This document provides an introduction to Quality by Design (QBD) in pharmaceutical development and manufacturing. It discusses the evolution of quality approaches from chance to design. Key aspects of QBD covered include critical quality attributes (CQAs), critical material attributes (CMAs), critical process parameters (CPPs), risk assessment tools, and the role of statistics. The document presents examples of how to apply QBD concepts like quality target product profiles (QTPPs), Kano modeling, quality function deployment (QFD), and design of experiments (DoE) to identify and control elements critical to ensuring product quality.

1. INTRODUCTION TO QBD
Rucha Deshpande
Ideator
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2. WHEN THE CRAFTSMEN MET WITH INDUSTRIAL
REVOLUTION
•Taylor’s System
•Increase productivity
without increasing
skilled craftsmen
Before World War II
•Efforts to reduce cost of
appraisal
•SPC-Walter Shewhart
•Father of SQC
World War II
•From Military goods to
civil goods
•Japan’s reputation for
shoddy exports
•Deming & Juran’s work
•TQM
Post World War II
•Motorola’s Six Sigma
approach
•ISO 9001 standard
Between Post
World War II and
Now •Data analytics
•Artificial intelligence
•Machine learning
Now
DEMINGShewhart
JURAN
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3. QUALITY BY CHANCE TO QUALITY BY
DESIGN
Variable Input
material
Fixed Process
Variable Output
Quality
Define output
Quality
Design Process
Controls &
Material Spec to
meet defined
Quality
Sale product if
Quality Spec met
• FDA 2011 Process Validation
• Q8- Pharmaceutical Development
• Q9- Quality Risk Management
• Q10- Pharmaceutical Quality
System
• Q11- Development and
Manufacture of Drug Substances
• FDA 2004 PAT-Framework for
Innovative Pharmaceutical
Development, Manufacturing and
Quality Assurance
Follow control
strategy
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4. TOOLS SUGGESTED IN QBD GUIDELINES
• Risk Assessment
• Cause and Effect (Ishikawa diagram)
• Risk Prioritization
• Failure Mode Effect Analysis
• Risk Ranking
• Risk Management
• Literature
• Experience
• Modelling & Simulation
• DoE
• PAT
• Revised Risk Assessment
• Control Strategy/ Design Space
• Overlay plots
• Edge of Failure
• Chemometric models
• Visually monitored controls
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5. Critical Quality Attributes
ELEMENTS OF QBD
Quality Target Product
Profile
Critical Process
Parameters
Critical Material Attributes
Whats? Hows?
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6. QTPP CQA
Clinical Or Patient centric
Use?
Route of administration?
Strength?
Dissolution? Container Closure System?
Sterility?
Purity?
Stability?
Ensure equivalency of Safety & Efficacy with respect to
RLD
All QTPPs are CQAs but all CQAs are not QTPPs
/s either a QTPP Or helps to achieve QTPP
Example of CQA which is a QTPP
Example of CQA which is not a QTPP
Essentially forms part of‘Whats’in House of
Quality/QFD
Relates to Drug Product
Relates to Drug Product
Relates to Drug Substance, Excipients & Intermediates
Eg., PSD to achieve dissolution profile
Eg., Dissolution Profile
Forms part of Whats in first House of Quality/QFD
Forms part of Hows in first House of Quality/QFD
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7. SIX SIGMA & QBD
DMAIC Milestone Meaning QbD- Terminology
Define
(Kano)
Know required quality attributes Identify QTPPs and CQAs
Measure
(ANOVA, GAGE R&R)
Know measurement methods
Develop measurement methods
Know the precision & accuracy of measurement
method
Is the method capable of differentiating between
positive control samples and negative control
samples?
Set specifications for required quality attributes
Identify Specification
Limits
Analyse
(Cause & Effect, QFD,
FMEA, Risk Ranking)
Risk assessment
Risk prioritization
Identify CMAs and CPPs
Improve (DoE,
Multivariate Models)
Risk management
Verification of risk management strategy
DoE, PAT, Literature,
Experience
Control (SPC) Implementation of risk management strategy Design space
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8. APPLICATION OF KANO MODEL FOR QBD
Level of quality
need
Example related to an
analgesic medicine
Expected quality
(QTPP)
An unexpired, pure, round and
blister packed tablet to
reduce pain immediately (Use,
PK need of fast Dt & IR)
Normal quality—
spokens (CQA)
Content uniformity, hardness
Normal quality—
unspoken (QA)
Package should look like the
innovator
Exciting quality
(QA)
Wow – weekly schedule
printed to know if dose is
missed
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9. House of Quality/QFD for QbD
Hows? (Material and Process Requirments) Comparison Action
Whats?
(CQAs
that are
QTPPs)
Targets
Inter-relationships between Hows
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10. Input
material
PSD
Compositi
on
Mixing
speed
Mixing
Time
Solvent
used
Comparison
with
RLD
Action
Dose Matches
Drug Release Slower Ask vendor for
lower PSD
Assay Matches
Stability Matches
Packaging 50 mL glass
bottle
Targets < 100 µ 0.3 to 0.4
g/mL
40-50
rpm
5 to 15
minutes
Water
Drug A is found to be effective in relieving cold when a formulation of drug A with 5%
weight/volume composition is administered orally. Drug A is stable and soluble in water.
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11. Identification of QbD Elements
On the basis of QFD example what are CQAs, CMAs and CPPs ??
CMAs CPPs
Mixing Speed (40-50 rpm)
Composition (fixed to 5% w/v)Input PSD (coarse & fine )
Mixing Time (5 -15 minutes)
CQAs
Solvent used
(water on the basis of
solubility & stability
reported in literature)
Dissolution
Related Substances
Assay
Dose
Packaging
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12. ROLE OF STATISTICS IN QBD
• Point specification Vs Specification range
• Identifying the source of variability: is it because of batch to batch variability
or some assignable cause?
• Is there a possibility of failure with current formula and process? If yes, then
how frequent?
• To what level I need to change my formula or process to meet desired
quality attributes?
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