1. QUALITY BY DESIGN
Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations
Mumbai, India
Date: May 2008

2. World Health Organization
13 November, 2018
QUALITY BY DESIGN
Dr Tom Sam
President
Industrial Pharmacy Section
International Pharmaceutical Federation (FIP)

3. QUALITY BY DESIGN
products
processes

4. What is Quality? Quality Patient
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.”

5. Which quality do we want for our medicines ? 6σ
Source: Motorola, Air Safety Online

6. With which quality do we manufacture our medicines: 6σ, 5σ, 4σ, 3σ, 2σ ?
Source: Motorola, Air Safety Online
Current Mfg
Quality provided
to patients

7. How do we fill this quality gap in the pharmaceutical industry?
Sigma
ppm Defects
Yield 2 s 3 4 5 6
308,537
66,807
6,210
233
3.4
69.2%
93.3%
99.4%
99.98% %
Cost of Quality
25-35%
20-25%
12-18%
4-8%
1-3%
Current Mfg
Quality provided
to patients
……by testing !!!!
Data from: Dr. Doug Dean & Frances Bruttin
PriceWaterhouseCoopers

8. The quality mantra
“Quality can not be tested into products; it has to be built in by design”

9. 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

10. Dr Ajaz Hussain
‘Pharmaceutical GMPs
for the 21st Century’

11. The knowledge pyramid Desired State Current State
First
Principles
Why?
Knowledge based decisions
Desired State
MECHANISTIC
KNOWLEDGE
How?
“CAUSAL" KNOWLEDGE
What “Causes” What?
Need for regulatory oversight
CORRELATIVE KNOWLEDGE
What Is Correlated to What?
Current State
DESCRIPTIVE KNOWLEDGE:
What?

12. The New Quality Paradigm – The Evolving Regulatory Framework
ICH Q8/Q8(R) - Pharmaceutical Development
PAT Guidance
ICH Q9 – Quality Risk Management
ICH Q10 – Pharmaceutical Quality Systems
Product
Design
Process
Scale-up &
Transfer
Commercial
Manufacture
Product Life Cycle

14. 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

15. Quality by Design approach can be used for
Simple dosage forms
Advanced drug delivery systems
Devices
Combination products (e.g. theranostics)
Active pharmaceutical ingredients
Materials incl excipients
Analytics

16. Impact of QbD Companies re-organize their science
Universities change their curriculum
Health authorities change their assessment and inspection

17. 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
Step 5. Define the Control Strategy
Step 6. Prepare QbD registration file
Step 7. Product lifecycle management and continual improvement
EMEA/CHMP/ICH/518819/2007

18. 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
5. ESTABLISH
CONTROL
STRATEGY

19. Step 1. Agree on the Target Product Profile
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).
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.

20. TPP for paediatric dosage form
TPP adult
TPP paediatric (may depend upon age group)

21. 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
5. ESTABLISH
CONTROL
STRATEGY

22. 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

23. 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.
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.

24. Product-centric Quality by Design
API
Purity
Chemical purity
Physical form
Raw Material quality
Excipient
Quality
Attributes
DRUG
PRODUCT
API
Quality Attributes
Formulation
Parameters
Formulation
Process Related
Particle size
Mechanical
Properties
Excipient
Compatibility

25. 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
5. ESTABLISH
CONTROL
STRATEGY

26. Step 3. Link the drug and excipient attributes and the process parameters to the CQAs
People
Quality Attributes
Inputs to the process
control variability
of the Output I N P U T S
(X)
Equipment
y = ƒ(x)
Measurement y
Process
OUTPUT
Materials
Source: Moheb Nasr, FDA
Environment

27. P2 might not be needed in the establishment of design space
Mapping the Linkage
Inputs:
Outputs: M1
CQA1
Critical
Quality Attributes M2
CQA2
Material Attributes
CQA3 P1 P2
Relationships:
CQA1 = function (M1)
CQA2 = function (P1, P3)
CQA3 = function (M1, M2, P1)
P2 might not be needed in the establishment of design space
Source: Moheb Nasr, FDA P3
Process Parameters

28. 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)
Experiment
Factor A
Factor B
Factor C 1 + - 2 3 4
3. Analyze Data
Determine significant factors

29. ICH Q9 Quality Risk Management
4. Risk Review
1. Risk Assessment
2. Risk Control
Initiate Quality Risk
Management Process
Output / Result of the Quality Risk Management Process
Formal Risk Management Process
The new language

30. 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
5. ESTABLISH
CONTROL
STRATEGY

31. 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.

32. Definition of Design Space
The material attributes and process parameters that assure quality.
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
Gap width
Screen Size

33. 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
5. ESTABLISH
CONTROL
STRATEGY

34. Design Space 1a Contour plot of in-vitro release
EMEA/CHMP/ICH/518819/2007
Response surface plot of in-vitro release
as a function of two critical parameters
of the mixing and lamination process.
Contour plot of in-vitro release

35. Design Space
Design Space
Knowledge Space
Control Space

36. 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

37. 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.

38. 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
5. ESTABLISH
CONTROL
STRATEGY

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

40. Better processes will lead to products with less variability
Now (GMP)
Variable Input
Fixed Process
Variable Output
Drug Product
PAT/QbD
Variable Input
Adapted Process
Consistent Output

41. 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