This presentation will cover introduction of QbD, benefits & misconception about QbD. Nowadays, the application of QbD in the PLCM is a widely used in the pharma industry to understand product thoroughly, reduce development and post approval cost and reduce failures. The topic is emphasis on QbD element, QbD stages, Optimization studies, Quality risk management, Risk management tools, Post submission phase and their relation.
Quality by Design (Qbd) in Product Life Cycle Management (PLCM)
1. QbD in PLCM
Dr Girish Sonar
Global formulation development &
Technology Transfer
Date: 13/08/2020
2. Confidential2
Disclaimer
Any views or opinions expressed herein are solely those of the
author and do not necessarily represent those of any company. This
presentation is solely for educational purposes and provides
information for beginner scientist to share experience.
For a complete requirements details, please consult to regulatory
expert and/or the relevant regulatory agency.
3. Confidential3
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
4. Confidential4
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
5. Confidential5
Product Lifecycle Management (PLCM)
Pharmaceutical
Development
Technology Transfer
Commercial
Manufacturing
Product
Discontinuation
Product
Launch
Product
Discontinue
Reference: ICH Q10 Pharmaceutical Quality System
7. Confidential7
Introduction to QbD
Systematic and proactive approach to pharmaceutical
development
Begins with predefined objectives (Define QTPP, Identify CQAs)
Emphasizes product and process understanding and process
control (Identify CMA & CPP and establish link between CMA/CPP to CQA)
Based on sound science and quality risk management (Science-
driven development - scientific literature, prior knowledge, DOEs
etc. and Risk-based development - ICH Q9)
Reference: ICH Q8 Pharmaceutical Development
8. Confidential8
Benefits of QbD (1)
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
Rapid introduction of state-of-the art science and technology
Encouraged continuous manufacturing process improvements
9. Confidential9
Benefits of QbD (2)
Real-time quality control and reduced end-product
release testing
Fewer lost batches
Fewer manufacturing deviations, saving costly investigative
hours
Reduced out-of-specification results, reducing rework
Reduce post approval changes/Variations
10. Confidential10
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
11. Confidential11
QbD elements – Flow diagram
QTPP CQA
Initial Risk
Assessment
Updated
Risk
Assessment
Risk
Mitigation
Design
Space
Quality Risk
Management
Control
Stage
Drug Substance
Formulation
Variables
Process
Packing
12. Confidential12
QbD elements – Flow diagram
QTPP CQA
Initial Risk
Assessment
Updated
Risk
Assessment
Risk
Mitigation
Design
Space
Quality Risk
Management
Control
Stage
Drug Substance
Formulation
Variables
Process
Packing
13. Confidential13
Quality Target Product Profile (QTPP)
Generic MUST be
‘‘essentially similar’’ to the -
1. Dosage form
2. Dose
3. Strength
4. Route of administration
5. Safety
6. Efficacy
7. Intended use
8. Indications
14. Confidential14
QbD elements – Flow diagram
QTPP CQA
Initial Risk
Assessment
Updated
Risk
Assessment
Risk
Mitigation
Design
Space
Quality Risk
Management
Control
Stage
Drug Substance
Formulation
Variables
Process
Packing
19. Confidential19
QbD elements – Flow diagram
QTPP CQA
Initial Risk
Assessment
Updated
Risk
Assessment
Risk
Mitigation
Design
Space
Quality Risk
Management
Control
Stage
Drug Substance
Formulation
Variables
Process
Packing
20. Confidential20
Updated Risk Assessment
o Updated Risk Assessment of Drug Substance
o Updated risk assessment of
Excipients
o Updated risk assessment of
Packaging material
21. Confidential21
QbD elements – Flow diagram
QTPP CQA
Initial Risk
Assessment
Updated
Risk
Assessment
Risk
Mitigation
Design
Space
Quality Risk
Management
Control
Stage
Drug Substance
Formulation
Variables
Process
Packing
27. Confidential27
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
28. Confidential28
Misconception about QbD (1)
QbD
Systemic development with
predetermine objective for
quality product
QbD contains DoE
No software mandatory to
establish QbD
DoE
Statistical technique used
in interpreting sets of experiments
aimed at making sound decisions
DoE may be part of QbD
DoE is implemented using
statistical software program
Conclusion : QbD and DoE are not interchangeable terminologies.
29. Confidential29
Misconception about QbD (2)
QTPP
Desired target for developmental work
Components of QTPP may or may not
be in specification
Not in spec – Dosage form, strength
In spec – Assay, impurities
Does not include acceptance criteria
Specifications
Includes all CQAs
Specification is a list of
- tests,
- references to analytical procedures
- acceptance criteria
Establishes the set of criteria to
which DP should conform to be
considered acceptable for its
intended use
Conclusion : Defining a QTPP does not mean setting all acceptance criteria or the product
specifications before development work begin.
30. Confidential30
Misconception about QbD (3)
QbD based PDR document mandatory for regulatory submission
and to make it for the sake to fulfill the submission criteria X
QbD is the USFDA requirement only X
DoE is mandatory for QbD as mentioned in published IR/MR
product example X
31. Confidential31
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
33. Confidential33
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
35. Confidential35
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
42. Confidential42
Process Optimization
Process optimization planned based on knowledge of –
1.Scale dependent equipment/Process parameter
2.Scale independent equipment/Process parameter
If R&D scale and commercial scale equipment have same
mechanism, same geometry and scalable based on scientific basis,
then process optimization batches can be performed in R&D scale
equipment. If not, then process optimization batches will be
performed in commercial scale equipment.
43. Confidential43
Process Optimization – Study Plan (1)
Equipment Scalable process
parameters
Recommended Remark
Wurster
(Bottom
spray)
Spray rate, atomization air
pressure, air flow volume,
dew point
ADP area is considered to calculate the scale up
factor and apply to all critical process parameter
except dew point and product temp
Scale
independent
RMG Impeller speed , Chopper
speed, Binder addition
time, Granulation time
Tip speed, Low speed = 3.0-3.5m/Sec,
High Speed = 6.0-7.0m/Sec at the R&D scale and
commercial scale
Scale
independent
FBP
(Top Spray
granulation)
Spray rate, atomization air
pressure, air flow volume,
dew point
Calculate the scale up factor based on vendor’s
recommendation and apply for critical process
parameters
Scale
independent
Multimill
Milling
screen opening, mill
speed and direction
Screen size/impeller direction/ mill speed should be
same
Scale
independent
Co- mill screen opening, mill
speed and direction
Screen size/impeller direction/ mill speed should be
same. Apply scale factor as per vendor’s
recommendation
Scale
independent
44. Confidential44
Process Optimization – Study Plan (2)
Equipment Scalable process parameters Recommended Remark
Blender No of revolutions, Blender
geometry
Blending : 300 ± 10 revolutions,
Lubrication: 50 ± 5 revolutions.
Calculate the blender rpm and time based
on Froude no calculation.
Scale
independent
Roller
Compaction
Roller speed, roller gap,
compaction force, milling
parameters
Scaling up factor varies from mechanism
of roller compaction and follow vendor’s
guideline for scale-up
Scale
independent
most of the time
Compression
machine
Turret speed, feeder speed,
pre-compression force, main
compression force, dwell time
Optimize the process parameters wrt
compression machine at manufacturing
site
Scale dependent
Coating Spray rate, atomization air
pressure, product temp, gun to
bed distance, pan rpm
Optimize the process parameters wrt
coating machine at manufacturing site
Scale dependent
50. Confidential50
Basic Risk Management Facilitation Method
1. Flowcharts;
2. Check Sheets;
3. Process Mapping; Cause and Effect Diagrams
(also called an Ishikawa diagram or fish bone diagram)
51. Confidential51
FMEA – Case Study (1)
Risk Assessment Risk Reduction
Source
Failure
mode
Effect
Severity
Cause
Occurrence
Current Controls
Delectability
RPN
Action Plan
Severity
Occurrence
Delectability
RPN
Document
reference
Remark
Granulation Dry
mixing
speed
slow
May not meet the
specifications for
Blend uniformity,
content uniformity
and Drug release
7 Mixing speed
of agitator not
within
acceptable
range
(50±5RPM)
4 Instruction for
standard mixing
speed and time
given in the BMR
4 112 Four eye
principle,
Documentatio
n for the same
in BMR with
signature.
4 1 1 4 BMR
Instruction
s in
granulation
section.
Risk
reduced.
Granulation Dry
mixing
Time
7 Mixing time
less than or
more than
5min
4 4 112 Four eye
principle,
Documentatio
n for the same
in BMR with
signature.
4 1 1 4 BMR
Instruction
s in
granulation
section.
Risk
reduced.
Granulation Time of
Binder
addition
Not meet the
physical
parameters of the
Blend and Blend
uniformity
10 Binder added
less than 1min
or more than
2min
7 Instruction for
standard binder
addition time
given in the BMR
4 280 Four eye
principle,
Documentatio
n for the same
in BMR with
signature.
7 4 1 28 BMR
Instruction
s in
granulation
section.
Risk
reduced.
52. Confidential52
FMEA – Case Study (2)
Risk Assessment Risk Reduction
Source
Failure
mode
Effect
Severity
Cause
Occurrence
Current Controls
Delectability
RPN
Action Plan
Severity
Occurrence
Delectability
RPN
Document
reference
Remark
Granulation Speed of
agitator
Not meet the
physical
parameters of the
Blend and Blend
uniformity
7 Speed of
agitator not
maintain slow
(50±5RPM)
4 Instruction for
standard binder
addition time
given in the BMR.
4 112 Four eye
principle,
Documentatio
n for the same
in BMR with
signature.
4 1 1 4 BMR
Instruction
s in
granulation
section.
Risk
reduced.
Granulation Use of
Chopper
(not to be
use)
Not meet the
physical
parameters of the
Blend and Blend
uniformity
10 Chopper
started.
7 Instruction for
not using
Chopper is given
in BMR.
4 280 Four eye
principle,
Documentatio
n for the same
in BMR with
signature.
4 4 1 16 BMR
Instruction
s in
granulation
section.
Risk
reduced.
Max
Average
Min
280
180
112
Max
Average
Min
28
11
04
54. Confidential54
QbD Stage III
QbD III Stage = Control Strategy
Control strategy should be discussed with manufacturing
person before finalize for the best results.
All critical attributes control should be mentioned clearly in
control strategy and mentioned the name of reporting
documents.
56. Confidential56
Product Lifecycle Management (PLCM)
Pharmaceutical
Development
Technology Transfer
Commercial
Manufacturing
Product
Discontinuation
Reference: ICH Q10
Pharmaceutical Quality
System
Product
Launch
Product
Discontinue
57. Confidential57
Discussion point
1. Introduction to QbD
2. QbD elements – Flow diagram
3. Misconception about QbD
4. Product Development Strategy
5. Initial batches
6. QbD Stage I, II and III
7. Conclusion
58. Confidential58
Conclusion
QbD is the effective tool, should be implement from the initial
stage of the product development independent of target market.
Discuss QbD scheme with manufacturing team to achieve aim of
QbD and keep future projection to avoid regulatory queries and
post approval changes/Variation.
DoE is not mandatory for QbD based submission.
Try to cover maximum range of formulation and process variables
during optimization study to make fastest and cost-effective post
approval changes/Variation.