Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

1. Quality-by-Design
Quality by Design
In
Pharmaceutical
Product Development
Dr. Ashwani Dhingra
9996230055
ashwani1683@gnkgei.ac.in

2. Quality-by-Design
QUALITY
is it important ???
YES !!!!!!!!!!!!!!!!!!!!!
Of course !!!!!!!!!!!!!!

3. Quality-by-Design
What is Importance of QUALITY ???

4. Quality-by-Design
What is QUALITY PRODUCT???

5. Quality-by-Design
Can we measure the QUALITY
??? YES !!!!!!!!!!!!
Can we measure
the QUALITY of Medicine???
NO
“You can’t test quality into drug products”

6. Quality-by-Design
Regulations for QUALITY Medicine
1960- FDA- GMP
1987- FDA - Validation
2002- FDA- cGMP
2006- ICH- Q9 (Quality Risk Mangement)
2008- FDA – Quality- by- Design
2008- ICH – Q8 (Pharmaceutical Development)
2011- ICH- Q10 (Pharmaceutical Quality System)
2012- ICH –Q11 (Development of Drug Substance & Others)
2013- US Laws for Quality Generics Medicine
Quality
by
Design

7. Quality-by-Design
Quality by design is -
• a systematic approach to development
• that begins with predefined objectives
• and emphasizes on
- product & process understanding
- process control,
• based on sound science and quality risk
management.
- ICH

8. Quality-by-Design
What is QUALITY MEDICINE ???
Quality
Patient
(or surrogate)
Target Product:
Quality Profile
Requirements,
need or
expectations
“Good pharmaceutical quality represents
an acceptably low risk of failing to achieve
the desired clinical attributes.”

9. Quality-by-Design
Quality
by
Design

10. Quality-by-Design
Quality-by-Design
Ensure higher level of assurance of product
quality for patient
 Improved product and process design & understanding
 Monitoring, tracking & trending of product & process.
More efficient regulatory oversight
Efficiency and cost saving for industry
 Increase efficiency of manufacturing process
 Minimize / eliminate potential compliance actions

11. Quality-by-Design
•Active pharmaceutical Ingredients
•Materials - excipients
•Analytics
•Simple dosage forms design
•Advanced drug delivery systems
•Develop Devices
•Combination products
Areas of Quality-by-Design

12. Quality-by-Design
System Comparison
Traditional vs. QbD
Product
Distribution
Product
Quarantine
Fixed
Packaging
Process
Fixed, Batch
Manufacturing
Process
Product
Development
Release Testing,
Document
Integrity
In-process
Testing,
Documentation
In-process
Testing,
Documentation
Fixed
Parameters,
Ranges
Patient
Production
System
Quality
System
As-Is: Traditional Pharmaceutical Product Supply System
Product
Distribution
Variable Pkg
Process
Variable Batch
or Continuous
Mfg Process
Product
Development
Real-time
Release
Maintain in Design Space
(PAT, etc.)
Design Space,
Variable
Parameters
Patient
Production
System
Quality
System
To-Be: QbD Pharmaceutical Product Supply System
Product
Distribution
Product
Quarantine
Fixed
Packaging
Process
Fixed, Batch
Manufacturing
Process
Product
Development
Release Testing,
Document
Integrity
In-process
Testing,
Documentation
In-process
Testing,
Documentation
Fixed
Parameters,
Ranges
Patient
Production
System
Quality
System
As-Is: QbT Pharmaceutical Product Supply System
Product
Distribution
Responsive Pkg
Process
Responsive
Batch or
Continuous
Mfg Process
Product
Development
Real-time
Release
Control Strategy: Maintain
in Design Space (PAT, etc.)
Design Space
Patient
Production
System
Quality
System
To-Be: QbD Pharmaceutical Product Supply System

13. Quality-by-Design
Current Approach QbD Approach
Quality assured by testing and
inspection
Quality built into product & process
by design, based on scientific
understanding
Data intensive submission –
disjointed information without “big
picture”
Knowledge rich submission –
showing product knowledge &
process understanding
Specifications based on batch history Specifications based on product
performance requirements
Focus on reproducibility – often
avoiding or ignoring variation
Focus on robustness – understanding
and controlling variation

14. Quality-by-Design
Pharmaceutical Development &
Product Lifecycle
Candidate
Selection
Product Design & Development
Process Design & Development
Manufacturing Development
Product
Approval
Continuous Improvement

15. Quality-by-Design
Design of
Experiments
(DOE)
Model Building
And Evaluation
Process Design & Development:
Initial Scoping
Process Characterization
Process Optimization
Process Robustness
Statistical Tool
Product Design & Development:
Initial Scoping
Product Characterization
Product Optimization
Manufacturing Development
and Continuous Improvement:
Develop Control Systems
Scale-up Prediction
Tracking and trending
Statistical
Process Control
Pharmaceutical Development & Product
Lifecycle

16. Quality-by-Design
Steps for 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 & Prepare QbD registration file
Step 6. Product lifecycle management and continual improvement

17. Quality-by-Design
What are the steps in a
Quality by Design approach?
TARGET
PRODUCT
PROFILE
CRITICAL
QUALITY
ATTRIBUTES
PRODUCT
LIFECYCLE
MNGMNT
LINK
MAs AND PPs
TO CQAs
ESTABLISH
CONTROL
STRATEGY
ESTABLISH
DESIGN
SPACE

18. Quality-by-Design
Target Product Profile (TPP)
What is TPP?
– A set of elements that defines the drug product
– The target or goal set in advance
– A guide to Drug Product development
When to define TPP?
– At the start of development
– Knowledge gained in development may change some elements
To design Fast Dissolving Tablet.
DT- 50 Sec. Friability - <0.6%, Dissolution – 90% in 5 min.

19. Quality-by-Design
TPP for Tablet
Components related to safety, efficacy, identity, purity and potency
Critical and non-critical components, e.g.
– Critical: Assay, content uniformity
– Non-critical: Appearance
Fixed and variable components
– Fixed elements must be present
e.g. Dosage form, strength
– Variable elements may have a range of acceptable values
e.g. Tablet weight, assay

20. Quality-by-Design
Appearance
Size & Shape
Weight
Hardness
Friability
Disintegration
Assay & Content
Uniformity
Dissolution
Pharmacokinetics
Stability
Control Parameters for FDT

21. Quality-by-Design
STEP - 2
TARGET
PRODUCT
PROFILE
CRITICAL
QUALITY
ATTRIBUTES
PRODUCT
LIFECYCLE
MNGMNT
LINK
MAs AND PPs
TO CQAS
ESTABLISH
TARGET
STRATEGY
ESTABLISH
DESIGN, CONTROL
SPACE

22. Quality-by-Design
Critical Quality Attributes
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.

23. Quality-by-Design
Critical Quality Attributes
 CQAs are a subset of the TPP
 Include critical parameters that are likely to
change based upon variations in raw materials
and processes.
 CQAs are monitored throughout the drug
product development.
 CQAs ensure that drug product remains within
safe and effective levels.

24. Chemical purity
Assay
Content Uniformity
Dissolution
Excipient
Compatibility
DT
Friability
Dissolution
Quality-by-Design
Product - Centric
Formulation
Process Related
DRUG
PRODUCT
API
Purity
Formulation
Parameters
Excipient
Quality
Attributes
API
Quality Attributes

25. Quality-by-Design
Appearance
Size & Shape
Weight
Hardness
Friability
Disintegration
Assay & Content Uniformity
Dissolution
Pharmacokinetics
Stability
Friability - 0.6%
Disintegration- 50 s
Dissolution – 90%
Appearance
Size & Shape
Weight
Hardness
Assay & Content Uniformity
Pharmacokinetics
Stability
Control
Parameters
Specific
Parameters
Non-Specific
Parameters

26. Quality-by-Design
STEP - 3
TARGET
PRODUCT
PROFILE
CRITICAL
QUALITY
ATTRIBUTES
PRODUCT
LIFECYCLE
MNGMNT
LINK
MAs AND PPs
TO CQAS
ESTABLISH
CONTROL
STRATEGY
ESTABLISH
DESIGN
SPACE

27. Quality-by-Design
People
Equipment
Measurement
Process
Materials
Environment
I
N
P
U
T
S
(X)
y = ƒ(x)
OUTPUT
y
Inputs to the process
control variability
of the Output
Observation
Individual
Value
40
38
36
34
32
30
28
26
24
22
20
120
115
110
105
100
95
90
_
X=102.37
UCL=116.68
LCL=88.05
I Chart
Observation
Individual
Value
60
58
56
54
52
50
48
46
44
42
40
115
110
105
100
95
90
85
80
_
X=97.94
UCL=112.65
LCL=83.23
I Chart
Observation
Individual
Value
80
78
76
74
72
70
68
66
64
62
60
115
110
105
100
95
90
_
X=99.63
UCL=111.55
LCL=87.71
I Chart
Observation
Individual
Value
100
98
96
94
92
90
88
86
84
82
80
110
105
100
95
90
85
_
X=98.76
UCL=111.17
LCL=86.35
I Chart
Observation
Individual
Value
60
58
56
54
52
50
48
46
44
42
40
115
110
105
100
95
90
85
80
_
X=97.94
UCL=112.65
LCL=83.23
I Chart
Observation
Individual
Value
80
78
76
74
72
70
68
66
64
62
60
115
110
105
100
95
90
_
X=99.63
UCL=111.55
LCL=87.71
I Chart
Observation
Individual
Value
91
81
71
61
51
41
31
21
11
1
115
110
105
100
95
90
85
_
X=99.95
UCL=114.17
LCL=85.72
I Chart

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

29. Quality-by-Design
Materials
API
Disintegrant- 01
Disintegrant - 02
Filler
Lubricant
Glidant
Taste Masking Agents
Colours
Process
Mixing
Shifting
Blending
Tableting
Packaging
P1
P2
P3
P4
P5
M1
M2
M3
M4
M5
M6
M7
M8
DT
Friability
Dissolution
Stability
Amount of Disintegrant - 01
Amount of Disintegrant - 02
Tableting – Pressure of Punches

30. Quality-by-Design
STEP - 4
TARGET
PRODUCT
PROFILE
CRITICAL
QUALITY
ATTRIBUTES
PRODUCT
LIFECYCLE
MNGMNT
LINK
MAs AND PPs
TO CQAS
ESTABLISH
CONTROL
STRATEGY
ESTABLISH
DESIGN
SPACE

31. Quality-by-Design
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.

32. Explore
Space
Quality-by-Design
Knowledge
Space
Design Space
Control Space
Target
Space

33. Quality-by-Design
Ingredient F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
API
DIS -01 2 4 6 8 - - - - 1 3 3 3
Dis – 02 - - - - 5 10 15 20 5 5 10 15
Filler
Lubricant
Glidant
Taste
Masker
Colour
DT (s) 124 96 68 45 172 118 75 56 101 99 66 41
Friability 0.4 0.9 1.3 1.8 1.6 1.2 0.9 0.8 1.0 0.8 0.6 0.4
DT – 50 Seconds
Friability - 0.6%
One Factor At A Time (OFAT)

34. Quality-by-Design
DT
(s)
Friability
Amt. of Dis- 01
Amt. of Dis- 01
Friability
DT
(s)
Amt. of Dis- 02
Friability
DT
(s)
DT
(s)
Friability
Amt. of Dis- 02
DT
(s)
Friability
Amt. of Dis- 01
Amt. of Dis- 02
DT – 50 Seconds
Friability - 0.6%

35. Quality-by-Design
Space Dis-01 Dis-02
Knowledge 2-20 % w/w 5-30 % w/w
Design 2-8 % w/w 5-20 % w/w
Control 1-3 % w/w 5-15% w/w
Target ??? ????
DT – 50 Seconds
Friability - 0.6%

36. Quality-by-Design
STEP - 5
TARGET
PRODUCT
PROFILE
CRITICAL
QUALITY
ATTRIBUTES
PRODUCT
LIFECYCLE
MNGMNT
LINK
MAs AND PPs
TO CQAS
ESTABLISH
CONTROL
STRATEGY
ESTABLISH
DESIGN
SPACE

37. Quality-by-Design
Design of Experiments (DoE)
Formulation by Design (FbD)

38. Quality-by-Design
DoE or FbD
A “holistic, mathematical, statically, computer
systems-based approach to the design,
development, and delivery of the BEST product
under a given set of conditions.”

39. Quality-by-Design
Terms Generally Used in DoE or FbD
Variables
1. Independent Variables: Formulation Variables, Process etc.
2. Dependent Variables: Control Parameters or Evaluation Parameters
Factors: Independent variables which tend to influence the product characteristics.
Level/ Codes: Value assigned to a factor (Low;-1, Medium; 0, High; +1)
Response: Characteristics of the finished product
Effect: The magnitude of the change in response by level of factor
Interaction: Additive response of factor (No Interaction, Synergetic or Antagonistic)

40. Quality-by-Design
Models used for DoE or FbD
Response Surface Factorial Design – 22, 32 Factorial Design
Central Composite Design - 33 Factorial Design
Box-Wilson Design - 33 Factorial Design
Box Benchen Design - 33 Factorial Design
Factorial Factorial Design – 2K Factorial Design
Taguchi Design – Screening Studies

41. Quality-by-Design
Models for DoE or FbD
Factors: 02
Level: 03
Factor Coded Value Actual Value
Low Medium High Low Medium High
Dis- 01 -1 0 +1 1 2 3
Dis-02 -1 0 +1 5 10 15
23 Factorial Design

42. Quality-by-Design
F. Code Dis-01 Dis- 02 DT (s) Friability (%)
T1 -1 -1 101 1
T2 -1 0 89 0.7
T3 -1 +1 62 0.5
T4 0 -1 99 1.2
T5 0 0 73 0.9
T6 0 +1 54 0.6
T7 +1 -1 91 1.4
T8 +1 0 66 0.8
T9 +1 +1 41 0.5

43. Quality-by-Design
ANOVA - Application
DT= 76.22 – 9 Dis-01 – 22.33 Dis-02 – 2.75 Dis01.Dis02
Design-Expert® Software
Factor Coding: Actual
DT (s)
Design Points
101
41
X1 = A: Dis-01
X2 = B: Dis-02
-1 -0.5 0 0.5 1
-1
-0.5
0
0.5
1
DT (s)
A: Dis-01 (mg)
B:
Dis-02
(mg)
50
60
70
80
90
100
dicted value
dicted value
-1
-0.5
0
0.5
1
-1 -0.5 0 0.5 1
40
50
60
70
80
90
100
110
DT
(s)
A: Dis-01 (mg)
B: Dis-02 (mg)

44. Design-Expert® Software
Factor Coding: Actual
Friability (%)
Design Points
1.4
0.5
X1 = A: Dis-01
X2 = B: Dis-02
-1 -0.5 0 0.5 1
-1
-0.5
0
0.5
1
Friability (%)
A: Dis-01 (mg)
B:
Dis-02
(mg)
0.6
0.8
1
1.2
oftware
ual
bove predicted value
elow predicted value
-1
-0.5
0
0.5
1
-1
-0.5
0
0.5
1
0.4
0.6
0.8
1
1.2
1.4
Friability
(%)
A: Dis-01 (mg)
B: Dis-02 (mg)
Quality-by-Design
ANOVA - Application
F %= 0.85 +0.08 Dis-01 – 0.33 Dis-02 – 0.1 Dis01.Dis02

45. Quality-by-Design
Plots for Combined Effect
DT
(s)
Friability
Amt. of Dis- 01
Amt. of Dis- 02
-1 -0.5 0 0.5 1
-1
-0.5
0
0.5
1
Desirability
A: Dis-01 (mg)
B:
Dis-02
(m
g)
0
0
0
0.2
0.4
0.4
0.6
0.6
0.6
0.8
0.8
Prediction 1.000
X1 0.770805
X2 0.749892
DT – 50 Seconds
Friability - 0.6%

46. Quality-by-Design
Solution by DoE or FbD
Solutions
Number Dis-01 Dis-02 DT
Friabilit
y
Desirability
1 0.771 0.750 50.0 0.600 1.000 Selected
2 0.744 0.760 50.0 0.600 1.000
3 0.976 0.661 50.0 0.602 0.999
DT – 50 Seconds
Friability - 0.6%

47. Quality-by-Design
Design of experiments (DoE)
– Useful for screening of variables with significant impact on DP CQAs
– Classical approach than OFAT (One Factor At A Time)
– Limited number of experiments gives huge information.
– DoE helps study effects of interaction of multiple factors at a time
– Used in optimization studies, enables creation of “target space”
– “Target space” is proposed by the applicant and subject to regulatory assessment
and approval.
– “Target space” developed at lab or pilot scale can be proposed for commercial scale,
but needs to be verified at production scale for scale dependant parameters.

48. Quality-by-Design
STEP - 6
TARGET
PRODUCT
PROFILE
CRITICAL
QUALITY
ATTRIBUTES
PRODUCT
LIFECYCLE
MNGMNT
LINK
MAs AND PPs
TO CQAS
ESTABLISH
CONTROL
STRATEGY
ESTABLISH
DESIGN
SPACE

49. Quality-by-Design
Minimal Approach QbD
Approach
• Reactive
(i.e., problem solving
and corrective action)
• Preventive action
• Continual improvement
facilitated

50. Quality-by-Design
Impact of QbD
Academics: Changes their curriculum
Research: New meaningful solutions
Industry: Changes their Research Methodology
Adopt the QbD Methodology for PD
Regulators: Changes their Laws.
Recent Advances in Pharmaceutical Education & Research

51. Quality-by-Design
Revolution in Quality Thinking
Quality can not be tested
into products;
it has to be
built in by design.

52. Quality-by-Design
Dr. Ashwani Dhingra
9996230055
ashwani1683@gnkgei.ac.in