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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Quality by Design (QbD)
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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Why QbD?
Higher level of assurance of product quality
Cost saving and efficiency for industry and regulators
Increase efficiency of manufacturing process and reduce manufacturing cost
and product rejects
Minimize/eliminate potential compliance actions, costly penalties & recalls
Enhance opportunities for first cycle approval
Streamline post approval manufacturing changes and regulatory processes
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FDA View on QbD
Quality by Design is: Scientific, risk-based, holistic and proactive approach to
pharmaceutical development
Deliberate design effort from product conception through
commercialization
Full understanding of how product attributes and process relate to
product performance
QbD informat ion and conc lus ions shou ld be shared wi th FDA,required start ing in 2013
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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
QbD System
Define desiredproduct performance
upfront;
identify product CQAs
Design formulation andprocess to meet
product CQAs
Understand impact ofmaterial attributes andprocess parameters on
product CQAs
Identify and controlsources of variability
in material andprocess
Continually monitorand update
process to assureconsistent quality
Risk assessment and risk control
Product & process design and development
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Approaches to Pharmaceutical Development
Aspects Traditional QbD
Pharmaceuticaldevelopment
Empirical; typically univariateexperiments
Systematic; multivariate experiments
Manufacturingprocess
Fixed; validation on 3 initial full-scalebatches; focus on reproducibility
Adjustable within design space;continuous verification within designspace; focus on control strategy androbustness
Process control In-process testing for go/no-go; offlineanalysis w/ slow response
All critical process variables understood
Productspecification
Primary means of quality control;based on batch data
Part of the overall quality controlstrategy; based on desired productperformance
Control strategyMainly by intermediate and endproduct testing
Risk-based; controls shifted upstream;real-time release
Lifecyclemanagement
Reactive to problems & OOS; post-approval changes needed
Continual improvement enabled withindesign space
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Designing a Robust Process
Problemsdetected after they occur,
through
product testing andinspection
Reproducible process
within
narrow operatingranges
Robust & reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PROCESS
CONTROL
High potential
for failures
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Quality by DesignThe Desired State
Product quality and performance achieved and assured by design ofeffective and efficient manufacturing processes
Product specifications based on mechanistic understanding of howformulation and process factors impact product performance
An ability to affect continuous improvement and continuous real timeassurance of quality
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Quality by DesignThe Way Forward
Identify and control all sources of
variability
Raw materials
Process
Environmental
Manage variability through the
process
Uncertainty the inability to determine or
the ambiguity in the true state of a system
caused by a combination of variability and
incomplete knowledge (ICH Q9)
Reduce UNCERTAINTY Control VARIABILITY
Mitigate risk
Knowledge transfer to manufacturing and regulatory bodies
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Quality Risk Assessment (QRA)
Risk scores based on probability, severity, and detectability Risk Prioritization Matrix
Quality Function Deployment
Fish bone or Ishikawa diagram
Pareto Chart
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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Risk Prioritization Matrix
Process and Formulation Inputs
QUALITYATTRIBUTES
WEIGHTED
AVERAGE
HPMCK100CR
CONCENTRAT
ION
BLENDTIME
LUBETIME
APIPARTICLE
SIZE
PRE-
COMPRESSION
FORCE
COMPRESSING
FORCE
MACHINESPE
ED
FEEDERSPE
ED
POROSITYO
F
RIBBON/ROLL
GAP
EXCIPIENT
PARTICLESIZE
PSDOFINTR
A-
GRANULAR
BLEND
REGULATOR
Y
MANUFACTUR
ING
DISSOLUTION 10 10 1 1 1 1 1 1 1 1 1 1 10 3
ASSAY/
POTENCY9 3 1 5 5 1 1 1 1 7 1 1 10 1
UNIFORMITY 7 1 7 1 5 1 1 5 7 7 3 5 5 1
HARDNESS 10 5 5 10 5 7 10 7 7 10 5 5 10 10
THICKNESS 5 3 1 1 1 7 10 3 1 1 1 1 1 5
FLOW 4 7 5 1 3 1 1 3 7 5 5 7 3 1
APPEARANCE 4 5 1 3 3 3 5 3 5 5 5 5 1 1
STABILITY 2 1 1 1 1 1 1 1 1 1 1 1 3 1
YIELD 7 1 1 1 1 1 1 10 3 3 1 3 7 10
TOTALS 256 156 192 178 156 209 235 200 236 144 180
PERCENTIMPORTANCE
11.95 7.28 8.96 8.31 7.28 9.76 10.97 9.34 11.01 6.72 8.40
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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Tablet Hardness
Basic risk facilitation methods
Cause EffectDiagram
for Tablet
Hardness
Compression
Roller Compaction
Raw MaterialBlending
EnvironmentalMaterial
Transfer
Hardness of Tablet
(Friability)
Pre & Post CompressionPress speed
Feeder speedMaterial addition
Feed frame settingFill Weight
Cam selectionTooling
Roll GapRoll force
Porosity (den)PSD
Ribbon strength
APIHPMC
TALCMg. Stea
Temp.Humidity
Blend time
Blend rpm
Order of ddn.Fill Vol.
Discharge rateSurface
DischargeStorage
MoistureTransport
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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Pareto Chart: Relative Importance of Inputs
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
HPMC
K100CR
POROSITY
PRESSSPEED
COMPRESSIO
N
FORCE
FEEDER
SPEE
D
LUBETIME
PSD
OFINTRA-
GRANULAR
BLEND
APIPARTICLESIZ
E
BLEND
TIME
PRE-COMPFORC
E
EXCIPIENT
PARTICLESIZE
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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Control/Design Space Critical Process Parameters
Critical Process Parameters (CPP) identified using a risk analysis investigatedextensively using a DOE.
Design Space
Established on the basis of the DOE and experience duringmanufacture of clinical/registration batches
In certain cases where response of critical quality attributestudied/investigated was insignificant, extrapolation was used toexpand/establish design space
Control Space
Subset of design space established on the basis of process
capability, prior knowledge Intent is to stay within the control space during commercial manufacturing
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Control/Design Space Non-Critical Process Parameters
Non-Critical Process Parameters those identified as low risk which
lead to low probability of product failure
Design Space
Established on the basis of range studies (in some cases
DOEs) and manufacturing experience at various scales
Control Space
Subset of design space established on the basis of process
capability, prior knowledge
Intent is to stay within the control space during commercial
manufacturing
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Design Space and Control Space
Design Space
Multi-dimensional space that encompasses combinations of product design,manufacturing process design, critical manufacturing process parameters andcomponent attributes that provide assurance of suitable product quality andperformance
Control Space
Multi-dimensional space that encompasses process operating parameters andcomponent quality measurements that assure process or product quality. It is asubset of the design space
Control Strategy
Strategy/Methodology to mitigate risks associated with the batch when thecritical and non-critical process parameters fall outside the control space butwithin the design space
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Quality by Design (QbD)