105
_
X=102.37
100

95 95
90
LCL=88.05

S
20 22 24 26 28 30 32 34 36 38 40
Observation
90

Process 85
LCL=85.72

(X)
I Chart
1 11 21 31 41 51 61 71 81 91
115 Observation
UCL=111.55
110

OUTPUT
Individual Value

105

_
100 X=99.63

95

90
LCL=87.71

60 62 64 66 68 70 72 74 76 78 80
Observation

Materials
I Chart

UCL=111.17
110

105
Individual Value

100 _
X=98.76

95

90

LCL=86.35
85
80 82 84 86 88 90 92 94 96 98 100
Observation

Environment Source: Moheb Nasr, FDA

Slide 26 May 2008

 Mapping the Linkage
Inputs: Outputs:
M1 CQA1
Critical
M2 CQA2 Quality
Material Attributes Attributes

Source: Moheb Nasr, FDA

CQA3
P1

P2 Relationships:
CQA1 = function (M1)
P3 CQA2 = function (P1, P3)
Process CQA3 = function (M1, M2, P1)
Parameters
P2 might not be needed in the
establishment of design space
Slide 27 May 2008
 Experimental Approach for Identifying
Parameters
Design of Experiments (DOE) is an efficient method to determine
relevant parameters and interactions
1. Choose experimental design 2. Conduct randomized experiments
Factor C Factor B Factor A Experiment

(e.g., full factorial, d-optimal) - - + 1

- + - 2

+ + + 3

+ - + 4

3. Analyze Data
Determine significant
factors

Slide 28 May 2008

 ICH Q9 Quality Risk Management

Initiate Quality Risk

Management Process

ge
Formal 1. Risk
ua
Assessment
Risk Management
ng
Process
w la
ne
h e 2. Risk Control

T
Output / Result of the Quality
Risk Management Process

4. Risk Review

Slide 29 May 2008

 What are the steps in a
Quality by Design approach?
2. CRITICAL 3. LINK
QUALITY MAs AND PPs
ATTRIBUTES TO CQAS

1. TARGET 4. ESTABLISH
PRODUCT DESIGN
PROFILE SPACE

6. PRODUCT 5. ESTABLISH
LIFECYCLE CONTROL
MNGMNT STRATEGY

Slide 30 May 2008

 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 material attributes and process parameters that

assure quality.

 The multidimensional combination

Roll pressure
and interaction of input variables
(e.g. material attributes) and Gap width

process parameters that have been 300

Screen Size
Dataset - Run1-10a.M3
Observed vs. Predicted $Time [Last comp.] (Aligned)

demonstrated to provide assurance 200

of quality. 100

-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 3. LINK
QUALITY MAs AND PPs
ATTRIBUTES TO CQAS

1. TARGET 4. ESTABLISH
PRODUCT DESIGN
PROFILE SPACE

6. PRODUCT 5. ESTABLISH
LIFECYCLE CONTROL
MNGMNT STRATEGY

Slide 33 May 2008

 Design Space

EMEA/CHMP/ICH/518819/2007
1a

Response surface plot of in-vitro release Contour plot of

as a function of two critical parameters in-vitro release
of the mixing and lamination process.

Slide 34 May 2008

 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 3. LINK
QUALITY MAs AND PPs
ATTRIBUTES TO CQAS

1. TARGET 4. ESTABLISH
PRODUCT DESIGN
PROFILE SPACE

6. PRODUCT 5. ESTABLISH
LIFECYCLE CONTROL
MNGMNT STRATEGY

Slide 38 May 2008

Step 7. Product lifecycle management
continual improvement
QbD Minimal Approach
Approach
• Preventive action • Reactive
(i.e., problem solving
• Continual improvement and corrective action)
facilitated

Slide 39 May 2008

Better processes will lead to products
with less variability

Now (GMP)

Variable Fixed Variable

Input Process Output

Drug
PAT/QbD Product

Variable Adapted Consistent

Input Process Output

Slide 40 May 2008

 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