Criticality Assessment- Identification of Critical Quality Attributes ...

Criticality Assessment- Identification of Critical
Quality Attributes (CQA) & Critical Process
Parameter (CPP) for a MR Dosage form (DP)
Shailesh Singh, Nirdosh Jagota, T.G. Venkateshwaran, &
Richard Saunders
AAPS Annual Meeting, November 2009
Pfizer • 0

Outline
� Define product goal via establishment of Quality target product
Profile (QTPP)
� Determination of Critical Quality Attributes (CQAs)-Identify the
CQAs based on prior knowledge and QTPP
� Use prior knowledge and risk assessment to identify the critical
parameters or attributes. Establish link between CPP & CQAs. Use
risk management techniques to prioritize the parameters to study.
� Establishment of Criticality- CPP & CQA
� Provide key learning from company experience and future
directions
1
Pfizer • 1

QbD Road Map – FDA Interpretation
Quality
by
Design
Continually
monitor and
update process to
assure consistent
quality
Identify and
control critical
attributes in
material and
process
*: Based on slides by Dr. Nasr, FDA, Feb 07
Product & process design and development
Define desired
product performance
upfront;
identify product CQAs
QRM and Knowledge Management
Design formulation
and process to meet
product CQAs
QRM and Knowledge Management
Understand impact of
material attributes
and process
parameters on
product CQAs
Pfizer • 2

Quality Target Product Profile – Beginning
with the end in mind
� Natural extension of the Target Product profile for product quality
� Prospective summary of the quality characteristics of the drug product taking
into account the safety, efficacy (and manufacturability) of the drug product
� Factors to be considered
– Identify Critical Quality Attributes of the Drug Product
– Route of Administration (Oral versus Intravenous drug product)
– Type of dosage form (Immediate versus modified release)
– High dose versus low dose
– Target population
– Type of therapy (life saving versus quality of life)
� Consideration should also be given to:
– Clinical usage Setting
– Supply chain requirements
– Special region/market requirements (e.g.) Japanese requirements for
appearance
Pfizer • 3

Example of a Quality Target Product Profile
Quality Attribute
Target Product Profile
Target Criticality
Dosage form ER, Film coated Tablet (

Prior Knowledge
� Summarize all Prior Knowledge
– Include all sources of knowledge :Literature, patents,
notes, company and personal experience with projects.
– Knowledge from experience with (similar) prior projects
with reference to API, drug product, material properties
of components, manufacturing process, equipments,
test methods, deviations, etc.
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Criticality Analysis
�Criticality is used to describe any feature or
material attribute, property or characteristic of a
drug substance, component, raw material, drug
product or device and/or any process attribute,
parameter, condition, variable or factor in the
manufacture of a drug product.
ISPE: Criticality paper in JPI, 2008
Pfizer • 6

Decision Tree to decide CQAs
Prior
Knowledge
Quality
Attribute not
a CQA
Quality Attribute may not
be a CQA but still be
critical from a business
perspective e.g. tablet
thickness, appearance
No
Start
Brainstorm list of
Quality Attributes
(potential CQAs)
Is this a CQA
(from a
patient
perspective)?
Yes
Apply suitable
QRA tool to rank
CQAs
List of CQAs
Unsure
QTPP
Experimental
work to
increase
knowledge
Critical Quality Attribute (CQA):
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.
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Critical Quality Attributes (CQA)
Manufacturability
Critical Quality Attributes
Safety & Efficacy
Drug Product CQA’s
Drug Substance CQA’s
Raw Material CQA’s
Identity; Assay;
Microbiology; UDU;
Mechanical & Physical
Props.; Description;
Purity; Dissolution;
Taste; Odor
Closely interlinked but not be identical
Identity; Assay;
Description; Purity;
Physical Properties
Material & Functional
Properties
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Input (Raw) Material Characterization
� Understanding the impact of raw materials on product
performance.
� Sources of variability in excipients
� Functionality or functional properties of excipients
� Important excipient properties and associated physical
test methods.
� Potential impacts of excipient properties against tests
that might be carried out
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Impact of raw material variability to Quality of
product
Fixed process
Feed forward
approach
Flexible process
Quality = f (Raw material , Process parameters,..)
T. Kourti, A. Phar. Rev., 2008.
Pfizer • 10

ISPE :PQLI Model for Quality Attributes
Continuum of Criticality
QTPP
Potential
Impact to Safety
Efficacy &
Quality?
YES
*A Severity Scale is used to assess
relative magnitude of impact. A
change in criticality only occurs w/
a change in severity.
ISPE Criticality Sub-team
Severity*
*Continual Improvement Iteration
NO
LOW RISK
HIGH RISK
Non-Critical
C
R
I
T
I
C
A
L
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Mapping the Linkage
M1
P2
Inputs:
P1
M2
Material Attributes
P3
Process
Parameters
Outputs:
CQA1
CQA2
CQA3
Relationships:
CQA1 = function (M1)
CQA2 = function (P1, P3)
CQA3 = function (M1, M2, P1)
Critical
Quality
Attributes
P2 might not be needed in the
establishment of design space
Pfizer • 12

Prior Knowledge & Risk Assessment
� Summarize all Prior Knowledge
– Include all sources of knowledge :Literature, patents, notes, company and
personal experience with projects.
– Knowledge from experience with (similar) prior projects with reference to
API, drug product, material properties of components, manufacturing
process, equipments, test methods, deviations, etc.
� Risk assessment (ICH Q9)
– Perform Initial risk assessment
– Ensure all forms of risk are acceptable
– Reduce potential variables to a manageable number.
– Limited risk assessments, important to prevent bias; systematic risk
analysis
– Should be clear, concise and current, basis for defining criticality.
� Prior knowledge and Risk assessment help in identifying the (knowledge
gaps) potential variables & prioritize them for further studies.
Pfizer • 13

Risk Assessment Tool Considerations
Product
Development
Process
Development
Process Scale-up
& Tech Transfer
Manufacturing
Platform / Prior Knowledge Specific Product Knowledge
General Risks Specific Risks
Qualitative Tools Quantitative Tools
More Simple Tools More Complex Tools
• Fishbone / Ishikawa
• PHA
• Risk Ranking & Filtering
• Fault Tree Analysis (FTA)
• HAZOP
• FMEA / FMECA
• HACCP
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Potential
Impact to
CQA?
Process Parameters
Continuum of Criticality
NO
YES LOW RISK
Probability
Detectability
CQA = f (PP 1, PP 2, …PP i)
ISPE Criticality sub-team
HIGH RISK
Non-Critical
C
R
I
T
I
C
A
L
Continual Improvement Iteration
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Criticality: Linkage between CPP & CQAs
� Criticality is based on the impact of quality attribute/ parameter on the
safety, efficacy & quality (manufacturability) of the product.
– Establish a link between CPP & CQAs: Identification of attribute or
parameters that can be used as a surrogate for clinical safety &
efficacy (important to patient).
– Manufacturability is also an attribute (important to business) that is
critical to quality.
– The level of criticality may differ for an API manufacturing process
relative to a drug product manufacturing process
• API is one component of a drug product and one step further away
from the patient
� Continuum of Criticality
– Several levels of criticality may be used to describe multiple levels of
risk
• As attribute or parameter boundaries approach edges of failure, the
level of criticality increases with the level of risk
Pfizer • 16

Risk Assessment Process Applied to Product
Development
Develop
Design Space
&
Control Strategy
(Risk Mitigation)
Perform
Experiments
Risk Assessment
Prioritize
Experiments
Experimentation
Prioritization
Product
&
Process
Understanding
Risk
Assessment
Experimental
Planning
ID Experiments
Understand
CQA =f(CPP)
DOE PAT Modelling
Identify Quality
Attributes
and How Measured
Quality
Risk Assessment
Identify and Prioritize
Process Parameters
Pfizer • 17

Summary of Pharmaceutical Development – Case
Study
� Characteristics of Compound (Product “X”)
� Relatively High Dose Compound (extremely stable)
� High Water Solubility, Moderate Permeability (BCS Class 3)
� Extended Release Formulation Required for Once-a-Day Dosing
� Process Development
�Formulation Initially Developed as a Wet Granulation Process
�During late phase development, Densification by Roller Compaction
Process Introduced
�Mitigated risk by risk assessment and through understanding of factors
controlling drug release
�Level A IVIVC has been established for all dose strengths – establish
clinical pharmacokinetic design space
� Potential Critical Quality Attributes
� Dissolution-----Clinical Relevance
� Hardness of Tablets---Manufacturability
Pfizer • 18

Target Product Profile – Quality Planning
Roadmap
Patient
Patient
needs
Easily
consumable
dosage form,
once a day
dosing,
Minimal nausea
�Assay – 90-110% LC
Patient
Needs
Product
Features
Tablet,
Sustained
Release, Dose
optimized
to minimize
nausea
Target Product Profile for Operations
�Impurities – Extremely stable compound – control of API impurities
is sufficient
�Dissolution – Extended release dosage form (based on IVIVC)
�Microbial limits – solid dose – low risk – non-critical
�Content Uniformity – USP criteria for UDU
Joseph M. Juran, “Quality by Design – The New Steps for Planning Quality into
Goods and Services,” pages 14-22, Free Press, 1992
Product
Features
Process
Features
Process
Features
Roller
Compaction to
achieve desired
bulk density
Process
Controls
Process controls
to ensure
operation is
within
CPP design space
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Preliminary Risk Analysis: Ishikawa or Fish bone
Diagram
Pfizer • 20

Case Study-Dry Granulation: Initial Risk
Assessment
Potential Parameters : During initial Development on Severity & probability
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Product X Development – Knowledge Gained
� Mechanistic understanding of formulation gained through product
development study design
– Product Performance is influenced by tablet surface area to volume ratio
and polymer concentration
– Small Variation in concentration yields acceptable performance
– Variation of polymer viscosity, particle size, moisture levels, Substitution
ratio has no impact on dissolution performance
– Dissolution performance is independent of API particle size distribution
– Dissolution is independent of manufacturing process (roller compaction
versus wet granulation)
� Coating is non-functional and had no impact on Dissolution
� Formulation Performance is Robust and Resistant to Variability in API
and Excipient Inputs
Pfizer • 22

Risk Assessment
Process and Control Parameters
Process Parameter Quality Attributes
Raw Material
Attributes
Bin Blend
Roller Compaction
Bin Blend
Compression
Film Coating
Polymer Viscosity,
Polymer Functionality
Blending time/end point
Roll force
Roll gap
Roll speed
Feed screw rate
Milling conditions
Blend time/end point
Compression force
Press speed
Feeder speed
Pan Speed
Environmental
Efficiency Factor (EEF)
Blend Uniformity
Ribbon Attributes
• Porosity
Granule Attributes
• psd
Tablet Hardness
Blend Uniformity
Tablet Attributes
• hardness
• dissolution
Appearance,
Tablet weight gain
Clinical relevance
Pfizer • 23

Risk Assessment: Criticality Vs Non- Criticality:
(dry granulation)
� CPP’s defined on the basis of a risk analysis
(rank order)
– Parameters having high risk of affecting
Safety/Efficacy & Product Quality and therefore high
probability of product failure – Critical
– Parameters having low risk of affecting
Safety/Efficacy & Product Quality and therefore low
probability of product failure – Non-critical
Pfizer • 24

Quality Risk Assessment : Failure Mode Effect
Analysis (FMEA)
� Team of experienced people from the organization
– R & D (Product Development, Analytical Development)
– Operations (Manufacturing, Technology, Process Engineering,
QA/QC)
� Review of the Process-Use flow chart & identify each component
� Structured evaluation of the process
– What can go wrong? Areas of failure
– What are the consequences? Failure modes
– Severity ? Probability (Occurrence) ? Detectability ?
� Preventive and corrective actions, Risk Mitigation
– Avoid failure modes; Increase Detectability; Decrease
Consequences
Pfizer • 25

Quality Risk Assessment (QRA): FMEA
Evaluation & Criteria
� Evaluation and quantification of risks
– Probability(P)= Probability of a certain failure to occur
– Severity (S) = Magnitude of the impact of such a failure
– Detectability (D) = The level or ability to measure such a
failure
– Risk Priority Number, RPN
– RPN = P x S x D
– Values can range from 1-125. (for 1-5 scale)
� Criteria for Risk Mitigation (is there a risk to product quality?)
– What is an acceptable RPN? For e.g. RPN > 60
– How do we define criticality? For e.g. Criticality > 15
– If any individual factor get highest ranking. For e.g. 5
Pfizer • 26

Risk Assessment: FMEA for Roller Compaction Unit
Operation
Potential Failure Potential Effect Of
Failure
No Roll Gap Control - Not be able to achieve
cannot maintain control compression parameters
Not be able to achieve
compression parameters
Not be able to achieve
compression parameters
Mill Unit Failure
material sticking
Not be able to achieve
compression parameters
large particles, foreign
matter, contamination,
incompressibility
Severity
Potential Causes
Occurance
Controls
3 Failure of Gap
control system
2 particle size PAT 2 12 6
3 API particle size; 2 Raw material physical 1 6 6
morphology
characteristics
3 Flow of blend, 2 Raw material
2 12 6
material bridging characteristics, rotary
valve, gap safety
shutoff, particle size
PAT
3 Improper set up, 2 training, tolerance and 2 12 6
preventive
maintenance,
equipment failure
feedback control loops
3 screen breakage 1 Particle Size PAT 2 6 3
burn granulation 3 clog of screen 1 Particle Size PAT,
material backup
Flow issues of blend; excess
fines
large particles,
incompressibility,
eventually damage
equipment
2 milling speed
incorrect,
computer failure
1 control loops rpm,
particle Size PAT
3 improper setup 1 training, particle size
PAT
Detection
RPN
2 6 3
2 4 2
2 6 3
Change in porosity, 3 Material sticking to 1 visual observation, 2 6 3
the kerning
scraper set up
Reduce Throughput 1 Material sticking to 1 visual observation, 2 2 1
the kerning
scraper set up
Total Risk Priority Number= 72
Pfizer • 27
Criticality

Risk Assessment :Individual risks (Roller
compaction)
RPN Numbers
14
12
10
8
6
4
2
0
Roller Compaction
Failure of Gap control system Flow of blend, material bridging Improper set up, preventive
maintenance, equipment failure
Potential Cause
Pfizer • 28

RPN Numbers
Risk Assessment: Individual risks (Tablet
compression)
30
25
20
15
10
5
0
over
compression
during roller
compaction
Equipment
setup,
mechanical
issues
w eight
variation, flow
issues
particle size
distribution,
too many
fines
Tablet Compression
flow ability of
blend
mechanical
issues -
paddles
Potential Causes
mechanical
issues -rotary
valve
segregation
of particle
size
tooling w ear failure of
w eight
checking
control loop
Pfizer • 29

Risk Assessment: Risk Prioritization Matrix
Risk Prioritization Matrix
QUALITY ATTRIBUTES POLYMER CONCENTRATION
POROSITY/ROLL FORCE/ ROLL GAP
COMPRESSION MACHINE SPEED
ROLLER COMPACTOR FEEDER SPEED
COMPRESSING FORCE
FINAL BLEND LUBRICATION TIME
API PARTICLE SIZE
PSD OF INTRA-GRANULAR BLEND
PRIMARY BLEND TIME
EXCIPIENT PARTICLE SIZE
PRE-COMPRESSION FORCE
DISSOLUTION 10 1 1 1 1 2 1 1 1 2 1 10 3
ASSAY/ POTENCY 5 7 1 1 1 5 5 1 3 2 1 10 2
UNIFORMITY 2 7 5 7 1 2 5 5 8 4 1 7 2
HARDNESS 6 9 7 7 10 10 6 5 6 5 8 3 10
THICKNESS 3 2 3 1 10 1 1 1 1 2 7 2 5
FLOW 7 5 4 7 2 2 5 8 5 5 2 1 4
APPEARANCE 5 5 3 5 5 3 3 5 1 5 3 6 4
STABILITY 1 1 1 1 1 1 1 1 1 1 1 6 1
YIELD 2 4 10 4 1 1 2 3 1 1 1 6 10
TOTALS (Quality ) 243 225 170 159 121 148 156 134 139 134 97
% IMPORTANCE 14.08% 13.04% 9.85% 9.21% 7.01% 8.57% 9.04% 7.76% 8.05% 7.76% 5.62%
rank 1 2 3 4 10 6 5 8 7 8 11
TOTALS (Manufacturing ) 188 212 229 183 196 156 141 153 125 129 153
% IMPORTANCE 10.08% 11.37% 12.28% 9.81% 10.51% 8.36% 7.56% 8.20% 6.70% 6.92% 8.20%
rank 4 2 1 5 3 6 9 7 11 10 7
where:
Priority = Importance of the Process Parameter (column) to the Quality Attribute (row) as determined
by the FMEA Team
QUALITY COMPLIANCE PRIORITY
Totals = the Sum of Each Priority in the specific column x Weighted Average for the Quality attribute
Percent Importance = the Total result for the column / sum of all totals
Rank = the rank of each parameter in respect to other parameters
MANUFACTURING PRIORITY
Pfizer • 30

Risk Assessment: Pareto Chart-Relative Importance
of Inputs
Percent Importance
16.00%
14.00%
12.00%
10.00%
8.00%
6.00%
4.00%
2.00%
0.00%
POLYMER
CONCENTRATION
POROSITY/ ROLL
FORCE/ ROLL GAP
COMPRESSION
MACHINE SPEED
ROLLER
COMPACTOR
FEEDER SPEED
COMPRESSING
FORCE
Quality Compliance Priority
Manufacturing Priority
FINAL BLEND
LUBRICATION TIME
API PARTICLE SIZE
PSD OF INTRA-
GRANULAR BLEND
PRIMARY BLEND
TIME
EXCIPIENT PARTICLE
SIZE
PRE-COMPRESSION
FORCE
Pfizer • 31

Risk Assessment Results: FMEA Vs Risk
Prioritization Matrix
� FMEA helped in identification of relative risks
associated within each unit operation. Based on the
RPN & Criticality we were able to identify the
individual risks with highest impact.
� Based on process understanding Risk Prioritization
Matrix was used to identify and prioritize both process
parameters (Inputs) and quality attributes(Outputs)
� Overall, both tools resulted in similar outcome.
Pfizer • 32

Risk Assessment: Conclusions
Identification of CPP & CQA
Process Parameter Quality Attributes
Raw Material
Attributes
Bin Blend
Roller Compaction
Bin Blend
Compression
Film Coating
Polymer Viscosity,
Polymer Functionality
Blending time / end point
Roll force
Roll gap
Roll speed
Feed screw rate
Milling conditions
Blend time/end point
Compression force
Press speed
Feeder speed
Pan Speed
Environmental
Efficiency Factor (EEF)
Blend Uniformity
Ribbon Attributes
• Porosity
Granule Attributes
• psd
Tablet Hardness
Blend Uniformity
Tablet Attributes
• Hardness
• Dissolution
Appearance,
Tablet weight gain
Clinical relevance
Pfizer • 33

B mm
A mm
Roll gap
Case Study-Dry Granulation Design Space:
Critical Process Parameters
Roll
force
x bar y bar
low
Critical Process Parameter
Polymer
Roll Gap
Roll Force
high
Critical Quality Attributes
Hardness
Dissolution
Pfizer • 34

Case Study- Takeaways
� Important to understand the properties of the Drug Substance and its
influence on Drug Product.
� Raw materials characterization-Functionality of excipients. Rationale for
excipients based on formulation dictated by the QTPP
� Identify the CQAs based on prior knowledge and QTPP.
� Use prior knowledge and risk assessment to identify the critical
parameters or attributes. Establish link between CPP & CQAs. Use risk
management techniques to prioritize the parameters to study.
� Primary assessment and designation of criticality is based on the impact
the quality attribute or parameter has on the safety, efficacy and quality of
the product.
� Criticality- can be viewed as a continuum.
� Selection of the CQAs and the CPPs is an important outcome that lays the
foundation for what is included in the design space and control strategy.
� Polymer is the primary driver of clinical performance
� Enhanced understanding of the product & process thus building product of
desired quality.
Pfizer • 35

Key Learnings and Challenges
� Basis for criticality should be clear and concise. Criticality can be a continuum.
Operationalization of QRM.
� Harmonize QbD concepts including terminology for risk management and its
understanding
– Enable common understanding of risk management between
industry/regulatory authorities
– Submission of risk assessment to dossiers- Need consistent process across
industry Raw material
� Characterization and functionality of excipients. Incorporate the variability of raw
materials in the DoE’s. Understanding on the limitations of the type of studies.
� Primary goal of QbD is to have an enhanced process and product
understanding.
� Based on the case study- Process understanding and control indicate the
potential of product release without dissolution- Opportunity for RTRT
� Some of the key challenges for implementation of control strategy in RTRT -
– Disaster recovery plans in the event of PAT failure, sample plan justification
– Model Maintenance, Handling of exceptions.
– Batch release process in the RTR environment.
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Acknowledgements
Parimal Desai
Syd Shah
Arwinder Nagi
Dominic Ventura
Loren Wrisley
Carl Longfellow
Chris Diorio
Ashwin Jain
Carlos Conde Reyes
Steve Simmons
Ferdinando Aspesi
ISPE-PQLI
Pfizer • 37