3rd Annual QBD Conference

8/12/2011
Quality by Design for the Development

of NDA and ANDA Products
Beth A-S. Brown, Ph.D., R.Ph., Sarah Betterman, and Stacy Levy
September 14, 2011
Objectives
` Quality by Design Highlights

` Utilizing QbD tools
` QTPP
` Process Mapping
` Risk Management Tools
` Case study – Use of QbD for an
ANDA product
NDA product
` Comparison Summary
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Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
A New Quality Paradigm
` Science and risk-based

approaches to product
development, dossier
submission, review,
inspection, and post-approval
change management.
` Manufacturers empowered
and accountable to effect
continuous improvement and
t h i l iinnovation
technical ti
throughout the product
lifecycle.
` Efficient and consistent
regulatory oversight
across/between regions
Adapted from J. Moranes, ISPE Nov 2007
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Benefits of Quality by Design

` QbD is an effective method for:
` Developing new products and processes
` Enabling effective technology transfer
` Optimizing and improving existing processes
` Design Space is a critical component of QbD producing:
` On-target and within-specs performance at minimum cost with
fewer deviations
` Greater flexibility in process operation
` Regulatory flexibility
` Technology
gy Transfer is more robust
` Process and product understanding built into control strategy and
change management systems
` Process control obtained through routine, coordinated
trending
Factors for Success

` Prior to effective QbD implementation within an
organization, the following success factors need to
be realized
` Recognition of the Value Proposition/Strong Management Support
` Timelines and Resources to Support QbD
` Quality Target Product Profile and Risk Management Tools
` Knowledge Management System
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Value Proposition/Management Support

` Successful organizations have QbD flowing from the
top-down
` Select “pilot”
pilot program to demonstrate the benefits of
some or all aspects of QbD implementation
` Value of resource savings, time savings, and
potential regulatory benefits should be presented to
management to gain support
Timelines and Resources to Support QbD

` QbD implementation requires a strong time
investment up-front to ensure understanding of
product and process
` Creating a culture change needs to be a top priority – faster is not
always better
` Pay now, not later mentality – early resource commitment ensures
data to support submission and regulatory review
` Coordinated, cross-functional strategy which clearly
defines roles and responsibilities is a necessity
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Quality Target Product Profile and

Risk Management Tools
` QTPP defines targets for product development

` Effective use of risk management tools will provide
key understanding of Critical Quality Attributes and
Critical Process Parameters
` Consistent use of these tools will provide maximum
benefit
Knowledge Management System

` Determine up-front how knowledge will be captured,
stored, and evaluated
` Sharing of information across departments and
across projects will increase efficiencies and
strengthen justification of design space
` Starting point for future development programs
utilizing similar drug delivery technology
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Objectives

` QTPP
` Process Mapping
ANDA product
` Case study – Use of QbD for a
NDA product
Quality Target Product Profile
` Needs to be derived from the Target Product Profile

` But what is the TPP,
TPP what is its scope,
scope and who is
responsible for maintaining it?
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Working Outside of the R&D Bubble!
TPP Collaboration and Multiple Touch

Points Throughout Development
Research and Clinical Development

Development
Marketing Regulatory
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Multiple Definitions
` Marketing: A document describing how the intended

product will be differentiated in the marketplace
` Clinical: An R&D tool used to guide the clinical
development program
` Regulatory: A document, in the format of draft
labeling, intended to facilitate discussions between
industry and regulators
Source: Tebbey, Rink, Journal of Medical Marketing, Vol. 9, 4, 301-307
Finding Common Ground

` Resources need to be available to commit to TPP
development, so that translation to a robust QTPP is
possible
` When the “end in mind” is not clearly defined, it is
difficult to systematically structure the development
program to meet desired endpoints
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` Intended use in the clinical setting
` Route of administration, dosage form (delivery systems),
and container closure system
` Quality attributes of drug product
` Appearance, Identity, Strength, Assay, Uniformity,
Purity/Impurity, Stability, and others
` Active pharmaceutical ingredient release or delivery and
attributes affecting pharmacokinetic characteristics (safety
and efficacy)
y)
` Dissolution, aerodynamic performance
Yu, Understanding Pharmaceutical QbD presentation
Modified Release Solid Oral Product

QTPP Example
QTPP Element Target Justification
Pharmaceutical equivalence
Dosage Form Tablet requirement
Route of Administration Oral requirement
Dosage Strength 10 mg requirement
Container Closure HDPE bottle with Child Resistant (CR)
System Caps Needed for commercial reasons
Example MR tablet provides initial
Biphasic release of the drug, initial plasma concentrations through the
rapid release followed by sustained first two hours that provide for a
release of dose. Fasting study and fed clinically significant therapeutic
study 90% confidence interval of the effect. Sustained release phase
Dissolution/ PK parameters AUC0‐2, AUC2‐24, designed to maintain plasma
Pharmacokinetic Profile AUC0‐∞, and Cmax should fall within concentrations for maintenance of
Requirements BE limits
BE limits. therapeutic effect
therapeutic effect.
Drug Product Quality
Attributes* See CQAs
At least 24‐month shelf life at room
Stability temperature Needed for commercial reasons
A scored tablet can be divided into
two 5mg tablets. Taken without Pharmaceutical equivalence
Administration regard to food (no food effect). requirement
*Appearance, ID, Assay, CU, Degradation products/residual solvents, Dissolution, Microbial Limits
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QTPP Example cont. (CQAs)
Drug Product Is this
Quality Attributes Target Critical*?
Similar in size and shape to
Appearance RLD, scored as RLD Yes
Identification Positive for drug substance Z
Positive for drug substance Z No
Assay 95.0 to 105.0% of label claim Yes
Complies with harmonized
requirements for uniformity of
Content dosage units (both whole and
Uniformity half tablet) Yes
NMT qualification threshold for
specified impurities, NMT ID
Degradation threshold per ICH QB3 (R2) for
Product/Residual un‐ID'd impurities, conform to
Solvent USP 467 No
Must provide rapid initial
release followed by sustained
release (specified apparatus
and pH buffers), similar release
for whole and half tablets,
alcohol induced dumping
Drug Release comparable to RLD Yes
*Critical Quality Attributes (CQAs) are those that can be potentially impacted by formulation and
manufacturing processes.
Process Mapping: Ishikawa Fishbone

Cause and Effect Diagram – a diagram which shows the
relationship between a quality characteristic (CQA) and
factors (CPP)
Hitoshi Kume, Statistical Methods for Quality

Improvement
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Ishikawa Fishbone Diagram – Helpful

Hints
` Identify all the relevant factors through examination
and discussion by many people
` Express the characteristic as concretely as possible
` Make the same number of cause-and-effect
diagrams as that of characteristics
` Choose a measurable characteristic and factors (if is
impossible to measure, consider substitute
characteristics)
` Discover factors amenable to action

Improvement
Ishikawa Fishbone Diagram Example
Blending Milling Tableting

Raw Materials
Time
Time Hardness
Excipients Batch Size
API Pressure
Tablet Speed
Meets Assay Specification
Yrs. Experience
Sampling
Training
Method
Personnel Analytical
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Process Mapping: Flow Down Map
Softgood Softgood Raw Material: Active pharmaceutical ingredient (API),

Raw Material
excipients, solvents, etc.
Process
Process: Manufacturing process such as blending, compression,
wet granulation, etc.
Intermediate
Intermediate: In-process material such as a powder blend,
uncoated
d tablet,
bl extrudate,
d etc.
Hardgood Raw Material: Typically packaging components such

as bottles, caps, desiccants, etc.
Flow Down Map Example
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Process Map Definitions

Inputs: Process Variables:
•Raw or in-process •Independent variables
material attributes
•Raw material levels
Process Variables
•Raw material grades
Inputs Unit Operation Critical Outputs
butes
Process Attributes: p
Critical Outputs:
Process Attrib
•In-process material •Critical process attributes
attributes created by that act as inputs to the
process next unit operation
•Process equipment
measurements (dependent
variables)
Process Map Example

emperature
Weight Gain
of Rotations
Fill Volume
Compresssion Force
nal Speed
Order off Addition
g Design
Press Speed
Atomization
Sprayy Rate
Product Te
Coating W
Blender F
Tooling
Rotation
Number o
ntegration
Uniformity
Content
Tablet Thickness
niformity
ardness
API Unifformity
Weight
ution
ution
Moisture C
Tablet W
Dissolu
Dissolu
Tablet Disin
Tablet Ha
Excipient U
Visual Un
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Class Exercise
` Divide room into groups of 3 to 5
` Select one process mapping tool
` 20 minutes to complete
` Discuss what information was gathered with each
tool
Benefits of Process Mapping Tools

` Ishikawa Fishbone Diagram
` Takes into more than just processes
` Operators
` Analytical methods
` Materials
` Focus on one critical quality attribute (characteristic)
` Flow Down Map
` One snapshot of the whole process & subprocesses
` See how each step feeds into other steps
` See how lower levels will affect higher levels
` Process Map
` Details of each unit operation
` Focus is on the variable/factor level
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Some Quality Risk Management Tools

` Risk Register (developed by USL)
` Qualitative “Stop Light” tool
` Cause and Effect Matrix
USL Risk Register – Probability and

Severity
Probability
Category Rank Likelihood of
Critical Quality Attribute: A physical,
Occurrence chemical, biological or microbiological property
Very High 5 Is almost certain to occur or characteristic that should be within an
High 4 Is likely to occur appropriate limit, range, or distribution to
Medium 3 Is as likely as not to occur ensure the desired product quality.
Low 2 May occur occasionally
Very Low 1 Unlikely to occur
Severity
Category Rank Definition
4
4 8 12 16 20 Very High 4 Critical quality attributes cannot be met
High 3 Critical quality attributes may not be met
3 6 9 12 15 Medium 2 Non-critical quality attributes may not be

3 met
Low 1 No effect, or aesthetic effects only
Severity
2 2 4 6 8 10
1 1 2 3 4 5
1 2 3 4 5
Probability
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Example USL Risk Register

Quality
Risk Description Probability Severity Score Attribute Document Link Risk Owner Action
API
Company X API may fail the release/
Particle Size Spec. due to its Particle
process variability. 1 2 2 Size Chemistry Monitor
API
FDA may require USL release/
tightening the particle size Particle
distribution criteria in future. 1 2 2 Size Chemistry Monitor
Roller Compaction Process:
Addition of fines from the
process back into the In-
granulation could impact process
processability 2 3 6 Spec Pharm Dev Exp.
API
Company X’s change in release/
manufacturing process could Particle
impact the particle size Size
distribution and processability Exp. with
of the API. 4 2 8 Pharm Dev new lot
Company X’s change in API
manufacturing process will release/
introduce new residual residual Test with
solvents to the API. 5 1 5 solvent Chemistry new lot
Qualitative “Stop Light” Tool Example

Drug Layer Formulation Variables
Drug Drug Viscosity of
Product
Product Core Selection substance
Core Selection substance Binder
Binder Binder lot to
Binder lot to API/Binder
API/Binder drug
drug layering
layering
CQA (type/size) particle size type/grade lot variation ratio solution
Assay Low Low Medium Low Medium Medium
Content
Uniformity High Low Medium Low Medium Medium
Drug
Release Low Low High Medium High Medium
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Cause & Effect Matrix

Criteria Assay Dissolution Appearance Stability
Strongly Strongly Strongly
Scoring: 9 Effect Strongly Effect Effect Effect
Moderate Moderate Moderate Moderate
3 Effect Effect Effect Effect
Minor Minor
1 Effect Minor Effect Minor Effect Effect
0 No Effect No Effect No Effect No Effect Total Weight

Weight 50 30 10 10 100
# Reviewer Process Step Total Score
1 DC Blending 9 3 9 3 660
2 TN Milling 9 9 1 3 760
3 DM g
Tableting 1 9 9 1 420
4 DM Packaging 3 1 9 9 360
Class Exercise continued

` Divide room into groups of 3 to 5 again
` Select one risk management tool
tool
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Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
ANDA Products - CMC

` API and excipients are well characterized
` Reference Listed Drug (RLD) Package
Insert/Deformulation
` Product formulation is semi-quantitatively known
` Good idea of manufacturing process
` Analytical methods may be USP monographed
` Aspects that may not be identical to RLD
` Formulation
` Manufacturing equipment & process parameters
` Packaging equipment & process parameters
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QbD Process Flow
ANDA Oral Solid Product Case

Study
Source: www.ispe.org/pqli
ANDA Quality Target Product Profile
Quality Target Product Profile: A prospective summary of

the quality characteristics of a drug product that ideally will be Target
achieved to ensure the desired q quality,
y, taking
g into account Product
safety and efficacy of the drug product. Profile
Definition
of Product
Attribute Target Intended
Use and
Dosage Form and Size Product X, XX mg dose
pre-
Strength XX mg API per X mg dosage unit definition
(XX.XX% w/w anhydrous drug load) of Quality
Targets
Appearance/Description Similar to Innovator
(clinical
Identity List API (include compendial references) relevance,
A
Assay C
Commonly l 90 – 110% efficacy,
safety)
Moisture List target
Uniformity Meets USP
Impurities List impurities and known limits
Stability XX Months
PK/PD (Bioequivalence) Passes BE testing
Manufacturing Process Scalable, Reproducible, and Robust
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ANDA Flow Down Map
ANDA Risk Assessment Overview

Prior
` Used the Quality Target Product Know-
ledge
Profile and the Process Map together Summary
to perform a risk assessment of Prior
Scientific
Knowledge
` Risks were identified as high or low (drug
substance,
` Any risk that was unknown was process,
unit ops,
etc.), Initial
labeled as high Risk
Assessment
to identify
Critical
Quality
Attributes
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ANDA Early Qualitative Risk

Assessment
Formulation Manufacturing
Composition Process Packaging
Dosage Form Low Low Low
St
Strength
th CPP L
Low L
Low
Appearance/Description CPP High Low
Identity CPP Low Low
Assay CPP Low Low
Moisture High High Low
Uniformity Low High High
Impurities Low Low Low
Stability Low Low High
PK/PD High High High
Manufacturing Process CPP High High
• Some aspects of the formulation are known at the

project start
• Many aspects of the manufacturing process and
packaging have high risk to the QTPP at this stage
Analysis Pointed to Formulation and

Processes
Process
Three high level sources of risk to the drug product: Develop-
ment
` Formulation
F l ti Composition
C iti
Overview of
Quality by
` Manufacturing Process Design key
actions and
` Packaging Process & Materials decisions
taken to
develop
New
Scientific
¾ All high risk areas were addressed using experimentation Knowledge,
¾ Both small scale and large scale equipment were utilized e.g. DoE,
PAT Risk
PAT,
¾ Experimentation was a mix of standard experimentation and Design of Assessment
Experiments and Risk
Control
¾Goal is to eliminate and/or mitigate all high risk areas (more learning can
change a high to a low OR identify Critical Process Parameters)
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ANDA Early Risk Assessment - Blending

Risk assessments can be focused to specific unit operations or raw
materials
Blender Fill
Volume Order of Addition # of Rotations
Strength Low Low Low
Appearance/
Description Low High High
Identity Low Low Low
Assay Low Low Low
Loss on Drying Low Low Low
Uniformity CPP High High
I
Impurities
iti L
Low L
Low L
Low
Stability Low Low Low
PK/PD Low Low Low
Manufacturing
Process High High High
ANDA Data Modeling

` Modeling of data is a useful tool for identifying a
design space, especially with multiple factors
(variables)
` Can be done “after the fact” – do not always need a
DOE designed at the experiment start
` Still need to make sure data covers the entire region of
interest
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ANDA Packaging DoE

Graph Builder
Parameter 3 (units) vs. Parameter 4 (units) by Parameter 2 (units) & Parameter 1 # Failures
(units) 0.0
Parameter 2 (units)
1.0
442 600 755
2.0
3.0
70
23
60 4.0
50 5.0 # Failures
40 6.0
7.0
70
8.0
Parameter 1 (units)
30
Parameter 3 (units)
60
50 9.0
40 10.0
0.0
70
1.0
37
60
2.0
50
40 3.0
4.0
70 5.0 # Failures
44
60
6.0
50
7.0
40
8.0
240260 280 300 320 340 240260 280 300 320 340 240260 280 300 320 340
Parameter 4 (units) 9.0
10.0
ANDA (High Level) Later Risk Assessment

Formulation
Composition Blending Packaging
Strength
g CPP Low Low
Appearance/Description CPP CPP Low

Assay CPP Low Low
Moisture CPP Low Low
Uniformity Low CPP CPP
Stability Low Low CPP
PK/PD Low Low Low
Manufacturing Process CPP CPP CPP

• High risk areas identified at project start are now either:
• Low – experimentation showed no effect on QTPP
• CPP – experimentation showed an effect on QTPP
and Critical Process Parameter is controlled
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Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
NCE NDA Products - CMC

` New to the world
` API
` Form(s)
` Physicochemical characteristics, eg. solubility
` Process for manufacture unknown
` Analytical Methods
` Formulation
` Manufacturing process
` P k i
Packaging
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505b2 NDA Products - CMC

` Knowns
` API
` Form(s)
` Process for manufacture
` Some analytical methods may be applicable
` Unknowns – New to the World
` Formulation
` Packaging
QbD Process Flow
505b2 Oral Solid Product

NDA Case Study
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NDA Quality Target Product Profile

Attribute Target
Dosage Form and Size Product Y, Maximum Size of XX dimensions

Target
Strength XX, XX, XX and XX mg Product
Appearance Colors defined by Marketing Profile
Identity API Name Definition
Assay 90-110% of Product
Intended
Uniformity Meets USP Use and
Degradation Products/ List impurities and/or degradation products and pre-
Impurities known limits definition
of Quality
Targets
Dissolution Timepoint 1: NMT XX% released (clinical
Timepoint 2: XX% - XX% released relevance,
Timepoint 3: XX% - XX% released efficacy,
Timepoint 4: NLT XX% released safety)
Stability XX months expiry
PK/PD List in vivo criteria
NDA Flow Down Map
Prior
Process
Know-
Outline
ledge
List of Unit Summary
Operations of Prior
that lead Scientific
to Knowledge
intended (drug
drug substance,
substance process,
or drug unit ops,
product etc.), Initial
(
(could
ld b
be Ri k
Risk
analytical) Assessment
to identify
Critical
Quality
Attributes
Drug Delivery Technology, Jan 2010, Vol.

10 No 1
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NDA (High Level )Risk Assessment
Unit Operations
Formulation Container
Composition 1 2 3 4 5 6 7 8 Closure System
Dosage Form Low Low Low Low Low Low Low Low Low Low
Strength Low Low Low Low Low Low Low Low Low Low
Appearance Low Low Low Low Low Low Low Low Low Low
Identity Low Low Low Low Low Low Low Low Low Low
Assay Low Low Low Low Low Low Low Low High Low
Uniformity Low High Low Low Low Low Low Low Low Low
Degradation Products Low Low Low Low High Low Low Low Low High
Dissolution High Low Low Low Low High High High High Low
Stability High Low Low Low High Low High Low Low High
PK/PD High Low Low Low Low High High High Low Low
Manufacturing Process High High High High Low High High High Low Low
Analysis Pointed to Manufacturing

Process
Process
Ten overall sources of risk to the drug product: Develop-
ment
` Formulation
F l ti Composition
C iti ` Unit
U it O
Operation
ti 5
Overview of
Quality by
` Unit Operation 1 ` Unit Operation 6 Design key
actions and
` Unit Operation 2 ` Unit Operation 7 decisions
taken to
` Unit Operation 3 ` Unit Operation 8 develop
New
` Unit Operation 4 ` Container Closure Scientific
Knowledge,
¾Process Steps
System
p 1-3 have the highest
g risk to the p
product p
progressing
g g
e.g. DoE,
PAT Risk
PAT,
(based on prior knowledge, experience, etc.) Assessment
and Risk
¾ More thorough understanding needed earlier rather than later Control
¾Formulation fixed based on in vivo performance requirements
¾Other Process steps are relatively straightforward
¾ Can be looked at in more detail at a later date (lower priority)
¾Container closure system has been explored
¾ Data in-process (stability)
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NDA Detailed Risk Assessment

Evaluation of Unit Operation 1 Evaluation of Unit Operation 2
Parameters Parameters
1 2 3 4 5 6 1 2 3
Assay Low Low Low Low Low Low Assay Low Low Low
Uniformity High High Low Low Low Low Uniformity Low Low Low
Degradation Degradation
Products Low Low Low Low Low Low Products Low Low Low
Sulfate/Sulfamate Low Low Low Low Low Low Sulfate/Sulfamate Low Low Low
Dissolution Low Low Low Low Low Low Dissolution Low Low Low
Stability Low Low Low Low Low Low Stability Low Low Low
PK/PD Low Low Low Low Low Low PK/PD Low Low Low
Manufacturing Manufacturing
Process Low High High High High High Process High Low High
Evaluation of Unit Operation 3 • All three unit operations are

Parameters linked together
1 2 3 4 5
Assay Low Low Low Low Low • Used DOE as an efficient
Uniformity Low Low Low Low Low way to screen through
Degradation Products Low Low Low Low Low
Sulfate/Sulfamate Low Low Low Low Low
parameters and focus on the
Dissolution Low Low Low Low Low few of high importance
Stability Low Low Low Low Low
PK/PD Low Low Low Low Low
Manufacturing Process High Low High High High
What is DoE?
` DoE is “a structured, organized method for
determining the relationship between factors (X’s)
affecting a process and the output of that process
(y).” (ICH Q8)
` Process = {unit operation, formulation, assay}
` X’s = controllable (e.g., time, temp, amount of a
component) and uncontrollable (e.g., instrument,
operator, media lot) factors
` y=response
response variable
ariable
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Goals of DoE
` Efficient experimentation - versus “one factor at a
time”(OFAT)
` Reduced number of runs
` Covers wider space
` Hidden replication
` Effective experimentation - versus “one
factor at a time” (OFAT)
` Mitigates impact of artifacts such as run order and
experimental clustering
` Acknowledges main effects and interactions
Types of Designs
` Screening designs
` Used to identify significant factors
` Used to verify ruggedness
` Response surface designs
` Used to optimize a process
` Used to model a process
` Special designs
` Simplex – iterative optimization
` Mixture – constrained factors
` R b t – stability
Robust t bilit tto noise
i ffactors
t
` Split-plot – experimental units split into two dimensions
` Optimal – model is specified
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Plackett-Burman Screening Design Used
- +
Factor 1 200 300
Factor 2 1500 2500 • 9 factors each at 2
levels giving 12
Factor 3 300 500 runs
Factor 4 0 60 • Study of main
effects only
Factor 5 43 53 • No interactions
Factor 6 50 80 • No curvature
Factor 7 800 1600

Factor 8 200 500
Factor 9 2 8
Data Collection
` Responses:
` Measured material attributes from in-process material
from Unit Operations 1,
1 2,
2 and 3
` Recorded dependent process information
` Calculated process yield
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Analysis Example for Usable Product from

Unit Operation 3
Sorted Parameter Estimates
Term Estimate Std Error t Ratio Prob>|t|
Factor 6(800,1600) -15.02878 2.056689 -7.31 0.0053*
Factor 1(200,300) -7.172118 4.659808 -1.54 0.2214
Factor 2(1500
2(1500,2500)
2500) -1.596386
1 596386 2.088476
2 088476 -0.76
0 76 0 5003
0.5003
Factor 9(49,53) -2.208199 3.272166 -0.67 0.5481
Factor 5(50,80) -1.308466 2.174117 -0.60 0.5897
Factor 3(300,500) 1.2461104 2.582938 0.48 0.6625
Factor 7(200,500) -0.767327 1.938503 -0.40 0.7187
Factor 8(2,8) -0.729208 2.054873 -0.35 0.7462
Factor 4(0,1) Zeroed 0 0 . .
90
• Factor 6 had a significant
80
negative effect on the
70
usable yield
Usable (%)
60
• The higher the value of
Factor 6, the lower the
50
usable yield
40
700 900 1100 1300 1500 1700
Factor 6
Linear Fit
Overall Design Outcome
Unit Operation 1: Unit Operation 2: Unit Operation 3:

` Factor 1 ` Factor 1 ` Factor 1
Factors with significant effects (blue) were identified for each unit operation.
One factor (red) could not be evaluated in this design due to equipment
constraints.
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Narrowing Down Factors to 4 for a RSM

Design
` Factor 1- a significant factor for all three unit
operations
` Factor 4 - not able to be evaluated during this
design
` Factor 5 - a significant factor on attributes from
Unit Operation 1 in-process material and is likely
related to Factor 1 and Factor 4
` Factor 7 – a significant factor for numerous
product attributes
Translation to RSM
- +
Factor 1 200 250
Factor 2 2000
Factor 3 500
Factor 4 0 20
Factor 5 48 52
Factor 6 70
Factor 7 800 1600
Factor 8 500
Factor 9 6
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Analysis Example for Unit Operation 2

Response
Factor 1(48,52) -0.143333 0.015699 -9.13 <.0001*
Factor 1*Factor 4 -0.135 0.027191 -4.96 0.0001*
Factor 7(800,1600)
7(800 1600) 0 0516667 0.015699
0.0516667 0 015699 3 29
3.29 0 0046*
0.0046
Factor 4*Factor 5 -0.0775 0.027191 -2.85 0.0116*
Factor 1*Factor 1 0.0426667 0.021062 2.03 0.0598
Factor 5*Factor 7 -0.05 0.027191 -1.84 0.0846
Factor 1*Factor 5 -0.04 0.027191 -1.47 0.1607
Factor 1*Factor 7 -0.04 0.027191 -1.47 0.1607
Factor 5(180,220) -0.019167 0.015699 -1.22 0.2398
Factor 4(0,20) -0.000833 0.015699 -0.05 0.9583
• Analysis gives a response surface

• Includes interactions
• Includes curvature
• Two main effects and two 2-factor
interactions were significant
• Can use many models together to
predict future behavior of the process
Mathematical Optimization was Performed to

Give Desired Responses
` Important goal was to have a high yield with minimal

waste
` All response surfaces generated were used to identify
processing parameters to meet this goal
` Final Outcome:
` Factor 1 Æ 200 (low)
` Factor 4 Æ 52 (high)
` Factor 5 Æ 0 (low), but formulation dependent
` Factor 7 Æ 1200 (center point)
` These parameters were used to manufacture small
scale material and were used to give starting points for
the commercial process.
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Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
Comparison Summary
` Major QbD Focus ANDA NDA
API √
Excipients √
Formulation √ √
Manufacturing √ √
Packaging √ √
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Conclusions
` Independent of the type of submission, QbD
principles can and are being applied in
bio/pharmaceutical development.
development
` Risk management tools provide a means for
determining the focus and how QbD is applied
throughout the development program.
` Higher risk, more complex technology = more
evaluation of p
process steps
p and factors ((CPP)) and
the determination of CQAs.
` The use of multiple tools allows the information to be
analyzed in different ways, providing new insights.
` Extra Slides
35
8/12/2011
Introduction to ICH Q8, Q9, Q10

` ICH Q8 – Pharmaceutical Development
` Describes the suggested content for the 3.2.P.2
((Pharmaceutical Development)
p ) Section of a
regulatory submission in the CTD format.
` Annex to the guidance describes the principles of
Quality by Design.
` ICH Q9 – Quality Risk Management
` Provides principles and examples of tools for quality
risk management that can be applied to different
aspects
p of p
pharmaceutical q
quality.
y
` ICH Q10 – Pharmaceutical Quality System
` Establishes a new ICH tripartite guideline describing
a model for an effective quality management system
for the pharmaceutical industry.
ICH Q8 - Highlights
` The aim of pharmaceutical development is to
design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product.
` Quality should not be tested into products, it
should be built in by design.
` Greater understanding of the product and its
manufacturing process,
process through the
implementation of quality by design, can create
a basis for more flexible regulatory
approaches.
36
8/12/2011
ICH Q9 - Highlights
` QRM is a systematic process for the
assessment, control, communication, and
control off risks to quality off a drug product
across the product lifecycle.
` Two primary principles of QRM:
` The evaluation of the risk to quality should be based
on scientific knowledge and ultimately link to the
protection of the patient
patient.
` The level of effort… of the QRM process should be
commensurate with the level of risk.
ICH Q10 - Highlights

A model for a pharmaceutical quality system that can be
implemented throughout the different stages of a product
lifecycle.
Implementation should result in achievement of three main
objectives:
Achieve Product Realization – establish, implement and
maintain a system that allows delivery of products with
appropriate quality attributes
Establish and Maintain a State of Control – develop and use
effective monitoring and control systems for process
performance and product quality
Facilitate Continual Improvement – identify and implement
appropriate product or process quality improvements
37
9/23/2011
Development of HPLC Methods:

a QbD Approach
Daniel Song
Pfizer Inc
Sept. 15, 2011
Outline
Benefits of analytical QbD and regulatory

expectation
t ti
New concepts for analytical QbD
Technique selection and development of
starting method conditions
Structured risk assessment
Establishment of method operation space
QbD method control strategy
Case study
1
9/23/2011
Recognized Opportunities for Improvement
Method validation and transfer a ‘check box’ exercise

Rather than adding value in assuring method performance through the
lifecycle.
Traditional approach to validation did not take account of
modern Six Sigma concepts.
Ability to introduce improvements to methods severely
constrained by regulatory requirements.
Myriad of expectations from different regulatory and
pharmacopoeial bodies on method updates - creating
significant waste
Industry group: Pfizer, Novartis, Abbott, GSK, Boehringer Ingelheim, Sanofi-Aventis,

Merck, Astra-Zeneca, Bayer Healthcare, Purac Sandoz, Roche
Benefits of Analytical QbD
Integrate
g into p
pharmaceutical QbD p process
Increase analytical method operational
flexibility – More robust and efficient.
Greater understanding of method capability
and sources of variability
Regulatory flexibility
Optimum method success over the product
lifecycle
2
9/23/2011
Regulatory Perspective
- Moheb Nasr IFPAC 2009 Baltimore January 2009
Current status of applying QbD principles to analytical methods
What to measure/ when/where
Right technique for

measurement/characterisation
Risk of parameter/ sample variation on results
Robust method potential for multi-variant

interactions
Quality system for method and system

suitability
Monitor method performance update as needed or

as analytical technology evolves
New Concepts for Analytical QbD
Analytical Target Profile (ATP)
Method Operable Design Region (MODR)
Method Control Strategy
3
9/23/2011
Prospective summary of the requirement of a measurement

y
system that,, if achieved,, will ensure an accurate assessment
of a product quality attribute
Forms the basis for development of a QbD method or any
changes made to the method throughout the lifecycle of the
product
Requirements are not intended to be technique-specific
ATP example for a drug product purity method:
The procedure must be able to quantify specified and unspecified impurities
in the presence of drug substance, excipients and other potential impurities
and degradation products over a range from the reporting threshold to the
specification limit. The accuracy and precision of the method must be such
that the measurements fall within the range of 100% ± 15% for impurity
levels ≤ 0.15% and 100% ± 10% for impurity levels > 0.15%.
ATP – New Development

(a Total Error Type Approach)
Examples:
ssay The
Assay: epprocedure
ocedu e must
ust be ab
able
e to accu
accurately
ate y qua
quantify
t yad drug
ug
substance in a drug product over the range 70 - 130% of the
nominal concentration with specificity, linearity, accuracy and
precision such that measurements fall within ± 3.0% of the true
value with a 95% probability.
Purity: The procedure must be able to quantify specified and

unspecified impurities relative to a drug substance in presence of
the drug substance, excipients, and impurities over the range from
reporting threshold to the specification limit. The specificity,
linearity, accuracy and precision of the method must be such that
measurements fall within ± 20% of the true value for impurity
levels ≤ 0.15%, with 80% probability, and within ± 15% of the true
value for impurity levels > 0.15%, with 90% probability
4
9/23/2011
Method Operable Design Region

(MODR)
MODR is defined as the set of method parameters over
which the robustness and ruggedness experimentation has
shown the method can meet the requirements of the ATP.
Unexplored Space
Knowledge Space
Method Operable
Design Region
Target
Method
Conditions
O ti off the
Operation th method
th d within
ithi the
th MODR
Evaluation of critical method attributes
Opportunities for Continuous Improvement
5
9/23/2011
Technique Selection
Analyte’s properties understanding

Different
Diff t analytical
l ti l ttechniques
h i capable
bl off
providing the measurement as required by
ATP.
Chromatography (HPLC, UPLC)
Spectroscopy (UV, NIR)
Different methodologies (different column and
mobile phase) using the same instrument
Consider QC-friendly method and long-term
cost
Technique Selection - Example
Quality Attribute 1 Quality Attribute 2 Quality Attribute 3 Quality Attribute 4 Quality Attribute 5 Quality Attribute 6 Quality Attribute 7 Quality Attribute 8 Quality Attribute 9
Quality
Q lit Att
Attribute*
ib t * to
t be
b
measured: Identification I (per Identificaiton II NIR for API form
Assay Content Uniformity Purity Disintegration Loss on Drying Dissolution
retetion time) (per UV spectrum) confirmation
Levels at which it will be

measured: 90.0% - 110.0% LC N/A N/A 90.0% - 110.0% LC 0.05% - 2.4% 0 - 20 minutes 3-7% 50-100% 15%-100%
accuracy required:
±1.5% N/A N/A ±1.5% ±10% ±10% ±10% ±2% N/A
Range required:
70% - 130% LC N/A N/A 70% - 130% LC 0.02% - 5% 0 - 30 minutes 0 - 10 % 0 -125% 15%-100%
Type of sample (e.g.,
IPC, intermediate, Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods
finished goods, etc.):
Testing environment
(e.g., on-line, at-line, Release and Release and Release and Release and Release and
release/stability testing Release Release Release Stability
Stability Stability Stability Stability Stability
labs, etc.):
Desired method cycle

time: ≤ 10 minutes per ≤ 10 minutes per ≤ 10 minutes per ≤ 10 minutes per ≤ 35 minutes per
≤ 30 minutes ≤ 6 hours ≤ 60 minutes ≤ 30 minutes
injection injection injection injection injection
Resolution of PRI,
degradants,
No signal (i.e.
analytical artifacts,
Resolution of PRI, Resolution of PRI, absorbance) was
expcipients and
degradants, Method must be Method must be degradants, observed from a Must be capable of
Needed selectivity/ability filter extractables ≥
analytical artifacts, able to provide a able to provide a analytical artifacts, sample of differentiatign Form
of method to 1.5 from main N/A N/A
expcipients and filter positive ID for positive ID for expcipients and filter formulation D from Form A and
discriminate: band and ≥ 1.0 for
extractables ≥ 1.5 Dimebon Dimebon extractables ≥ 1.5 excipients amorphous form.
separation of
from main band from main band prepared in
specified
dissolution media.
impurities from
each other.
6
9/23/2011
Development of Starting Method Conditions
Include sample preparation and measurement

measurement.
Select dissolving solvent for rapid disintegration,
full recovery and good solution stability for HPLC.
Method screening and use of simulation
software.
M
Meet APT requirements
i
Development of Chromatographic Conditions
KPSS KPSS = Key Predictive

Sample Set
Yes No
ID. Known?
Color Key
RP
column Red: experimental
screening studies
Green:in silico
Plot of log D modeling
Column & pH Alternative
versus pH
selection mechanisms Black: Decision
points
Gradient & Temperature

Screening

Optimization
No
Meet Criteria? Yes

Verify Separation Draft method
(Rs, TF, time)
7
9/23/2011
Method Screening: Log D vs pH

3
0
0 2 4 6 8 10 12 14
Log D
-1
-2
-3
-4 pH=2.7
pH
Provides preliminary information about robustness
Method Screening: Chromatographic Conditions

Sample Set
Yes No
ID. Known?
Color Key
Red: experimental
RP studies
column Green:in silico
screening modeling
Black: Decision
Plot of log D Alternative points
Column & pH
versus pH mechanisms
selection

Screening

Optimization
No
Meet Criteria? Yes

(Rs, TF, time)
8
9/23/2011
Method Screening: Gradient and

Temperature Optimization
Identifies a suitable design region (draft method) for further evaluation
Structured Risk Assessment
Identifyy method p
parameters that could
influence method performance.
Invite method users from different labs.
Generate process map
Create cause & effect matrix
Scoring of method parameters is based on
knowledge of product and method, and ATP
requirements.
9
9/23/2011

Full Process Map
Sub Process Map
(HPLC Analysis)
Sub Process Map

(Sample Prep)
Sub Process Map (Standard Prep)
The process map for HPLC analysis includes,

Standard preparation
Sample preparation
Chromatography
Categorization of method parameters

Controllable parameters (i.e. column type)
Experimental parameters (i.e. flow rate) – for
multivariate (DOE) study
Noise parameters (i.e. column age) – for univariate
(OFAT) study
10
9/23/2011
DOE & OFAT Experimentations for

Establishment of MODR
Focus on experimental parameters and noise parameters identified in

risk assessment
assessment.
Determine critical attributes of the method (i.e. purity HPLC method)
Sensitivity (LOQ)
Accuracy
Resolution (critical pair)
Multivariate Design of Experiment (DOE) for experimental parameters

Univariate One Factor at a Time (OFAT) to study noise parameters
Established MODR based on statistical analysis
Each method parameter was evaluated against the critical
method attributes to determine operation ranges
Selection of Target Method Conditions (TMC)
Select TMC based on:

MODR
Set TMC within MODR

Consider common practice and long-term cost
Validate the TMC per ICH guideline

Also verify if edge points of the MODR can meet
the ATP criteria
11
9/23/2011
Operation of the method within the established

MODR .
Implement meaningful system suitability
checks using critical method attributes.
Continuous improvement
Facilitate the implementation of CI for analytical
methods throughout the product lifecycle
Provides extensive knowledge to make changes
within allowable limits
Case Study
Develop a QbD impurity analytical method for a drug product
12
9/23/2011
ATP for the Impurity Method
Must accurately and precisely measure specified and

unspecified impurities across a range of expected levels
in the presence of the active component, excipients, and
impurities.
The accuracy and precision of the method must be such
that measurements fall within the range of 100% ± 15%
for impurity levels ≤ 0.15% and 100% ± 10% for
impurity levels > 00.15%.
15%
Any measurement technique that is capable of achieving
this target is suitable for the testing.
Considerations for Technique Selection
Resolution:
Resolution
R l ti off critical
iti l pairs
i off d
degradants
d t ≥ 1.2
12
Accuracy:
100% ± 15% for impurity levels ≤ 0.15%
100% ± 10% for impurity levels > 0.15%
Sensitivity (LOQ):
S/N ≥ 10 for API at of 0.05% of nominal
HPLC is chosen for the impurity method
considering all the ATP requirements.
Reserved-phase gradient elution
13
9/23/2011
Development of Starting Chromatographic

Conditions for the Impurity HPLC Method
Separation of impurities is very sensitive to

organic ratio in the mobile phase (MP)
(MP).
Mostimpurities are separated in the first 18-min
where the organic in MP in increased by only 8%.
HPLC column and mobile phase screening:
Comet program
8 HPLC columns
l
4 HPLC mobile phrases
ACD program to assist method development

CHROMATOGRAPHIC CONDITIONS
Column: Luna 3u C18(2) 100A 150 x 4.6 mm

Column Temperature: 30C
Injection Volume: 5 µL
Flow Rate: 1 mL/min
Detection: 270 nm
Run Time: 35 minutes
Mobile Phase A: 0.05% TFA in H2O
Mobile Phase B: Acetonitrile/H2O/TFA = 95/5/0.05
Diluent: 0.05% TFA in H2O/ACN = 90/10
Linear Gradient Table:
Time (minutes) %A %B
0 90 10
2 90 10
20 82 18
30 45 55
30.1 90 10
35 90 10
14
9/23/2011
Risk Assessment of the Impurity Method
Included all the labs that ran the method

Development labs
QC labs
Stability labs
Risk assessment - Focus on chromatographic parameters
Chromatography
Sample preparations
Standard preparations
Method parameters were categorized – Focus on experimental and
noise parameters
Experimental (most chromatographic parameters such as flow rate)
Noise (column age)
Controllable (column stationary phase, particle size, diameter/length, etc.)
Scoring for method parameters is based on the prior knowledge of the
method and expected influence on the method performance
Use Cause and Effect Matrix
The most critical parameter with the high scores were identified for further study
Method Parameters Identified in the

Chromatography Focus Area for Further Study
Key Method parameters Identified in Parameter Type Experimental

the Risk Assessment Strategy
St ti
Stationary Phase
Ph Type
T & Particle
P ti l Size
Si Controllable Fixed
Column Preconditioning Experimental DOE 2
Column Temperature Experimental DOE 1
Stationary Phase Batch Number Noise DOE 1

Flow Rate Experimental DOE 1
Injection Volume Experimental DOE 1
TFA concentration in the mobile phase Experimental DOE 1
Gradient Profile
•% Organic Ramp 1 Experimental DOE 1
•% Organic Ramp 2
Detector Wavelength
g Experimental DOE 1
Detector Type (PDA or Single Experimental DOE 1
Wavelength)
Column Age - # of injections Noise OFAT
Column Diameter Controllable Fixed
Column Length Controllable Fixed
Column Storage Solvent Experimental DOE 2
Column Vendor Controllable Fixed
DOE = Multivariate Design of Experiments; OFAT = Univariate One Factor at a Time
15
9/23/2011
DOE and OFAT for Establishment of MODR

- Determination of the Impurity Method’s Critical Attributes
1 Resolution (≥1
1. (≥1.2)2) between these two primary degradation
products (a critical pair for resolution)
2. Accurate quantitation of the primary degradant (± 15% at
0.15 % level)
3. LOQ (S/N ≥ 10 for API at 0.05% of nominal)
The sample set used to evaluate critical method attributes
in the DOE and OFAT studies includes,
A blank (diluent) sample
A stability sample that contain the two primary degradation products.
An LOQ standard
DOE Study Involved 9 Method Parameters
Column temperature
Column
C l b
batch
t h number
b
Mobile phase flow rate
Injection volume
Aqueous mobile phase TFA concentration
Starting organic mobile phase percentage of gradient ramp 1
Detector wavelength
Detector type
Note: This is a large number of parameters. In the DOE study, the number might be
reduced.
16
9/23/2011
Parameter Ranges Studied in DOE for Purity Method
Experiment Design for DOE Study

3 10
Injection Volume (µL)
7 Ramp 1
13 7 Ramp 1 13
Beginning Beginning
Organic (%) O
Organic
i (%)
0.1
TFA Conc in
MP (%)
22
at o 2
0.05
R Fl 1.
Graphical
e w
/
in L
m (m
Organic (%)
8
Beginning
0.
27 33 27 33 27 33 27 33
)
Ramp 2
View of the
278
TFA Conc in
0.1
Design of
MP (%)
Wave Length (nm)
DOE
e w2
0.05
at o 1.
/
in L
14
m (m
R Fl8
0.
27 33 27 33 27 33 27 33
)
onc in
MP (%)
0.1
TFA Co
22
at o 2
0.05
R Fl 1.
e w
/
in L
m (m
8
Organic (%)
0.
27 33 27 33 27 33 27 33
Beginning
)
Ramp 2
262
TFA Conc in
0.1
MP (%)
at o 2
14
e w
/
R Fl 1.
in L
0.05
m (m
8
27
0.
27 33 27 33 33 27 33
Column Temp (°C) Column Temp (°C)

PDA – Column Batch 1 UV – Column Batch 1
17
9/23/2011
Experiment Design and Read-out of DOE
TFA Ramp
Flow Conc 1 Ramp Primary
Rate in Begin 2 Wave Column Critical Impurity
Temp (mL/ MP Org. Begin Inject. Length Detector Batch LOQ Pair Area Main Band
Run Block ((°C)
C) min) (%) (%) Org. (%)
Org Vol. (µL)
Vol (nm) Type # S/N Res
Res. % RT (min)
1 L01 30 1.0 0.075 10 18 7 270 PDA 1 22.0 2.01 0.15 17.266
2 L1 27 1.2 0.100 7 14 3 278 PDA 2 12.3 2.59 0.15 24.439
3 L1 27 0.8 0.050 7 14 3 262 PDA 1 24.4 2.71 0.26 25.096
4 L1 27 1.2 0.050 7 22 10 262 PDA 1 32.6 1.82 0.26 15.051
5 L1 27 0.8 0.100 7 22 10 278 PDA 2 32.5 0.06 0.14 20.67
6 L02 30 1.0 0.075 10 18 7 270 UV 1 49.5 1.99 0.15 17.516
7 L2 33 0.8 0.050 7 22 3 278 UV 1 20.7 1.27 0.14 17.473
8 L2 33 1.2 0.050 7 14 10 278 UV 2 35.5 3.17 0.14 20.593
9 L2 33 0.8 0.100 7 14 10 262 UV 1 22.9 1.43 0.24 26.268
10 L2 33 1.2 0.100 7 22 3 262 UV 2 24.2 1.31 0.26 17.465
11 L3 27 0.8 0.050 13 14 3 278 UV 1 10.2 1.28 0.15 14.578
12 L3 27 1.2 0.050 13 22 3 278 UV 2 13.0 0.95 0.17 9.039
13 L3 27 1.2 0.100 13 14 10 262 UV 2 17.2 1.51 0.31 17.184
14 L3 27 0.8 0.100 13 22 3 262 UV 1 28.1 0.56 0.32 15.759
15 L03 30 1.0 0.075 10 18 7 270 UV 2 25.2 1.97 0.14 17.975
16 L4 33 0.8 0.100 13 14 3 278 PDA 1 3.6 1.42 0.13 20.604
17 L4 33 0.8 0.050 13 22 10 262 PDA 2 33.5 0.32 0.26 10.761
18 L4 33 1.2 0.100 13 22 10 278 PDA 1 17.0 1.03 0.14 10.918
19 L4 33 1.2 0.050 13 14 3 262 PDA 2 3.3 0.85 0.26 8.999
20 L04 30 1.0 0.075 10 18 7 270 PDA 2 16.5 2.04 0.14 17.724
Statistical Analysis Results of DOE Study
Wave length should be set to 270 nm or higher. Otherwise, primary

d
degradant
d t area % wouldld be
b too
t far
f from
f 0.15%.
0 15%
The critical pair resolution is the limiting factor for the method quality
attributes selected for the study.
Medium to high flow rate (1.0 to 1.2 mL/min) and low to medium
TFA concentration in mobile phase (0.05 to 0.075%) are preferred.
High levels of beginning organics (%) for the two gradient ramps
should be avoided ((e.g.,
g close to 22 for rampp 2 and close to 13 for
ramp 1.
Column temperature (27 to 33°C), and injection volume (3 to 10 µL)
can be set in their respective ranges.
Detector type (PDA vs. UV) and column batch number seems to
have no impact on the responses.
18
9/23/2011
Establishment of Method Operable Design

Region (MODR)
The region of acceptable resolution (yellow colored) was established at flow rate of 1 mL/min and TFA
concentration of 0.075%.
Region of
Region of unacceptable
acceptable resolution
resolution
95%
confidence
limit
Method operable
99%
design region confidence
limit
(MODR)

Region (MODR)
Contour Plot of Critical Pair Resolution vs. Ramp 1 Beginning Organic and Ramp 2 Beginning
Organic (Flow rate: 0.8 mL/min, TFA Conc: 0.1%; all other factors set to their centers).
19
9/23/2011

Region (MODR)
Plot of primary degradant area% vs. wave length (nm)
Acceptable Method Parameter Ranges

within MODR
Range Studied
Target Acceptable
Parameter
Low Mid High Setting Ranges
Column Temperature (°C) 27 30 33 30 27 ~ 33
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1 ~1.2
0.05 0.075 0.1 0.05 0.05 ~ 0.075

TFA Concentration in Phase (%)
Ramp 1 Beginning Organic (%) 7 10 13 10 7 ~ 11
Injection Volume (µL) 3 6.5 10 6.5 3 ~ 10
Wave Length (nm) 262 270 278 270 270 ~ 278
Detector Type PDA, UV Any PDA or UV
Column Batch # 1, 2 Any Any
The operable ranges identified by the DOE for the method parameters are independent from each other.
The operable ranges proposed for column temperature, injection volume, wavelength, and detector type
were fully accepted per the DOE outcome.
The operable ranges of flow rate, TFA concentration, ramp 1 organic (%), and ramp 2 organic (%) were
narrowed from the proposed ranges based on the DOE results.
20
9/23/2011
Establishment of MODR for a

Similar Column
Select a similar column based on column

screening study performed at the earlier stage
Same type (i.e. C18), but different brand
Share same key method parameters
Same DOE experiment and statistical analysis
were performed
Compare the MODR’s from the two columns.

Similar Column
Similar column:
Range Studied
Hig Target Acceptable

Parameter Low Mid h Setting Ranges
Column Temperature (°C) 27 30 33 30 27 - 33
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 - 1.2
0.07
TFA Concentration in Phase (%) 0.05 0.1 0.05 0.05 - 0.10
5
Ramp 1 Beginning Organic (%) 7 10 13 9 7 - 11
Injection Volume (µL) 3 6.5 10 6.5 4.5 - 10
Wave Length (nm) 262 270 278 270 270 - 278
Original column:
Range St
Studied
died
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 ~1.2
0.07
0.05 0.1 0.05 0.05 ~ 0.075
TFA Concentration in Phase (%) 5
Wave Length (nm) 262 270 278 270 270 ~ 278
21
9/23/2011
Construction of a Common MODR

for Both Columns
Flexibilityy in column switching

g during
g the
lifecycle of the product.
Ensure successful method performance
Validation at the TMC may be needed for the
2nd column (not performed in this study)

for Both Columns
22
9/23/2011

for Both Columns
Suggested TMC and a common method operable design region (MODR) for
both columns.
Range Studied
Target Acceptable
Parameter
Setting Ranges
Low Mid High
27 30 33 30 27 - 33
Column Temperature (°C)
0.8 1.0 1.2 1.0 1.0 - 1.2
Flow Rate (mL/min)
0.05 0.075 0.1 0.05 0.05 - 0.075
7 10 13 10 7 - 11
Ramp 1 Beginning Organic (%)
14 18 22 18 14 - 18
PDA, UV Either PDA or UV
Detector Type
3 6.5 10 6.5 6.5 - 10
262 270 278 270 270 - 278
Wave Length (nm)
Assessment of MODR by Experiment
Select the original column for the study

S
Same criteria
it i off the
th critical
iti l method
th d attributes
tt ib t
used in the DOE were used
A total of 8 extreme chromatographic
conditions within MODR established by DOE
were selected for the study
All the criteria of the critical method attributes
were successfully met, confirming the MODR
established by the DOE
23
9/23/2011
Wave
Flow TFA Ramp 1 Ramp 2 Length Col Injection Resolution Primary Main
Rate Conc. Organic Organic (µm) Temp Volume of Critical S/N of Impurity Dimebon
Iminium Band
Run (mL/min) (%) (%) (%) DAD ((°C)
C) (µL) Pair LOQ Area % RT
01 1.0 0.05 10 18 270 30 5 2.1 24 0.11 15.4
1 1.2 0.05 11 14 278 30 5 2.1 17 0.11 14.2
2 1 0.075 11 14 270 30 5 2.2 10 0.11 20.3
3 1 0.05 11 18 270 30 5 1.9 18 0.11 13.8
4 1 0.075 7 14 278 30 5 2.9 33 0.10 24.6
5 1 0.05 7 18 278 30 5 2.3 17 0.10 18.6
6 1.2 0.075 7 18 270 30 5 2.2 22 0.11 19.3
7 1.2 0.05 7 14 270 30 5 3.1 10 0.12 21.2
8 1.2 0.075 11 18 278 30 5 1.9 10 0.11 14.8
1
Run 0 are the conditions set in TM10000613
Q lit attributes
Quality tt ib t used
d ffor th
the assessment:
t
Accuracy:
Limit of quantification: S/N ≥ 10 for 0.05% of the API content
Resolution of critical pairs of degradants: ≥ 1.2
Determination of HPLC Column

Preconditioning Time by DOE
This separate DOE was designed to assess
impurity method column preconditioning timetime.
It was observed in testing that the peak
retention time was not consistent.
The current method requires 5 hours
preconditioning time.
It was informed by column vendor that
injection of testing sample would facilitate the
column conditioning.
24
9/23/2011

Method parameters selected for DOE include:
1. Column preconditioning time: 0~6
0 6 Hours
2. Column storage solvent:
Initial mobile phase (10% ACN with 0.05% TFA)
50/50% ACN/Water
3. Number of samples injected during preconditioning:
0 ~ 12
Critical method attributes selected for the evaluation:
1. Critical pair resolution: ≥ 1.2
2. Limit of quantification: S/N ≥ 10 for API at 0.05% of
nominal
3. Main band retention time (for information only)

DOE experiment for column preconditioning
Numbers of
Injection of
Preconditioning
Run Storage Solvent Preconding
(hours)
Sample
1 50/50 ACN/Water 6 3
2 Initial Mobile Phase 9 6
3 50/50 ACN/Water 9 6
4 50/50 ACN/Water 0 3
5 50/50 ACN/Water 6 0
7 50/50 ACN/Water 3 6
8 50/50 ACN/Water 12 3
14 50/50 ACN/Water 6 3
25
9/23/2011

DOE read-outs for HPLC column pre-conditioning

Number of
Pre-
Samples Retention LOQ
Run Storage Solvent conditioning Resolution
Before Time S/N
Hours
Preconditioning
1 50/50 ACN/Water 6 3 16.5 1.89 18
2 Initial Phase 9 6 16.3 1.94 17
3 50/50 ACN/Water 9 6 16.2 1.96 17
4 50/50 ACN/Water 0 3 16.3 1.98 16
5 50/50 ACN/Water 6 0 16.4 1.99 19
6 Initial Phase 3 6 16.2 2.05 23
7 50/50 ACN/Water 3 6 16.2 2.07 24
8 50/50 ACN/Water 12 3 16.2 2.06 21
9 I iti l Ph
Initial Phase 12 3 16 2 05
2.05 18
10 Initial Phase 0 3 15.9 2.06 21
11 Initial Phase 6 0 15.9 2.04 21
12 Initial Phase 6 3 15.9 2.04 24
13 Initial Phase 6 3 15.8 2.04 21
14 50/50 ACN/Water 6 3 16 2.06 20

TWG6
DOE Results:
Retention time is affected significantly by the interaction of storage solvent and preconditioning
time.
time
For a column stored in initial mobile phase, the retention time tends to be significantly shorter
than a column stored in 50/50 ACN/Water if the column is not pre-conditioned at all.
On the other hand, if a column was pre-conditioned for 6 hours, the retention times would
have no significant difference for a column stored in initial mobile phase and in 50/50
ACN/Water.
Resolution is affected significantly by the interaction of pre-conditioning time and number of
sample injections before preconditioning.
Increasing number of sample injections before preconditioning will increase resolution.
However, after more than three hours pre
However pre-conditioning,
conditioning the increased number of sample
injections actually would make the resolution worse.
It seems that it may be necessary to perform both sample injections and preconditioning if
pre-conditioning time is short (<3 hours) and the number of sample injections is small (< 6).
LOQ S/N is also affected significantly by the interaction of pre-conditioning time and number of
Increasing both the number of sample injections and pre-conditioning time would be able to
increase the LOQ S/N ratio except that using more than 6 sample injections and pre-
conditioning more than 3 hours.
26
Slide 52
TWG6 would need to be more concise...given that you have a summary slide next, I would recommend
skipping
Timothy W. Graul, 9/13/2011
9/23/2011

DOE Conclusions:
For
F a column
l stored
t d iin iinitial
iti l mobile
bil phase,
h it
may not be necessary to pre-condition the
column before use if injected at least two
samples before preconditioning.
For a column stored in 50/50 ACN/Water, it is

necessary to pre-condition for at least 3 hours
before use. During preconditioning, injection of
samples may not be needed.
Column Age Assessment by OFAT
Objectives - assess column use period (# of Injections)

E
Experiment
i t - one factor
f t att a time
ti (OFAT) experiment
i t
Column - 3 new columns with a different batch number
Injections – up to 3,000 injections
Critical method attributes used for the evaluation include
Critical pair resolution: ≥ 1.2
Limit of quantification: S/N ≥ 10 for API at 0.05% of nominal
Retention time (for information only)
Three replicate injections were made at each testing point.

The experiment might be stopped if unacceptable resolution, S/N
ratio, or main band retention time was obtained after certain
numbers of injections.
27
9/23/2011
Sampling points in OFAT experiment for HPLC column use period
Sample Sample Sample Sample Sample Sample Sample

Column
initial #1 #2 #3 #4 #5 #6
1 x x x x x x x
1200 injections
1800 injections
3000 injections
120 injections
360 injections
600 Injections
2 x x x x x x x
3 x x x x x x x
OFAT results for column use period evaluation
Column Injection LOQ Resolution Retention time

1 0 127 1.74 15.4
1 120 99 1.75 15.4
1 360 89 1.75 15.4
1 600 42 1.74 15.2
1 1200 137 1.76 15.1
1 1800 72 1.79 15.1
1 3000 99 1.79 15
2 0 35 2.01 18
2 120 56 2.02 18
2 360 32 2 17.7
2 600 34 2.05 17.9
2 1200 46 2.05 17.6
2 1800 32 2.05 17.3
2 3000 42 2.14 17.2
3 0 30 1.76 17.5
3 120 38 1.82 17.7
3 360 49 1.95 17.9
3 600 49 1.87 17.7
3 1200 43 1.83 17.3
3 1800 68 1.96 17.1
3 3000 28 2.06 17.1
28
9/23/2011

OFAT study conclusions:
All three columns were able to meet the criteria after 3500 injections.
Within the 3500 injections, the S/N of LOQ was all higher than 10 and did not
show any consistent trend.
Within the 3500 injections, the resolution data showed a slightly increasing
linear trend (increased 0.18 - 0.7 unit per 10000 injections).
Within the 3500 injections, the retention time showed a slightly decreasing
linear trend ((decreases between 1.4 to 2.8 minutes per
p 10000 injections).
j )
Since there was no clear sign showing deterioration of the new

columns after being injected 3500 times, the use period of a new
column could be longer than 3500 injections.
Conclusions
AQbD provides method operation flexibility and consistent

quality measurement.
AQbD involves the key steps of defining ATP, technique
selection/method development, risk assessment, DOE,
MODR establishment, and method control strategy.
APT isn’t intended to be technique specific. It forms the
basis for development of a QbD method or any changes
made throughout the lifecycle of the product
Method parameters can be categorized as Controllable,
Noise, and Experimental in the risk assessment
29
9/23/2011
Conclusions (continued)
DOE experimentation can be used to study multiple
method pparameters and their interactions for
establishment of MODR.
Critical method quality attributes should be selected in
the DOE study (i.e., resolution, accuracy, and LOQ for
an impurity method).
Common MODR can be determined for two similar
HPLC columns where the two columns can used
interchangeably.
QbD method control strategy involves operation of the
method within MODR and implementing system
suitability check.
Acknowledgement
Fashengg Li Jeff Harwood

Andy Blachard Jim Morgado
Karen Bronk Jack Pellett
Tim Graul Chand Sishta
Loren Wrisley Melissa Hanna-Brown
Kimber Barnett
30
9/23/2011
Backup slides
Rationale for Factor Range Selection
Column Temp: The column temperature range is 30 ± 3 0C which could cover any
potential variations of the column temperature. We learned that the column temp has
a minimum impact p to the method pperformance,, so temp
p range
g selected is suitable for
our future testing needs.
Injection Volume: The injection volume set point is 5 ųL and the range is 3-10
ųL. The 3 ųL is close to the limit of injection volume used in a typical HPLC impurity
method and 10 ųL has doubled the injection volume at the set-point, which is
sufficient for the future testing need.
Flow Rate: The flow rate range is 1.0 ± 0.2 mL/min which will cover potential flow rate
variations of the HPLC system or meet the needs to adjust the flow rate to achieve
desired peak retention time.
UV Wavelength: The UV wavelength range is 270 ± 8 nm that is broad enough for
the purpose of operable region study.
TFA Concentration: TFA target concentration is 0.05% and the range is proposed as
0.05%-0.010%. The TFA concentration lower than 0.05% is not recommended due to
its poor pH buffering capacity.
Ramp 1 and Ramp 2: The selectivity of this impurity method is very sensitive to
organic percentage in the mobile phase. The most impurity peaks are eluted and
separated in the first 20 minutes where the organic percentage in the gradient elution
is changed by only 8%. As a result, a small organic percentage ranges of 10 ± 3%
and 18 ± 4% are commended for gradient ramp 1 and ramp 2, respectively.
Detector type: UV WVD and PDA cover the detectors used for this method.
31
QbD and Knowledge Management
Eda Ross Montgomery | September 15, 2011
©2011 Vertex Pharmaceuticals Incorporated

Outline
• QbD in Product Development

• Implementing QbD at Contract Manufacturing
Organizations
– Establishing Criticality
– Defining a Control Strategy
– Defining the design space
– Interfacing QbD with CMO quality systems Implementing QbD in batch
records
• Product Review Process
– Trending for continuous improvement
– Ongoing risk management
– Differences under QbD
• Monitoring Products during Commercial Manufacturing
– Moving to continuous process verification

QbD is Implemented in Stages
Develop Product Develop matrix showing Agree on classifications of Perform trending

material attributes, IPCs, deviations
and process parameter
control that ensures CQAs
are met
Understand product Develop real-time release Agree on change Interpret results across
strategy classifications trending parameters
Develop specifications Develop post-approval Agree on process for Identify opportunities for
change strategy including NORs and PARs improvement; implement
in batch record as appropriate
Perform risk Assessment Develop “product and Agree on overall control Publish trends and metrics
process description” strategy
strategy for marketing
application
Define design space Develop comparability Agree on trending protocol Set goals for continuous
protocol strategy and process improvement

Pharmaceutical Development Under QbD Starts with a Target
Product Profile
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
Identify Identify Critical Perform Initial Perform Risk
Performance Quality Risk Criticality Assessment
Requirements Attributes Assessment Assessment on Critical and
Key Aspects of
the Process
Tablet CQAs
Stage 6
Conduct Process
DPI CQAs Verification and
Continuous
Process
Improvement
DS CQAs
Comprehensive Quality
Systems

A Single Approach to Assessing Criticality is Used for all Aspects
of the Process

Control Strategy Ensures Drug Substance Quality and Identifies
Attributes to be Monitored Throughout the Product Lifecycle
Critical Quality Attribute Starting Step 1 Step 2 Step 3 Specification
Material
Appearance Specification
Identification Specification
Purity Specification CPP Real-

time
release
Impurities Specification CPP
Residual Solvents Real-

time
release
Physical Form KPP
Inorganic Impurities Specification
CPP = Critical Process Parameter KPP = Key Process Parameter

Defining the Design Space
Outside Design Space
(Outside PAR)
Design
Space
(PAR)
Operating/Control
Space
(NOR)
Validated range for

traditional products
Commercial Manufacturing - Implementation of QbD at Contract
Manufacturing Organizations with Traditional Quality Systems
• Vertex Quality systems completely embrace QbD

• CMO Quality systems should not be different for QbD and “traditional”
products
– Changes to CMO Quality systems should be minimized
– Use change management procedures to drive implementation of changes
– Use nonconformance and process monitoring to identify potential changes
and drive continuous improvement
• Vertex drives continuous process improvement with the support of and
input from the CMO(s)

Implementation of QbD in Batch Records at Contract
Manufacturing Organizations
• Batch records are designed to ensure the process is operated where

it performs best
– NOR ranges are intended for routine commercial manufacturing
• The batch record includes the NORs for critical and key process
parameters and in process control (IPC) tests
• Batch record can also include ranges for non-critical parameters
• Tighter operating ranges or a mid-points may be implemented to avoid
excursions outside the NOR or maximize product performance
– PARs for critical and key process parameters and IPCs are
included or referenced in the batch record
• This makes the information readily available to manufacturing
supervision

Implementation at Contract Manufacturing Organizations:
Classifying Deviations relative to NORs and PARs
Deviation (Outside Design Space)
Predicted Output
Parameter 2
Parameter 1
Edge of Design
Operating/Control Space Space
Observation (Outside NOR but

within Design Space)

Implementation at Manufacturing Sites: Classification of
Post-Approval Changes is Consistent with SUPAC
Minor Change
Major Change Moderate Change

Risk Management and Continuous Improvement are Achieved
Through a Coordinated Trending Process

Managing Risk from Technology Transfer throughout the Product
Lifecycle
• Coordinated approach to evaluation (trending) of
– Product performance based on process parameters, IPCs, material
attributes
– Key performance indicators that may be indicative of product performance
or could indicate a trend with CMO’s systems, e.g.
• Confirmed OOS
• Deviations (Major and Minor)
• Observations
• Complaints
• Coordinated, periodic sharing of results with CMOs
– Each CMO reports product performance and key performance indicators to
Vertex
– Vertex’ conclusions on product performance and key performance
indicators are shared with CMOs
• Coordinated approach to continuously improving product quality and
performance

Trending Protocol Describes how the Product will be Monitored on
an Ongoing Basis
• Prospective, documented plan for monitoring during

routine manufacturing
– Critical and key process parameters
– Critical and key material attributes
– Activities where frequency of failure is above a threshold
– Key performance indicators
• Predefined responsibility for monitoring, frequency of
reporting, statistical tools to be used, and thresholds for
key performance indicators
• Describes content of trending report and method for
modifying trended parameters

©2009
Trending Report Serves as the Means to Capture Increasing
Product Understanding During the Commercial Phase
• Comprehensive and cumulative
– Quarterly reviews
– Designed to meet annual product review requirements
• 4th trend report is the annual product review
– Jointly authored by Quality and Technical functions
• Trend reported for all product performance measurements and
all key performance indicators
– Evaluation of observed trend to predicted trend
– Evaluation of discrete “events” that can signal other issues
– Evaluation of actual vs. predicted frequency of “events” based on risk
assessment
• Quarterly management reviews built into the trending process
• Conclusions and recommended changes to
– Process parameters, IPCs, or material attributes
– CMO operations or equipment
– Methods
– Implementation of key performance indicators or alert limits
Trending leads to Improvements in Process or Equipment
Batch 1 Batch 2 Batch 3 Batch 4 Batch 5 Batch 6

*
PAR
Equipment malfunctioned
Temperature lowered
PAR
Time
•Temperature decreased to control at different target value

•After equilibration, minor variations in temperature
•Equipment malfunction resulted in addition of chiller capacity
Knowledge Management: Correlating Drug Product Assay with
Input Material
DP
•No consistent bias

•Provides insight into method performance at both CMOs

Process Understanding Enables Prediction and Ongoing
Verification of Product
In-Process WetPerformance
SDD D50 Data:
Lots HQ00070 - HQ00072
140
130
120
D50 Wet (μm)
110
100
Response
90 ± d50 PAR
80 ± d50 NOR
70 d50 Predicted (μm)
60 d50 OFFLINE
Measured(μm)
50
40
• Predictive model built from development runs
• Good agreement between actual and predicted value

Trending Key Performance Indicators Allows Product Optimization
Observations
Minor Deviations
Major Deviations
•Increased frequency of minor deviations

•Minor deviations were for isolation time and temperature (non-critical parameter)
•Filtration capacity increased

Ensure Ongoing Product Quality
• Use Statistics to
– Establish process capability
– Evaluate inter and intra-batch variability
– Justify sampling procedures and sampling frequency
• Verify suitability of sampling procedures and sampling frequency
– Confirm assumptions around sampling procedures during process
qualification
• Modify as needed during commercial production and/or when changes are made
– Vary sampling frequency
• Development through process qualification
• During continuous process verification
• Perform continuous process verification as described in FDA’s January
2011 Process Validation Guidance
– Ongoing program is needed
– Quality and Technical units review data, evaluate trends, and coordinate
actions

Final Thoughts
• Leverage the knowledge gained during the

development phase
– Focus on key and critical parameters and key
performance indicators
– Construct regulatory filing to allow continuous
improvement
• Leverage the strengths of Commercial
Organizations
– Keep processes and expectations clear and
consistent
– Minimize high impact changes to Quality
systems
– Identify trending logistics up front
• Leverage the data generated in Commercial
Manufacturing
– Review the Process Regularly
• Identify knowledge improvements
• Include corrective and preventative actions
Acknowledgements
• Tom Gandek
• Kelly Tolton
• Geny Doss
• John Bric
• Simone Ferdinand
• Chris Hooper
• Carole Varanelli
• Antoinette Paone
• Trish Hurter

9/23/2011
Th QbD Collaboration
The C ll b ti Imperative:
I ti
How to Get the Most Value
From Your Data and Your Colleagues
Justin O. Neway, Ph.D.

Chief Science Officer
Aegis Analytical Corporation
jneway@aegiscorp.com
www.aegiscorp.com
Why Collaborate?
The Business Perspective
GOAL: Reduce the cost, time and risk of scale-

scale-up and tech
transfer to commercial operations: avg ~ $1.4Million/day
– Most new processes must perform within the constraints of
existing manufacturing facilities - captive and contract (CMOs)
– The people who develop the new processes are the same ones
who later provide support when there are problems
– The most effective QbD risk analysis comes from a consensus

between experienced professionals in PD, MFG and QA
– The knowledge base is trending away from groups of experts at

every site towards fewer more widely dispersed groups
1
9/23/2011
Why Collaborate?
The Regulatory Perspective
“Many of the manufacturing problems that the agency

sees in the field result from communication failures
between the process developers and manufacturers in
the same company.”
company.”
FDA Manufacturing Subcommittee Meeting Transcript
“…facilitate innovation and continual improvement and

“…facilitate
strengthen the link between pharmaceutical
development and manufacturing activities.”
ICH Q10
Why Collaborate?
The Regulatory Perspective
Process validation is defined as the collection and

evaluation of data
data, from the process design stage
throughout production,
production, which establishes scientific
evidence that a process is capable of consistently
delivering quality products
FDA Guidance on Validation
“It is the knowledge gained and submitted to the

collected, that
authorities, and not the volume of data collected,
forms the basis for science-
science- and risk
risk--based
submissions and regulatory evaluations.”
FDA Guidance on ICH Q8
2
9/23/2011
What’s Stopping Us?
Traditional Approach #1
COLLECTION
Weekly Data Report
Continuous
(per Product)
UPSTREAM Historian
JMP Script
DATA Single Point
Batch Up Mfg Excel Control Charts/ Capability

Records ~100 variables
HGS1021 S-3 pH Continuous Trend
LIMS DATA Multi point 7.4
7.3
/ Continuous
(Release,..)
7.2
7.1
pH
7.0
Manual Update 6.9
6.8
6.7
Excel
0 20 40 60 80 100 120 140 160
S-3 Time (hours)
3001001341 (Gold) 3001001768 3001001766 3001001760
Layout File
Multi-Point / Continuous
Trend Overlays
Pur. Mfg Excel

AU pH
Batch 7.0
200 variables
3.0
Records
6.0
PURIFICATION 2.0
1.0
5.0
4.0
DATA
Collect ion Start
Collect ion Start
Collect ion End
Collect ion End

Wash 1 Begin
Wash 1 Begin
Wash 2 Begin
Wash 2 Begin
3.0
Elut ion Begin
Elut ion Begin

Load Begin
Start Equil
0.0
0 200 400 600 800 l
Chromatogram
Overlays
UNICORN UNICORN
(Continuous I/O) “Evaluate”
3
9/23/2011
COLLECTION
Weekly Data Report
Continuous
(per Product)
UPSTREAM
U S Historian
JMP Script
DATA Single Point

7.3
/ Continuous
(Release,..)
7.2
7.1
pH
7.0
Manual Update 6.9
6.8
6.7
0 20 40 60 80 100 120 140 160
S-3 Time (hours)
3001001341 (Gold) 3001001768 3001001766 3001001760
Excel
Trend Overlays
Layout File
Pur. Mfg Excel AU pH
Batch 7.0
200 variables 3.0
Records 6.0
PURIFICATION 2.0
1.0
5.0
4.0
DATA
Collect ion Start
Collect ion Start
Collect ion End
Collect ion End

Wash 1 Begin
Wash 1 Begin
Wash 2 Begin
Wash 2 Begin
3.0
Elut ion Begin
Elut ion Begin

Load Begin
Start Equil
0.0
0 200 400 600 800 l
Chromatogram
Overlays
UNICORN UNICORN
COLLECTION
Weekly Data Report
Continuous
(per Product)
UPSTREAM Historian
JMP Script
DATA Single Point

7.3
/ Continuous
(Release,..)
7.2
7.1
pH
7.0
Manual Update 6.9
6.8
6.7
0 20 40 60 80 100 120 140 160
S-3 Time (hours)
3001001341 (Gold) 3001001768 3001001766 3001001760
Excel
Trend Overlays
Layout File
Pur. Mfg Excel AU pH
Batch 7.0
200 variables 3.0
Records
6.0
PURIFICATION 2.0
1.0
5.0
4.0
DATA
Col lection Start
Col lection Start
Col lection End
Col lection End
3.0
Wash 1 Begin
Wash 1 Begin
Wash 2 Begin
Wash 2 Begin
ElutionBegin
ElutionBegin
Load Begin
Start Equil
0.0
0 200 400 600 800 l
Chromatogram
Overlays
UNICORN UNICORN
4
9/23/2011
5
9/23/2011
Where Do We Need to Be?
The QbD Collaboration Goal
Quality
Safe and Efficacious Product
• Fast CMC Preparation & Approval
• Fast Time to Market
• High Yield and Quality
• Low Cost MFG
Process
With all the Supporting Data Development
and Institutionalized Knowledge
6
9/23/2011
How do We Get There?
Requirements for QbD
THE GOAL: Enable early and sustained

collaboration between Process Development
(PD) Manufacturing (MFG) and Quality (QA)
– Provide a self
self--service, on
on--demand data access platform for
all process and quality data, including paper
paper--based data
– Provide automated data contextualization for observational

and investigational analytics
– Provide access to all types of data, including continuous

and discrete
– Enable use by non

non--programmers and non
non--statisticians
7
9/23/2011
Types of Process Data
Discrete data
– Measured once per batch
– MES,
MES EBR,
EBR LIMS,
LIMS ERP
ERP, Paper,
P Others
Oth
Continuous data
– Strip charts – time series profiles
– SCADA, Historians, DCS, PLC, Instruments
Replicate data
– Several measurements, same sample/time
– MES, EBR, LIMS, Paper, Others
Spectral data
– Continuous
C ti d
data,
t discrete
di t extracts
t t and
d deconvolutions
d l ti
Event data
– Batch, equipment records, SCADA, etc.
Keyword and free text data
– Enables records to be retrieved and understood
Context is King
Context is the organization of related elements that

enables analysis and interpretation
Other examples of meaningful contexts for data analysis:

– Data type context: enables specific types of data analyses
– Batch context: enables batch-
batch-to-to-batch comparisons
– Process context: enables process-
process-to-to-process comparisons
– Site context: enables site
site--to
to--site comparisons
– Genealogy context: enables upstream / downstream correlations
8
9/23/2011
Genealogy Context:
Lot Traceability
Process Step 1 Process Step 2 Process Outcome
S2 B1 ID
S1 B1 ID
S2 B2 ID S3 B1 ID
S2 B3 ID
S1 B2 ID S3 B2 ID
S2 B4 ID
S2 B5 ID S3 B3 ID
S1 B3 ID
S2 B6 ID
Genealogy Context:
Lot Traceability
S2 B1 ID
S1 B1 ID
S2 B2 ID S3 B1 ID
S2 B3 ID
S1 B2 ID S3 B2 ID
S2 B4 ID
S2 B5 ID S3 B3 ID
S1 B3 ID
S2 B6 ID
9
9/23/2011
Proportionating Genealogy:
Correlating Upstream / Downstream
S2 B1 ID
S1 B1 ID
S2 B2 ID S3 B1 ID
S2 B3 ID
S1 B2 ID S3 B2 ID
S2 B4 ID
S2 B5 ID S3 B3 ID
S1 B3 ID
S2 B6 ID
Proportionating Genealogy:
Correlating Upstream / Downstream
Process Step 1 Process Step 2 Process Step 3 Process Outcome
S1 B1 ID S3 B1 ID
S2 B1 ID
S1 B2 ID S3 B2 ID S4 B1 ID
S1 B3 ID S3 B3 ID
S2 B2 ID S4 B2 ID
S1 B2 ID S3 B4 ID
S1 B4 ID S3 B5 ID S4 B3 ID
S2 B3 ID
S1 B2 ID S3 B6 ID
10
9/23/2011
Paper Data Entry
Data Sources
Paper Records
Sponsor Mfg.
CMO
Process Dev.
Pilot Plant
Paper Data Entry
Data Sources
Paper Records
Sponsor Mfg.
CMO
Process Dev.
Pilot Plant
11
9/23/2011
Data Access and Contextualization
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
HIST
Dynamic
Mapping Engine
Process Dev.
AG
Analysis
Group
Pilot Plant
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
ERP
HIST
Dynamic
Mapping Engine
Process Dev.
CAPA
AG
Analysis
Group
Pilot Plant
MES
SAP
EG
12
9/23/2011
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
ERP
HIST
Dynamic
Mapping Engine
Process Dev.
CAPA
AG
Analysis
Group
Pilot Plant
MES
SAP
EG
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
ERP
HIST
Dynamic
Mapping Engine
Process Dev.
CAPA
AG
Analysis
Group
Pilot Plant
MES
SAP
EG
13
9/23/2011
Using AG Data Within Discoverant
Trending,
g,
Alerting,
Trouble-shooting,
Plotting,
Univariate &
Multivariate
Statistics,
Fermentation,
Chromatography
Chromatography,
Stability, etc.
AG
Analysis
Group Dynamic
Mapping Engine
Using AG Data Outside Discoverant

Templated
Reports:
CTD, CMC, APR, Trending,
Q , etc.
PQR,
Alerting,
Dashboard Trouble-shooting,
Displays:
Plotting,
Web-based,
Mobile, etc. Univariate &
Multivariate
Information Statistics,
Portals: Fermentation,
Web-based,
p , etc.
Sharepoint,
Chromatography,
Stability, etc.
Specialized
Analytics:
Umetrics, JMP, ODBC
Minitab, eChip, etc.
AG
Analysis
Group Dynamic
Mapping Engine
14
9/23/2011
Data Sources
HIST
HIST
Sponsor Mfg.
CMO LIMS
AG
Analysis
Group
ERP
Dynamic
Mapping Engine
Process Dev.
Data
Warehouse
Pilot Plant RIF
Paper
Records
Industry Myth - #1
If its difficult to access data in multiple

sources we can solve l the
th problem
bl by
b
moving all the data into a single source
NOT TRUE
– Multiple data sources are not the problem
– Multiple data organizations are not the problem
– Need a flexible platform for on-
on-demand contextualization
– Leave the source data where it is, organized “as is”
– Make discrete and continuous data available together
15
9/23/2011
That’s Fine for Manufacturing,

But What About
Process Development?
PD Data Access:
The Evolutionary Approach
Raw
Sponsor Mfg. Materials
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Process Dev. Steps…
Final
Product
Pilot Plant
HIST
16
9/23/2011
PD Data Access:
Raw
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Final
Product
Pilot Plant
HIST
PD Data Access:
Raw
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Final
Product
Pilot Plant
HIST
17
9/23/2011
PD Data Access:
Raw
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Final
Product
Pilot Plant
HIST
PD Data Access:
Raw
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Final
Product
Pilot Plant
LIMS HIST
18
9/23/2011
Case Study Example
Step I: Risk Assessment

– Outline the p
process flow and define the scope
p ((focus areas)) for
risk assessment
– Identify Key Quality Attributes (KQA’s) based on potential to

impact the safety, efficacy and/or performance of the final
drug delivery system
– Identify Key Process Parameters (KPP’s) based on potential to

impact the quality attributes
– Develop scoring criteria and prepare a cause

cause--and
and--effect matrix
– Perform numeric scoring to identify critical parameters
McCurdy et al, Pharmaceutical Engineering, July/August 2010
Drug Product Focus Areas:

Key Parameters & Attributes
Key Process and Quality Parameters

Are Identified by Team Consensus
19
9/23/2011
Discoverant Process Hierarchy
Pre-Blending
Milling
Blending
Roller Compaction/Mill
Final
Blend Comp
Coat
Examples of Ranking Criteria
Quality Attributes:
■ 10 – known or expected direct impact on safety and/or efficacy of
product
■ 7 – unsure or expected impact on product safety or efficacy, or on
process efficiency
■ 5 – unlikely impact on product quality or process efficiency
■ 1 – no impact on product quality or process efficiency
Process Parameters:
■ 10 – known or expected direct strong impact based on data in hand
or experience
■ 9 – unsure but expect a strong relationship
■ 5 – medium relationship or not sure
■ 1 – known that there is not a relationship
20
9/23/2011
Example Cause-
Cause-and-
and-effect Matrix
Key Attribute Y Y Y
Rank 7 7 7 Exp't
Stratified Tablet Score
Blend Impurity Strategy
Quality Parameter Content
y
Uniformity Profile
Uniformity
Dispense and Pre-Blend
(Focus Area #1)
API Particle Size 10 5 1 112 OFAAT**
Agglomeration of API 10 5 1 112 OFAAT
Container Loading (% fill) 10 5 1 112 DoE
Order of API Addition 10 5 1 112 DoE
Impurity Levels in Excipients 1 1 10 84 DoE/FMEA*
API Impurity Profile 1 1 10 84 OFAAT
API Milling Procedure 5 1 5 77 OFAAT
Blend Time 5 1 1 49 DoE
Sampling Procedure 1 1 1 21 FMEA
RC/Mill and Blend
(Focus Area #5)
Roll Force 10 10 1 147 DoE
Screen Size 10 5 1 112 DoE
Gap Width 10 5 1 112 DoE
Roll Speed 5 1 1 49 DoE
Granulator Speed 5 1 1 49 DoE
**OFAAT - One Factor At A Time
*Failure Mode Effects Analysis
Setting Up the Process Impact

Rank Ranges In Discoverant
21
9/23/2011
Setting Key Process Parameters

In Discoverant
Threshold = 110
Setting Critical Process Parameters

In Discoverant
Threshold = 110
22
9/23/2011
Case Study Example
Phase II: Design Space Experimentation

– One Factor At A Time (OFAAT/Univariate) preliminary experiments
– Design of Experiments (DoE) on individual unit operations
– DoE across selected unit operations
– Formulation and stability characteristics
– Operating ranges and specifications
Prepare Tech Transfer Documentation and CMC/CDT
Support Tech Transfer and Commercial Operations
McCurdy et al, Pharmaceutical Engineering, July/August 2010
Self-service, On
Self- On--demand
Access to Designated Parameters
23
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Building the Process Model

And Design Space for the CMC
Building the Process Model &

Design Space for the CMC
24
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25
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Result Method as a Study Object
The Results
Chemistry, Manufacturing & Controls Submission
Raw
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Final
Product
Pilot Plant
LIMS HIST
26
9/23/2011
But How Can This Help Me

With My CMOs?
Sponsor has Discoverant:

Spreadsheet Import
27
9/23/2011

PRIMR Input and Spreadsheet Import

PRIMR Input
28
9/23/2011
Paper Data Capture with PRIMR
Data Sources
Paper Records
Sponsor
CMO
Self-service, On
Self- On--demand
Access to Designated Parameters
29
9/23/2011
Prepare a Result Method

for Scheduled Reports, Analysis
Report & Analysis Examples
30
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31
9/23/2011
32
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Dashboard Display Examples
66
33
9/23/2011

Live Link to Sponsor Data
LIMS
PRIMR
HIST
CMO Has Discoverant:

Sponsor has a Discoverant Client
34
9/23/2011
Sponsor & CMO Have Discoverant

Full Collaboration
Summary
Successful QbD depends on effective collaboration between the

whole PD,
PD, MFG & QA team across geographic boundaries
Collaborative behavior requires a supporting platform technology
that includes an effective cure for “Spreadsheet Madness”
– Self
Self--service access to data from multiple disparate sources
– Flexible, accurate capture of data from paper records
– Automatic contextualization for specific types of analysis
– Working with continuous and discrete data together
– Domain-specific observational and investigational analytics
– Automated analysis and reporting (e.g. Batch Reports, APRs, PQRs)
35
9/23/2011
Example Implementations
Customer CMO Deployments
36
9/23/2011
From Practical Experience
Process Data Management and Multivariate Analysis, a

Key Tool for Quality by Design (QbD) and Continuous
Improvement of Biotech Manfacturing Processes
Damien Voisard, Merck Serono, Vevey & Geneva, CH
Process 2 Product Conference, Bethesda, MD, October 20-21, 2010
Selection and Implementation of a Data Analysis System

John Georger,
Georger, Human Genome Sciences, Rockville, MD, USA
Process 2 Product Conference, Bethesda, MD, October 20-21, 2010
Links to the videos of these presentation are available on request
Thank you
Justin O. Neway, Ph.D.
Vice President and Chief Science Officer
Aegis Analytical Corporation
jneway@aegiscorp.com
http://www.aegiscorp.com
37
A Quality by Design Based Approach to
Process Design, Control and Improvement
Ronald D. Snee
Snee Associates, LLC
IVT’s 3rd Annual Bio/Pharmaceutical Conference on
Quality by Design
San Francisco, CA
September 14-16, 2011
1 Snee Associates, LLC
Agenda
≡ Today’s Realities – Need to Improve
= FDA’s Quality by Design and Process Validation
Guidance
= ISPE Product Quality Lifecycle Implementation Plan
≡ Building Blocks of QbD
≡ Process Performance and Product Quality
= Process Stability and Capability
= A Systems Approach
≡ Tips and Traps – What to Watch Out For
≡ Summary

Desired State for
Pharmaceutical Manufacturing
“A maximally efficient, agile, flexible pharmaceutical
manufacturing sector that reliably produces high quality
drug products without extensive regulatory oversight.”
Janet Woodcock, FDA
Quality by Design – An Effective Approach

Systematic approach to product and process development
• Begins with predefined objectives
• Emphasizes product and process understanding and
process control
• Based on sound science and quality risk management
From ICH Q8(R1) Step 2
Quality by Design is about

Building Quality into Products and Processes
Building Blocks for Quality by Design
≡ Identification of Critical to Quality Attributes (CQA)
≡ Raw Material Variation Characterization
≡ Identification of Critical Process Parameters (CPP)
≡ Characterization of Design Space
≡ Process Capability, Control and Robustness
≡ Analytical Method Capability, Control and Robustness
≡ Risk Analysis and Management
≡ Life Cycle Management of the System
= Continued Process Verification
= On- Going Checking and Enhancement
QbD Develops Process Understanding

Process
Capability
Process
Control
Process
Critical Quality Model
Attributes (Ys) Y=f(X) Design
Space Risk
Critical Process Process Level
Parameters (Xs) Robustness
Raw
Materials
(Xs)
Failure Modes and Effects Analysis
“Process” = Process and Analytical

Life Cycle Management and Continuous Improvement
Continued Process Verification
Variation, Process Understanding, and Risk Reduction
Analyze
Process Variation
Processes Process Enhanced Compliance

Vary Understanding Reduced Risk
Reduced Process Variation

Enhanced Prediction of
Process Performance
Analyzing Process Variation Leads to
≡ Increased Process Understanding
≡ Reduced Process Variation
≡ Reduced Risk 8 Snee Associates, LLC
Check List for Process Understanding
≡ Critical variables (Xs) that drive the process are known
≡ Critical uncontrolled (Environmental) variables that
affect the process output (Ys) are known and:
= Process has been designed to be insensitive to these
uncontrolled variations (robustness)
≡ Measurement systems are in place and the amount of
measurement variation is known
≡ Process capability is known
≡ Process failure modes are known
≡ Process control procedures and plans are in place
≡ You can accurately predict process performance
QbD Provides Methods and Tools for
Developing Process Understanding
Product Quality Lifecycle Implementation (ISPE)
Berridge, etal 2009

Stable Manufacturing Process
Upper Control Limit (UCL)
Process Variable
Average
Lower Control Limit (LCL)
Time or Sequence
≡ A process in a state of statistical control consistently

produces product that varies within the process
control limits; typically
= Upper Limit: Process Average + 3(Process Std Dev)
= Lower Limit: Process Average – 3(Process Std Dev).
≡ Process that is in a state of statistical control as
= Each batch of tablets is being produced
= Batches of tablets are produced over time.
Capable Process
≡ Consistently produces
tablets that are within
specifications for all tablet
parameters.
≡ Process capability
analysis compares the
process variation to the
lower and upper
specification limits
≡ Broadly used measure of
process capability is the
Ppk index

Reducing Process Risk
Improving Process Stability and Capability
Statistical Process Control

Process Capability Indices

Common Causes of Variation
If only common causes of variation are present, the
process output is stable over time and is predictable
Common Causes:
−Present all the time
−Influences all process outputs
−Require process changes to reduce
−Minimum variation process is likely
to exhibit

Special Causes of Variation
If special causes of variation are present, the process
output is not stable and is not predictable
Special Causes:
−Due to outside influences
−Affect some of the process outputs
−Can cause data to form non-normal
patterns

Shewhart Control Chart

Process Variable
Average
Time or Sequence
Control Limits Are Not Specification Limits!

Product A – Tablet Thickness
Unstable Process
Time Series Plot of AVGThickness
0.228
0.226
AVGThickness
0.224
0.222
0.220 4 Tablet
0.218
Presses Used
1 6 12 18 24 30 36 42 48 54 60
Index

Product A – Dotplot of
Tablet Thickness by Press Number
Dotplot of AVGThickness vs Press No_
50
Press No_
90
100 Press 120
120
0.2184 0.2198 0.2212 0.2226 0.2240 0.2254 0.2268 0.2282
AVGThickness

Tablet Weight – Stable Process – Two Presses
I Chart of Tablet Weight by Press

Tablet Press A Tablet Press B
1.08
UCL=1.07360
1.07
Individual Value
1.06
_
X=1.05489
1.05
1.04
LCL=1.03619
1.03
1 19 37 55 73 91 109 127 145 163 181
Sample of 10 Tablets

Assay – Process Unstable
No Out-of- Spec Product Produced
I Chart of Assay% by Year
Year 1 Year 2 Year 3
102
UCL=101.818
101
100
Individual Value
99 _
X=98.682
98
97
96
LCL=95.546
95
1 14 27 40 53 66 79 92 105 118
Batch

Assessing Process Stability
≡ Q: When Should I worry about process stability?
= A: When Long-Term process variation is too high
≡ Q: How high is too high?
≡ A: Long-Term variation becomes a concern when it represents more
than 20% of the total variation
= Total Variation = Long-Term Variation + Short-Term Variation
≡ This guideline is based on the assumption that
= Well-controlled process will detect a shift of 1.5 short-term
standard deviations
Process Stability Long-Term Variation

Not a Problem < 20%
May be A Problem 20 – 30%
Corrective Action May be Needed > 30%

Schematic - Between and Within Variation
3 Batches, 2 Samples per Batch
Within-Batch
Short-Term
Variation
Between-Batch
Long-Term
Variation
Batch
Mean

Example – Variation in Quality
Process Not Stable – Long-Term Variation Large

Example – Three Groups
Short-Term and Long-Term Variation
Short-Term: Within Groups
Long-Term: Between Groups
LT Variation = 73% (p=.000)
Group 1
Group 3
Group 2
Group Mean Std Dev

1 4.5 .17
2 4.1 .12
3 4.4 .11
All Data 4.3 .21

Long-Term (LT) Variation Analysis
1.08
LT Variation = 18% LT Variation = 44%
(p=.000) (p=.001) UCL=1.07360
1.07
Individual Value
1.06
_
X=1.05489
1.05
1.04
LCL=1.03619
1.03
1 19 37 55 73 91 109 127 145 163 181

102
UCL=101.818
101
100
Individual Value
99 _
X=98.682
98
LT Variation LT Variation
97 =6% =23%
(p=.41) (p=.14)
96
LV Variation LCL=95.546
95 = 64%
1 14 27 40 53 66 79 92 (p=.001)
105 118
Batch

Measuring and Reducing
Process Risk Using
• Short-Term (Cp and Cpk)
• Long-Term (Pp and Ppk)

Capability versus Performance
• Process Capability is the
variation the process would
Process
exhibit if only common cause
Performance
Process
variation were present:
Capability
− “The variation in the
process if the angels ran
the process”
• Process Performance is the
total variation experienced by
the customer; includes
common cause, structural, and
special cause variation:
− “The variation when we
mortals run the process”
Measuring Process Capability
Cp Index Compares Process Variation to Spec Limits
Tolerance
USL – LSL
Cp =
6 (Short-term Standard Deviation)

Cpk Index Compares Process Variation to
Difference Between Process Average and Specs
Cpk = USL – Average = 1.33 Good!!


Cpk Index Compares Process Variation to
Difference Between Process Average and Specs
Average – LSL
Cpk = = 0.33 Poor

Traditional Performance Indices
Two traditional measures of process performance:
USL – LSL
Pp =
6 (Long-term Standard Deviation)
Where:
LSL = Lower Specification Limit
USL = Upper Specification Limit
Ppk = Min (USL – Average, Average – LSL)


Levels of Process Capability
Marginally Capable
LSL USL
LSL
Cp = 1.0 USL
Poor
Capability
Cp < 1.0
40 45 50 55 60 65 44 46 48 50 52 54 56 58
Robust Process
LSL
Cp = 2.0 USL
44 46 48 50 52 54 56

Interpreting Cp and Cpk
Rating Cp Cpk
Excellent > 1.67 > 1.53
Good 1.33 – 1.67 1.33 – 1.53
Fair 1.00 – 1.33 1.09 – 1.33
Poor < 1.0 < 1.09
Cp Typical % Defective*
2.0 0.00034
1.67 0.023
1.33 0.6
1.0 6.7
* Assumes the Process has Shifted 1.5 Std Dev

Process Stability and Capability
Appropriate Actions
Process Capable?
Process
Stable? Yes No
Use SPC to • Shift Average to Target,
Yes Maintain • Reduce Variation Around Average
Performance • Both
• Reduce Variation, • Increase Process Understanding
No • Improve Control • Identify Appropriate Action

How Large a sample Do I Need?
95% Confidence Interval for Ppk=1.33 LIMIT
LOWER
1.7 MEAN
UPPER
1.6
1.5
Mean
1.4
1.3
1.2
1.1
1.0
30 60 120
SAMPLE SIZE
Capability Indices are Highly Variable when

Estimated from Small Samples

Sampling to Assess Process Capability
Depends on Process, Business Need, and Objectives
Time Frame Practical Statistical

Significance Significance
Short Term Short Term Variation n > 30
Sampled (ex: 30 Days,
measured daily)
Long Term Total Range of n > 60
Process Variation
Sampled (ex: 90 Days,
measured daily)
Capability Indices are Highly Variable when

Estimated from Small Samples

Process Management System Use of Data
Process Control, Improvement and Design Integrated
Customers Process
Design/Redesign
Process Process
The Process
Performance Improvements
Data
Feedback Process Improvement

Adjustments Feedback
Projects
Reports & Periodic Process

Information to Analysis and Improvement
Management Reviews System

Periodic Reviews of Process Performance
A Team Sport
Review Team Timing
≡ Process Operators ≡ Daily/Hourly

≡ Area Manager and ≡ Weekly
Direct Reports
≡ Site Manager and ≡ Monthly
Direct Reports
≡ Business Manager and ≡ Quarterly
Direct Reports

Process Tracking at Different Levels
Company
Div A Div B Div C
Plant A Plant B Plant C
Pdtn Line # 2
Pdtn Line # 1 Pdtn Line # 3
Mfg. Engineer / Operator Team Mfg. Engineer / Operator Team Mfg. Engineer / Operator Team
Machine A Machine B Machine C

Individual Batch Monitoring System
Individual
Batch
Production
Process Process
Data Process
Models
Adjustment
Y=f(X)
Monitoring Tools
Periodic •Control Charts
Data Analysis •Capability Analysis
and •Variance
Review Components
•Histograms
•Pareto Charts

Predicting Process Performance
Controlled Variables (Xs)
• Press speed
• Compression forces
• Pre-compression forces
Y = f (X)
• Punch separation
Process Inputs (Xs) Process Outputs (Ys)

• Raw Materials • Thickness
• Energy Compression
Process • Hardness
• Tooling • Friability
• Weight
• Yield
Uncontrolled Variables (Xs) • Waste
• Ambient Temp and Humidity • Dissolution
• Shift
• Operators
• Machine
• Raw Material Lot
• Powder Flow Characteristics
Process Adjustment Model
Process Model Y=f(X)
Current (X, Y)
Performance
Deviation
Target from Target
Required
Change in X

Process Adjustment - Example
Process Model Y=26 + 0.4x – 0.003x**2
Process Model Y=f(X)
Current
Performance
=38
Target
Deviation
=34
from Target
38-34=4
Required
Change in X
= -16

Batch Production Monitoring System
Batch
Production
Over Time
Batch Process Process

Quality Data Adjustment Models
Y=f(X)
Periodic
Monitoring Tools Data Analysis Process
•Control Charts and Improvement
•Capability Review
Analysis
•Variance
DMAIC
Components
•Histograms
•Pareto Charts 46 Snee Associates, LLC
DMAIC Process Improvement Framework
Sense of Lean Six Sigma

Urgency Tools Results ($$)
Data Control
Improve
Analyze
Leadership
Measure Teamwork
Stakeholder Building
Define Project Management

Sources of Special Cause Variation
Controlled Variables
• Temperature
• Pressure
• Flow rate
• Catalyst concentration
Process Inputs Process Outputs

• Raw materials Manufacturing • Yield
• Water Process • Waste
• Energy • Capacity
• Downtime
• Production rate
Uncontrolled Variables
• Ambient Temperature and Humidity
• Shift
• Team Typical Sources of
• Operators Special Cause Variation
• Machines

Tracking Special Cause Variation to
Identify Systemic Problems
Special Causes – Some Examples
≡ Raw material lot variation
≡ Differences between pieces of equipment
= Tablet presses
= Bioreactors
= Test instruments
≡ Sources of Human Intervention
= Operating teams
= Lab analysts
≡ Production lines
≡ Day of week
Special Cause Variation Can Be Shifts in
Process Variation as Well as Process Average Performance
Tips and Traps
Operating Effective Process Monitoring Systems
≡ Process understanding - A deep knowledge of the variables

that drive the process exists
≡ Magnitudes of the measurement variation are known.
= Gage studies measure method repeatability and reproducibility
= Ruggedness studies assess method sensitivity to protocol
variations
≡ Systematic method to keep track of special cause variation to
determine if systemic problems are present.
≡ Two common problems
= Data are not analyzed routinely
= When problems are identified, no action is taken.
≡ Regular management reviews are essential

My Message
≡ QbD produces process understanding that is
fundamental to creation of
= Design Space and sustaining performance
= Process control and improvement system
= Continued process verification
≡ Process Control and improvement,
= Incorporating continued process verification
= Integrated and guided by periodic management
review, results in
− Improved process performance and compliance
− Regulatory flexibility
− Enhanced bottom-line results

Some Further Reading
ICH Harmonised Tripartite Guideline: Pharmaceutical Development, Q8(R2), Current
Step 4 Version, August 2009.
Snee, R. D. (2007) “Lean Six Sigma and Outsourcing – Don’t Outsource a Process
You Don’t Understand”, Contract Pharma, October 2006, 4-10.
Snee, R. D. (2009) “Quality by Design: Four Years and Three Myths Later”,
Pharmaceutical Processing, February 2009.
Snee, R. D. (2009) “Building a Framework for Quality by Design”, Pharmaceutical
Technology, October 2009, Online Supplement.
Snee, R. D. (2010) “Critical Considerations in Monitoring Process Performance and
Product Quality”, Pharmaceutical Technology, October 2010.
Snee, R. D. (2011) “Using Quality by Design to Enable CMO Manufacturing Process
Development, Control and Improvement”, Pharmaceutical Outsourcing,
January/February 2011, 10-18.
Snee, R. D. and E. C. Gardner (2008) “Putting it All Together – Continuous
Improvement is Better than Postponed Perfection”, Quality Progress, October
2008, 56-59.
Snee, R. D. and R. W. Hoerl (2003) Leading Six Sigma – A Step by Step Guide should
be taken into account when developing and Based on the Experience With
General Electric and Other Six Sigma Companies , FT Prentice Hall, New York,
NY.

Questions and Comments
??????
For Further Information, Please Contact:
Ronald D. Snee, PhD
(610) 213-5595
Ron@SneeAssociates.com
www.SneeAssociates.com

Early Development Quality by Design –
Start with End in Mind
Leverage Early Phase QbD to Enhance

Commercial Design and Mitigate Risk
Charles Yang, Ph.D., Principle Scientist

Small Molecule Process & Product Development Early Development serves as the foundation for QbD
Amgen Inc., Thousand Oaks, CA
development and implementation
Collaborated with S. Singh

IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
Sept 14- 16, 2011, San Francisco 2
Sept 14- 16, 2011, San Francisco
View of QbD Principles
by Amgen Small Molecules A Deeper View of the Process…
Small Molecule QbD Based Strategy for Development
RISK ASSESSMENT and
PRODUCT DESIGN RISK MITIGATION and CONTROL
CHARACTERIZATION
PRODUCT DESIGN
Overall
Prospective Risk Analysis PAR,
PST Target Product Profile (TPP) Project Plan Design Space Definition
(e.g. FMEA) NOR
RISK ASSESSMENT Goal
AND
CHARACTERIZATION
Quality Target Product Profile Operations Knowledge acquisition Selection of Final Composition
Execution CPP
RISK MITIGATION (QTPP) Goal (theory, models, DOEs, etc) and Process Parameters
GOT/CMC
AND CONTROL
Flexibility
Critical Quality Attributes Understanding and Control
Goal DP/DS Specifications and and
(CQA) (e.g. Process Analysis
Drivers Regulatory Submission Potential
(safety and efficacy) Characterization)
benefits
Increase Product Understanding Throughout Development x An actionable QTPP becomes available during P2 development (~ P2a-P2b transition). May be
updated as additional information becomes available.
x Process characterization incorporates the elements of prospective risk analysis
x Process analytical technology (PAT) should be encouraged as a control option, where appropriate
3 4
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Early Phase Development – Relevant Information can be Extracted from TPP
Product Design to Create Product Design Drivers and QTPP
TPP example:
Base / Preferred Actions for Product Design
1. No Cmax induced AEs 1. Consider appropriate drug delivery technology
Formulation Safety / tolerability to reduce Cmax without impact exposure
2. No significant interactions with commonly
Development prescribed medication (per indication). 2. Case-by-case
Drug
1. Oral dosage form: 1. Consider controlled released formulation to
TPP QTPP Product
a. Base: twice daily achieve once daily dosing
QA
b. Preferred: once daily
Process 2. Develop a formulation provide appropriate
2. Food effect:
Selection release characteristic to mitigate food effect
a. Base: moderate – recommend taking on
empty stomach
Administration
b. Preferred: minimum – no diet restriction
3. Pediatrics and older adults formulation 3. Develop appropriate taste masking formulation
to support PK/registration studies
a. Base: powder for reconstitution
b. Preferred: ready-made suspension or
chewtab
Goal:
Focus on safety and efficacy within the dose range Price / COGs
Estimated $2 per day Develop appropriate commercial composition
COGs: Less than 10% of the selling price and process to achieve target COGs

Sept 14- 16, 2011, San Francisco 5 6
Separated Considerations for Clinical
Development and Commercial QTPP
Case Study #1:
Understanding the Impact of API Properties to

Drug Product Quality Attributes
* If appropriate, quality attributes for

drug product intermediates should
also be documented.
7
Components of Oral Absorption Early Development on API QAs
• Develop safety boundaries for the API

Physicochemical Properties: • Impurity levels for toxicology evaluations
(e.g. Solubility, LogP, pKa,
Stability) • Include impurity might be introduced in the future routes
• Preliminary risk assessment on API process
• Impact of process on API quality attributes e.g.:
• Selection of salt form
• Polymorph screening
• Particle size impact
• Linkage of API critical quality attributes (CQA’s) to drug
Formulation: GI Physiology:
product performance
(e.g. Solubility Enhancement, (e.g. Gastric Emptying, • Material characterization
Particle Size Distribution, pH Along GI tract,
Processing) Bile Salts)
• Facilitates development of an initial control strategy

9 Sept 14- 16, 2011, San Francisco 10
Initial Risk Assessment:
Impact of API on Drug Product CQA’s Compound X: BCS Class II Free Acid Molecule
• Log P = 5.1
• pKa1 = 4.0, pKa2 = 8.1
• Non-hygroscopic
• Low aqueous solubility
Focus initial risk assessment on safety and efficacy

Product Design Risk Assessment Actions Taken to Address Bioavailability Risk
• Low solubility + predicted medium-high human dose Evaluate API size reduction
Æ high dose number 1. Explore milling approaches, jet / pin/ slurry mills
Æ exposure concern 2. Understand risk and ensure suitable for scale-up
3. Close collaboration between Chemistry Process, Analytical, and
Pharmaceutical R&D
• What can be done during early formulation development to
understand the risk?
Animal PK: appropriate design of a animal study is essential
1. Cross-over design
2. Need one arm to reference results w/ previous studies
3. Target no less than 5x PSD difference
Strive for IVIVR when possible
13 14
Non-Human Primate PK Study Showed Dissolution Results Tablets Prepared for Non-
Bioavailability Is API Particle Size Dependent Human Primate PK 20 mg Tablet
Dose AUClast AUC0-inf AUCExt. F
Formulation Subject
(mg) (hr*ng/ml) (hr*ng/ml) (%) (%) Early method: USP II, pH 6.8, 75rpm
Solution 20 0001M 5550 5660 2.01
20 0002M 4550 4710 3.49
20 0003M 4630 4670 0.910
20 0004M 8870 8910 0.395
N 4 4 4
Mean 5900 5990 1.70
SD 2030 2000 1.37
CV% 34.5 33.4 80.5
Tablet 1 20 0001M 5570 5610 0.729 99.1
20 0002M 3420 3450 0.958 73.2
20 0003M 3910 4010 2.58 85.9
20 0004M 4860 4990 2.69 56.0
N 4 4 4 4
Mean 4440 4520 1.74 78.6
Mean Concentration (ng/mL)

SD 963 970 1.04 18.4
CV% 21.7 21.5 59.7 23.4
Tablet 2 20 0001M 2220 2430 8.86 43.0
20 0002M 1710 1780 3.72 37.7
20 0003M 1060 1180 10.2 25.2
20 0004M 1840 1920 4.07 21.6 Time (hr)
N 4 4 4 4
Mean 1710 1830 6.70 31.9
SD 483 516 3.28 10.1
CV% 28.3 28.3 49.0 31.8
• Tab-1 (small DS, pin milled, d50= 3.1Pm, d90= 8.5 Pm) provided comparable exposure to sol’n API particle size of Compound X impacts both dissolution profiles and in-
• Tab-2 (large DS, slurry milled, d50= 33.9Pm, d90= 131.2 Pm) offered significant lower exposure vivo performance
Summary
Outcomes
Case Study #2:
• Set the API PSD internal target for early phase (not specification)
o D90 < 10 Pm
o Pin milling achieved required particle size reduction
Next Steps
Addressing Negative Food Effect
• Continue to monitor the lot-to-lot PSD variation in API
• Select appropriate formulation to deliver clinical trial material
Prior to End of Phase 2

• Design appropriate study to define API PSD specification for Ph3/commercial
• Ensure the drug product process robustness
17
Typical Factors to Consider in Early
Components of Oral Absorption Formulation/Process Development
Formulation:
(e.g. Solubility Enhancement,
• Formulation Design
Particle Size Distribution, • What is the BCS classification for the compound?
Processing) • Preferred dosage form
• Risk assessment and rationale for choice of excipients
• Rationale for level of excipients in formulation
• Process Design
• Necessary process to achieve specific drug delivery system
• Risk assessment and rationale for choice of process
• Were the risks of scale-up considered in choice of the manufacturing
process?
GI Physiology: • Existing commercial capability, or CM
Physicochemical Properties:
(e.g. Gastric Emptying,
pH Along GI tract,
Stability)
Bile Salts)

19 20
Risk Assessment: Observed Negative Food Effect When Dosed
Formulation Compositions on Drug Product CQA’s Compound X 25mg Tablets
• Free acid; Log P = 5.1; pKa1 = 4.0, pKa2 = 8.1; non-hygroscopic; low
aqueous solubility
• Human study during single ascending dose study
• Non-cross over design; N = 6
• Negative food effect: 68% decrease in Cmax ; 64% decrease in AUC
Help to prioritize development efforts on high risk material

attributes
Compound X Concentration (ng/mL)
Time (hr)
Physicochemical Properties and Physiology Food Components Have Positive or no Impact
That Could Induce Negative Food Effect to the Solubility of API or Tablets
• Both skim and whole milk increases the solubility
• Interact physically or chemically with API • Fat, sugars, and amino acid have no effect on the solubility/dissolution of API X
• API X chelates Ca2+ in the food to reduce the solubility • Protein: e.g. albumin, casein, can bind API X and increase the solubility
• API X binds food components to reduce its diffusivity for membrane permeation
• Change gastrointestinal (GI) pH Æ intestine has lower pH in fed state

• Reduce the solubility/dissolution of free acid API X
Solubility profiles of API X or

crashed tablet in different
media (4 h, 37°C, 300 rpm)
* Except labeled, pH is about 5

23 24
Typical pH Profiles in Gastric (upper) and
Duodenal (lower) Phases in Healthy Subjects Leading Hypothesis of the Negative Food Effect
Physiology1:
• Solid food delays the gastric emptying
• With food, the pH in the small intestine reduces from ~6.8 to ~5.0
pH = 6.8
Dosing
pH = 5.0
30 min
Drug Transition to SI
Lower solubility in Fed SSIF Slower Dissolution in Fed SSIF
• Slower dissolution/absorption rate under fed state due to pH difference

• Limited absorption window in GI tract
1J. Dressman et al. “Upper gastrointestinal (GI) pH in Young,
healthy men and women” , Pharm Res. 1990, p756
Product Design Risk Assessment and Product Design to Mitigate the Food Effect for
Mitigation Plan Compound X
• Eliminating/reducing food effect by achieving rapid dissolution in both FeSSIF
• Leading hypothesis of “negative food effect” root causes and FaSSIF
• Limited absorption window in GI tract • Alternative IR formulations:
• Significant slower absorption rate under fed state due to pH difference o Liquid filled gelatin capsules
o Tablets containing amorphous DS by HME and SD
o Alternative API form: Na salt (major impact to the timeline)
• Alternative IR formulations:
• Facilitate absorption by increasing the dissolution rate in upper GI
• Liquid filled gelatin capsules
• Tablets containing amorphous DS by HME and SD
• Alternative API form: Na salt (major impact to the timeline)
Depends on the testing condition,

amorphous DS dissolves up to 20x
faster than crystalline free acid.
27 28
Tablet Formulations Containing ASD by Hot
Liquid Filled Capsules Melt Extrusion and Spray Drying
• Work flow of LFC development: Lead formulations:
• Solubility screening based on Amgen internal LFC prior experience Direct compression tablet formulations containing 40% ASD (20% DL)
• Evaluate performance using pH gradient method
• Assess physical stability and processibility
• Monitor chemical stability and performance after storage ASD by SD ASD by HME:
API + HPMC-E5 (or PVP k29/32) API + PVP-VA64 (+ PVP k29/32)
USP II, FeSSIF (pH 5.0)

• Lead formulations:
• PEG400/PEG600 + HPMC
• Labrasol + Cremophor + HPMC
29 30
While Alternative Formulations Dosed in Animal, Non-Human Primate PK Study: Cross-over, 10
Additional Human Data Becomes Available mg
No significant food effect was observed at 100mg dose !! • All tested alternative formulation showed higher exposure than crystalline
- Human Study: cross-over, N = 12 free acid tablets in non-human primate under fasting condition
Individual non-human primate AUC with

geometric mean and 95%CI
• However, all formulations still showed
food effect with significant decrease in
exposure
o Non-human primate is not a good food
effect model for Compound X
Fasted Fed Fasted Fed

High Fat Meal Low Fat Meal
What are the possible reasons for the negative food effect observed at Compound X AUC (ng.hr/mL)
25mg tablets?
• Smaller N, not a cross-over study, high subject-to-subject variability
• Could food effect be dose level related?
– Hypothesis: Compound X may interact with food components to form
complexation resulting in lower AUC
31 32
Summary
• Appropriate PK study design, both animal and human, is essential Case Study #3:
o Cross-over design is a must
o Set successful criteria while designing the study
o If resource available, power up the study (higher N)
Identifying suitable modified release drug
• Demonstrated alternative formulations can effective enhance delivery technology
bioavailability of a BCS II compound
• Use caution when designing animal study to predict food effect
33
Components of Oral Absorption Challenges
Formulation:
(e.g. Solubility Enhancement,
1. All three components of oral absorption act in concert with each
Particle Size Distribution, other
Processing)
2. How do we separate formulation effects from:
• the other two components of absorption?
• compound distribution, metabolism and excretion?
3. Ultimately, how should we deliver the active ingredient to better
achieve the desired absorption profile and therapeutic outcome in
patients?
GI Physiology:
Physicochemical Properties:
(e.g. Gastric Emptying,
pH Along GI tract,
Stability)
Bile Salts)
35 36
Product Design Risk Assessment Design and Execute a GI Site Absorption Study
A: oral solution
Key points to cover: as reference
• Chronic indication and TPP calls for QD dosing

D: dosed to Colon
• AUC and Ctrough are key PK parameters to achieve desired efficacy via EnterionTM Capsule
PSB B: dosed to Proximal
Colon 1st meter of Small Bowel via
• High Cmax could induced AEs jejunum Enterion Capsule
Ascending, hepatic
and transverse
However,
DSB
• Current available IR formulation, only when dosed BID, can provide Last meter of Treatment Solution
ileum
100mg Compound Y to be delivered
sufficient AUC and Ctrough without high Cmax C: dose to Distal Small A
in 80mL of 1.25mg/mL solution)
Bowel via EnterionTM
Capsule B
100mg Compound Y to be delivered
C
in 1mL of 100mg/mL solution)
D
Absorption for Compound Y mainly in upper
GI (proximal and distal small intestine) Summary – Implication and Path Forward
Treatment Tmax Cmax AUClast AUCratio Cmax ratio
hr ng/mL ng*hr/mL % %
• Formulation would need to allow absorption in upper GI (proximal and distal
A N 15 15 15 small intestine, within 3 – 6 hrs) and avoid extensive release (i.e. colon)
Mean 1.9 472.7 1660.9 100 100
SD 1.3 234.6 1070.9
CV% 68.8 49.6 64.5
Proximal small intestine (B) vs Oral solution (A) Geo Mean 1.4 418.2 1452.6 100 100
• Conventional sustain release (SR) technology can not reduce Cmax without
negative impact to AUC and Ctrough for Compound Y
• ~11% higher in AUC, ~90% higher in Cmax B N 13 13 13 o Most common technology, such as matrix tablets & multi-particulates capsules, will require
Mean 0.5 851.9 1778.5 107.1 180.2 significant absorption in colon
SD 0.3 226.4 956.5
Distal small intestine (C) vs Oral solution (A) CV% 53.1 26.6 53.8
Geo Mean 0.5 819.6 1624.3 111.8 196.0
• ~41% lower in AUC, ~36% lower in Cmax • “2 to X hrs control release” technology
C N 13 13 13 o Require PKDM input on desired PK parameters, then convert to in-vitro requirements
Mean 1.2 360.3 1036.3 62.4 76.2 o Options: slower dissolving tablets, Osmotic (SCT or Micropump) dosage form
Colon (D) vs Oral solution (A) SD 0.3 269.4 626.7
• ~91% lower in AUC, ~95% lower in Cmax CV% 21.2 74.8 60.5
Geo Mean 1.2 269.0 848.8 58.4 64.3
• Gastric Retention Technology
D N 13 13 13
Mean 1.8 33.5 261.6 15.8 7.1
SD 1.8 36.5 335.3
CV% 100.7 108.9 128.2
Geo Mean 1.0 20.1 133.7 9.2 4.8
Selecting the Right Technology for a Controlled
Release Dosage Form
Case Study #4: Toxic region
IR
Utilizing Physiologically Based Absorption
therapeutic
Model (GastroPlus) in Product Development window
CR
Plasma drug level
Non-effective region
Time after administration (24hrs)
Narrow therapeutic window; target peak-trough ratio at ~1.5;

sufficient bioavailability no less than 80%
42
Common In-vitro and In-vivo Tools to Compare the Performance of
the Technology Æ Optimization Prior to Human Testing
Product Design Risk Assessment
Dissolution Testing
100 100 120
80 80 100
• For both chronic and acute treatment (Hydrogel) Matrix 80
60 60
Tablet Technology 60
40 40
40
20
MR matrix 20
Osmotic MP
• Narrow therapeutic window 20
0 0 0
0 4 8 12 16 20 24 0 4 8 12 16 0 4 8 12 16
• High inter-subject variability
Simulated Gastric Model (TNO)
• Significant amount of human PK data available Osmotic pump 80
technology 60
40
MR matrix tablet
Osmotic tablet
20 MP capsules
% Bioaccessible
0
0 10 20 30
Multiparticulate Time (hr)
Animal PK
technology
400 MR Matrix Tablet
350
Osmotic Tablet
300
250
Multiparticulate (MP)
Capsules
200
150
100
50
0
Plasma concentration (ng/ml)
0 4 8 12 16 20 24
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference Time (hr)
43 44
FDA Publication: Utility of Physiologically GastroPlus is a Repository of Pertinent Data
Based Absorption Modeling in QbD for PK Modeling and Simulation
• GastroPlus incorporates in-vitro data into simulations

• In-vitro data that can help build GP model
o Pre-Formulation:
- logP/logD, pKa
- pH solubility profile, solubility in bio-relevant media,
- PSD, chemical stability, polymorphs, salt form, precipitation characterization
o Analytical: Dissolution/disintegration in bio-relevant media, content uniformity,
stability
o PKDM:
- permeability, fraction unbound in plasma, blood to plasma partition coefficient
- identification of major metabolic enzymes
- unbound intrinsic clearance (vmax and km unbound for major metabolic enzymes in
liver/gut microsomes, hepatocytes)
- identification of transporters, determination of transporter and metabolic enzyme
expression levels in relevant species, identification of metabolites, inhibition studies
Advanced Compartmental Absorption and Transit Model (ACAT)
• Better inputs, better models and simulations
45 46
Iterative Process Combining Simulations and Built GP Model w/ Existing Cp-Time Profiles
Experimental Testing to Predict in-vivo PK from IV & IR
Validate Deconvolute in-
Build GastroPlus
GastroPlus vivo release from
model
model Cp-time profile
Optimize Create bio-

formulations relevant in-vitro
with desired method
release
Input the
predicted in- Predict in-
vivo release vivo release
into validated via in-vitro
GP model
Sept 14- 16, 2011, San Francisco 47 Sept 14- 16, 2011, San Francisco 48
A GP Model was Built Based on IV and IR Cp-
Time Profiles with Estimated PK Parameters Step 2: Validate the GP model
PK Parameters Estimated Values Validate Deconvolute in-

Build GastroPlus
model
V1 (L/kg) 0.16 model Cp-time profile
V2 (L/kg) 3.24
k12 (1/h) 7.1
k21 (1/h) 0.35 Optimize Create bio-
Vmax (mg/s) 2.1 x 10-2 with desired method
release
Km (mg/L) 1.12
Oral absorption
(ACAT model) k12
V1 V2 Input the
k21 predicted in- Predict in-
Vmax/Km into validated via in-vitro
GP model
Validated the GP Model with Additional PK
Profiles from IR Formulations Step 3: Deconvolution
Build GastroPlus
model

with desired method
release
Input the
into validated via in-vitro
GP model
Deconvoluting in-vivo Release Rate from the MR Step 4: (a) Create Bio-Relevant in-vitro
Formulation PK Profiles (12.5mg, fasted) Method, (b) Design Formulation
Build GastroPlus
model
Adjusted in-vivo
dissolution and
absorption

with desired method
~52% absorption release
Input the
GastroPlus model suggests incomplete in-vivo release into validated via in-vitro
GP model
Original In-vitro method over predicting the in- Bio-Relevant Dissolution Method Risk
vivo release Assessment
• Possible Causes of Slower Release at Lower GI Tract?

1. Higher buffer capacity in lower GI tract
2. In-vivo volume is too low for drug dissolution
a) In-completed drug release
b) Released, but precipitated
Samples Duodenum Small intestine Ascending Colon Phosphate buffer Phosphate buffer
(Fasted) 1 (Fasted) 2 (Fasted) 3 (50mM) 4 (100mM) 5
Buffer Capacity 5.6 10.0 21.4 18 34
In-vivo release rate at lower GI tract is slower than predicted from original QC (mmol/L/'pH)
dissolution method Dissolution -- -- 20-30 ml 900 ml 900 ml
Volume (liquid/solid: 70%/30%) (100% liquid) (100% liquid)
Only approximately 50% Compound Y is released in human GI tract. Potential
1 Lida et al, Pharm. Res. 23 (1) 2006, 165 – 176 2 Ekarat Et al, Pharm. Res. 25 (7) 2008, 1663-1676
impact: 3 Amalia Et al, Pharm. Res. 26 (9)2009, 2141-2151 4, 5 Determined at Amgen
o increased food effect

o increased inter-subject variability?
Effect of Ionic Strength and Buffer
Concentration on MR Tablet Dissolution Profile Formulation Design Risk Assessment
Consideration while developing a predictive method • Understand the release mechanism of the MR dosage
1. The medium selected needs to be bio-relevant • Matrix vs. Osmostic vs. Multi-particulate
2. DoE to screen buffers, concentration, paddle speed, etc • What factors can impact the release rate
3. Aim to match the in-vivo release profile • Physiological
• Physicochemical
• Formulation composition
• Aim to achieve desired in-vivo release profile
Step 5: Screen Formulations and Predict the Simulated In-Vivo Cp-Time Profiles Using the In-Vitro
Performance Dissolution Profiles as the In-Vivo Release Profiles
Validate Deconvolute in- In-Vitro/in-vivo Release Profiles Convolution to Derive In-Vivo

Build GastroPlus
GastroPlus vivo release from of MR Matrix Tablets
model Cp – Time Profiles
Form 1 Form 2 50
Form 3 Form 4
Form 5 Form 6 45
120
40
100 35
Form 1
80 30
25 Form 2
Optimize Create bio- 60
20 Form 3
relevant in-vitro
Cp (ng/mL)
% Release
formulations 40 Form 4
method 15
with desired Form 5
20 10
release Form 6
5
0
0
0 4 8 12 16 20 24
-1 4 9 14 19 24
Time (hr) Time (hr)
Input the
vivo release vivo release Slower release: lower bioavailability, greater food effect, increased variability
into validated via in-vitro Faster release: higher bioavailability, and lower inter subject variability
GP model
A MR Formulation with Faster Release Rate was
Selected for Human PK Study
(tid) (bid) (bid)
Summary
IR F1 F2
Peak to Trough 2.09 1.37 1.51
GP prediction, when comparing with IR (tid):

A fast release MR (bid) can deliver sufficient exposure and achieve target peak-to-
trough ratio
Sept 14- 16, 2011, San Francisco 61
Early Phase QbD Acknowledgement
• Focus on product design Amgen Small Molecule QbD Team Jackie Milne Shailesh Singh, Sandoz Inc.
Angela Olsofsky Jessica Tan
• Considering separated clinical and commercial QTPP Armen Pirjanian Shukun Wang
• Implement risk assessment whenever possible to document prior John Chung Fang Wang
knowledge and identify the gaps Fernando Alvarez-Nunez Melissa Mrozek-Morrison
Dominick Daurio Vincent Chow
• Multiple tools available to help define quality attributes of
Lingyun Xiao Chris Banfield
formulation
Mike Kennedy
• Utilize cross-over design PK study
Steve La
• Human GI site adsorption study
Mike Bi
• Simulated gastric-intestine model experiment
Alvarez Paco
• Physiologically based absorption modeling
Tian Wu
• Predicative in-vitro methodology
Karthik Nagapudi
Janan Jona
Arwinder Nagi
63 64
9/23/2011
Quality by Design for the Development

of NDA and ANDA Products
Beth A-S. Brown, Ph.D., R.Ph., Sarah Betterman, and Stacy Levy
September 14, 2011
Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
1
9/23/2011
Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
A New Quality Paradigm
` Science and risk-based

approaches to product
development, dossier
submission, review,
inspection, and post-approval
change management.
` Manufacturers empowered
and accountable to effect
continuous improvement and
t h i l iinnovation
technical ti
throughout the product
lifecycle.
` Efficient and consistent
regulatory oversight
across/between regions
Adapted from J. Moranes, ISPE Nov 2007
2
9/23/2011
Benefits of Quality by Design

` QbD is an effective method for:
` Developing new products and processes
` Enabling effective technology transfer
` Optimizing and improving existing processes
` Design Space is a critical component of QbD producing:
` On-target and within-specs performance at minimum cost with
fewer deviations
` Greater flexibility in process operation
` Regulatory flexibility
` Technology
gy Transfer is more robust
` Process and product understanding built into control strategy and
change management systems
` Process control obtained through routine, coordinated
trending
Factors for Success

` Prior to effective QbD implementation within an
organization, the following success factors need to
be realized
` Recognition of the Value Proposition/Strong Management Support
` Timelines and Resources to Support QbD
` Quality Target Product Profile and Risk Management Tools
` Knowledge Management System
3
9/23/2011
Value Proposition/Management Support

` Successful organizations have QbD flowing from the
top-down
` Select “pilot”
pilot program to demonstrate the benefits of
some or all aspects of QbD implementation
` Value of resource savings, time savings, and
potential regulatory benefits should be presented to
management to gain support
Timelines and Resources to Support QbD

` QbD implementation requires a strong time
investment up-front to ensure understanding of
product and process
` Creating a culture change needs to be a top priority – faster is not
always better
` Pay now, not later mentality – early resource commitment ensures
data to support submission and regulatory review
` Coordinated, cross-functional strategy which clearly
defines roles and responsibilities is a necessity
4
9/23/2011
Quality Target Product Profile and

Risk Management Tools
` QTPP defines targets for product development

` Effective use of risk management tools will provide
key understanding of Critical Quality Attributes and
Critical Process Parameters (CPP)/Critical Material
Attributes (CMA)
` Consistent use of these tools will provide maximum
benefit
Knowledge Management System

` Determine up-front how knowledge will be captured,
stored, and evaluated
` Sharing of information across departments and
across projects will increase efficiencies and
strengthen justification of design space
` Starting point for future development programs
utilizing similar drug delivery technology
5
9/23/2011
Objectives

` QTPP
` Process Mapping
ANDA product
` Case study – Use of QbD for a
NDA product
` Needs to be derived from the Target Product Profile

` But what is the TPP,
TPP what is its scope,
scope and who is
responsible for maintaining it?
6
9/23/2011
Working Outside of the R&D Bubble!
TPP Collaboration and Multiple Touch

Points Throughout Development
Research and Clinical Development

Development
Marketing Regulatory
7
9/23/2011
Multiple Definitions
` Marketing: A document describing how the intended

product will be differentiated in the marketplace
` Clinical: An R&D tool used to guide the clinical
development program
` Regulatory: A document, in the format of draft
labeling, intended to facilitate discussions between
industry and regulators
Source: Tebbey, Rink, Journal of Medical Marketing, Vol. 9, 4, 301-307
Finding Common Ground

` Resources need to be available to commit to TPP
development, so that translation to a robust QTPP is
possible
` When the “end in mind” is not clearly defined, it is
difficult to systematically structure the development
program to meet desired endpoints
8
9/23/2011

` Intended use in the clinical setting
` Route of administration, dosage form (delivery systems),
and container closure system
` Quality attributes of drug product
` Appearance, Identity, Strength, Assay, Uniformity,
Purity/Impurity, Stability, and others
` Active pharmaceutical ingredient release or delivery and
attributes affecting PK/PD characteristics (safety and
efficacy)
y)
` Dissolution, aerodynamic performance

QTPP Example
QTPP Element Target Justification
Dosage Form Tablet requirement
Route of Administration Oral requirement
Dosage Strength 10 mg requirement
Container Closure HDPE bottle with Child Resistant (CR)
System Caps Needed for commercial reasons
Example MR tablet provides initial
Biphasic release of the drug, initial plasma concentrations through the
rapid release followed by sustained first two hours that provide for a
release of dose. Fasting study and fed clinically significant therapeutic
study 90% confidence interval of the effect. Sustained release phase
Dissolution/ PK parameters AUC0‐2, AUC2‐24, designed to maintain plasma
Pharmacokinetic Profile AUC0‐∞, and Cmax should fall within concentrations for maintenance of
Requirements BE limits
BE limits. therapeutic effect
therapeutic effect.
Drug Product Quality
Attributes* See CQAs
At least 24‐month shelf life at room
Stability temperature Needed for commercial reasons
A scored tablet can be divided into
two 5mg tablets. Taken without Pharmaceutical equivalence
Administration regard to food (no food effect). requirement
*Appearance, ID, Assay, CU, Degradation products/residual solvents, Dissolution, Microbial Limits
9
9/23/2011

QTPP Example cont. (CQAs)
Drug Product Is this
Quality Attributes Target Critical*?
Similar in size and shape to
Appearance RLD, scored as RLD Yes
Identification Positive for drug substance Z
Positive for drug substance Z No
Assay 95.0 to 105.0% of label claim Yes
Complies with harmonized
requirements for uniformity of
Content dosage units (both whole and
Uniformity half tablet) Yes
NMT qualification threshold for
specified impurities, NMT ID
Degradation threshold per ICH QB3 (R2) for
Product/Residual un‐ID'd impurities, conform to
Solvent USP 467 No
release followed by sustained
release (specified apparatus
and pH buffers), similar release
for whole and half tablets,
alcohol induced dumping
Drug Release comparable to RLD Yes
*Critical Quality Attributes (CQAs) are those that can be potentially impacted by formulation and
manufacturing processes.
Process Mapping: Ishikawa Fishbone

Cause and Effect Diagram – a diagram which shows the
relationship between a quality characteristic (CQA) and
factors (CPP,
(CPP CMA)

Improvement
10
9/23/2011
Ishikawa Fishbone Diagram – Helpful

Hints
` Identify all the relevant factors through examination
and discussion by many people
` Express the characteristic as concretely as possible
` Make the same number of cause-and-effect
diagrams as that of characteristics (CQAs)
` Choose a measurable characteristic and factors (if it
is impossible to measure, consider substitute
characteristics)
` Discover factors amenable to action

Improvement
Ishikawa Fishbone Diagram Tablet Example
Blending Milling Tableting

Raw Materials
Time
Time Hardness
Excipients Batch Size
API Pressure
Tablet Speed
Meets Assay Specification
Yrs. Experience
Sampling
Training
Method
Personnel Analytical
11
9/23/2011
Process Mapping: Flow Down Map
Softgood Softgood Raw Material: Active pharmaceutical ingredient (API),

Raw Material
excipients, solvents, etc.
Process
Process: Manufacturing process such as blending, compression,
wet granulation, etc.
Intermediate
Intermediate: In-process material such as a powder blend,
uncoated
d tablet,
bl extrudate,
d etc.
Hardgood Raw Material: Typically packaging components such

as bottles, caps, desiccants, etc.
Flow Down Map Example
12
9/23/2011
Process Map Definitions

Inputs: Process Variables:
•Raw or in-process •Independent variables
material attributes
•Raw material levels
Process Variables
•Raw material grades
Inputs Unit Operation Critical Outputs
butes
Process Attributes: Critical Outputs:
p
Process Attrib
•In-process material •Critical process attributes
attributes created by that act as inputs to the
process next unit operation
•Process equipment
measurements (dependent
variables)
Process Map Example

emperature
Weight Gain
of Rotations
Fill Volume
Compresssion Force
nal Speed
Order off Addition
g Design
Press Speed
Atomization
Sprayy Rate
Product Te
Coating W
Blender F
Tooling
Rotation
Number o
ntegration
Uniformity
Content
Tablet Thickness
niformity
ardness
API Unifformity
Weight
ution
ution
Moisture C
Tablet W
Dissolu
Dissolu
Tablet Disin
Tablet Ha
Excipient U
Visual Un
13
9/23/2011
Class Exercise
` Divide room into groups of 3 to 5
` Select one process mapping tool
tool
Benefits of Process Mapping Tools

` Ishikawa Fishbone Diagram
` Takes into account more than just processes
` Operators
` Analytical methods
` Materials
` Focus on one critical quality attribute (characteristic)
` Flow Down Map
` One snapshot of the whole process & subprocesses
` See how each step feeds into other steps
` See how lower levels will affect higher levels
` Process Map
` Details of each unit operation
` Focus is on the variable/factor level
14
9/23/2011
Some Quality Risk Management Tools

` Risk Register (developed by USL)
` Qualitative “Stop Light” tool
` Cause and Effect Matrix
USL Risk Register – Probability and

Severity
Probability
Category Rank Likelihood of
Critical Quality Attribute: A physical,
Occurrence chemical, biological or microbiological property
Very High 5 Is almost certain to occur or characteristic that should be within an
High 4 Is likely to occur appropriate limit, range, or distribution to
Medium 3 Is as likely as not to occur ensure the desired product quality.
Low 2 May occur occasionally
Very Low 1 Unlikely to occur
Severity
Category Rank Definition
4
4 8 12 16 20 Very High 4 Critical quality attributes cannot be met
High 3 Critical quality attributes may not be met
3 6 9 12 15 Medium 2 Non-critical quality attributes may not be

3 met
Low 1 No effect, or aesthetic effects only
Severity
2 2 4 6 8 10
1 1 2 3 4 5
1 2 3 4 5
Probability
15
9/23/2011
Example USL Risk Register

Quality
Risk Description Probability Severity Score Attribute Document Link Risk Owner Action
API
Company X API may fail the release/
Particle Size Spec. due to its Particle
process variability. 1 2 2 Size Chemistry Monitor
API
FDA may require USL release/
tightening the particle size Particle
distribution criteria in future. 1 2 2 Size Chemistry Monitor
Roller Compaction Process:
Addition of fines from the
process back into the In-
granulation could impact process
processability 2 3 6 Spec Pharm Dev Exp.
API
Company X’s change in release/
manufacturing process could Particle
impact the particle size Size
distribution and processability Exp. with
of the API. 4 2 8 Pharm Dev new lot
Company X’s change in API
manufacturing process will release/
introduce new residual residual Test with
solvents to the API. 5 1 5 solvent Chemistry new lot
Qualitative “Stop Light” Tool MR Tablet Example
Drug Layer Formulation Variables
Drug Drug Viscosity of
Product
Product Core Selection substance
Core Selection substance Binder
Binder Binder lot to
Binder lot to API/Binder
API/Binder drug
drug layering
layering
CQA (type/size) particle size type/grade lot variation ratio solution
Assay Low Low Medium Low Medium Medium
Content
Uniformity High Low Medium Low Medium Medium
Drug
Release Low Low High Medium High Medium
16
9/23/2011
Cause & Effect Matrix

Criteria Assay Dissolution Appearance Stability
Strongly Strongly Strongly
Scoring: 9 Effect Strongly Effect Effect Effect
Moderate Moderate Moderate Moderate
3 Effect Effect Effect Effect
Minor Minor
1 Effect Minor Effect Minor Effect Effect
0 No Effect No Effect No Effect No Effect Total Weight

Weight 50 30 10 10 100
# Reviewer Process Step Total Score
1 DC Blending 9 3 9 3 660
2 TN Milling 9 9 1 3 760
3 DM g
Tableting 1 9 9 1 420
4 DM Packaging 3 1 9 9 360
Class Exercise continued

` Divide room into groups of 3 to 5 again
` Select one risk management tool
tool
17
9/23/2011
Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
ANDA Products - CMC

` API and excipients are well characterized
` Reference Listed Drug (RLD) Package
Insert/Deformulation
` Product formulation is semi-quantitatively known
` Good idea of manufacturing process
` Analytical methods may be USP monographed
` Aspects that may not be identical to RLD
` Formulation
` Manufacturing equipment & process parameters
` Packaging equipment & process parameters
18
9/23/2011
QbD Process Flow
ANDA Oral Solid Product Case

Study
ANDA Quality Target Product Profile
Quality Target Product Profile: A prospective summary of

the quality characteristics of a drug product that ideally will be Target
achieved to ensure the desired q quality,
y, taking
g into account Product
safety and efficacy of the drug product. Profile
Definition
of Product
Attribute Target Intended
Use and
Dosage Form and Size Product X, XX mg dose
pre-
Strength XX mg API per X mg dosage unit definition
(XX.XX% w/w anhydrous drug load) of Quality
Targets
Appearance/Description Similar to Innovator
(clinical
Identity List API (include compendial references) relevance,
A
Assay C
Commonly l 90 – 110% efficacy,
safety)
Moisture List target
Uniformity Meets USP
Impurities List impurities and known limits
Stability XX Months
PK/PD (Bioequivalence) Passes BE testing
19
9/23/2011
ANDA Flow Down Map
Prior
Process
Know-
Outline
ledge
Operations of Prior
to Knowledge
intended (drug
drug substance,
substance process,
or drug unit ops,
(could be Risk
to identify
Critical
Quality
Attributes
ANDA Risk Assessment Overview

Prior
` Used the Quality Target Product Know-
ledge
Profile and the Process Map together Summary
to perform a risk assessment of Prior
Scientific
Knowledge
` Risks were identified as high or low (drug
substance,
` Any risk that was unknown was process,
unit ops,
etc.), Initial
labeled as high Risk
Assessment
to identify
Critical
Quality
Attributes
20
9/23/2011
ANDA Early Qualitative Risk

Assessment
St
Strength
th CPP L
Low L
Low
Appearance/Description CPP High Low
Assay CPP Low Low
Moisture High High Low
Uniformity Low High High
Stability Low Low High
PK/PD High High High
Manufacturing Process CPP High High
• Some aspects of the formulation are known at the

project start
• Many aspects of the manufacturing process and
packaging have high risk to the QTPP at this stage
Analysis Pointed to Formulation and

Processes
Process
Three high level sources of risk to the drug product: Develop-
ment
` Formulation
F l ti Composition
C iti
Overview of
Quality by
` Manufacturing Process Design key
actions and
` Packaging Process & Materials decisions
taken to
develop
New
Scientific
¾ All high risk areas were addressed using experimentation Knowledge,
¾ Both small scale and large scale equipment were utilized e.g. DoE,
PAT Risk
PAT,
¾ Experimentation was a mix of standard experimentation and Design of Assessment
Experiments and Risk
Control
¾Goal is to eliminate and/or mitigate all high risk areas (more learning can
change a high to a low OR identify Critical Process Parameters)
21
9/23/2011
ANDA Early Risk Assessment - Blending

Risk assessments can be focused to specific unit operations or raw
materials
Blender Fill
Volume Order of Addition # of Rotations
Strength Low Low Low
Appearance/
Description Low High High
Identity Low Low Low
Assay Low Low Low
Loss on Drying Low Low Low
Uniformity CPP High High
I
Impurities
iti L
Low L
Low L
Low
Stability Low Low Low
PK/PD Low Low Low
Manufacturing
Process High High High
ANDA Data Modeling

` Modeling of data is a useful tool for identifying a
design space, especially with multiple factors
(variables)
` Can be done “after the fact” – do not always need a
DOE designed at the experiment start
` Still need to make sure data covers the entire region of
interest
22
9/23/2011
ANDA Packaging DoE

Graph Builder
Parameter 3 (units) vs. Parameter 4 (units) by Parameter 2 (units) & Parameter 1 # Failures
(units) 0.0
Parameter 2 (units)
1.0
442 600 755
2.0
3.0
70
23
60 4.0
50 5.0 # Failures
40 6.0
7.0
70
8.0
Parameter 1 (units)
30
Parameter 3 (units)
60
50 9.0
40 10.0
0.0
70
1.0
37
60
2.0
50
40 3.0
4.0
70 5.0 # Failures
44
60
6.0
50
7.0
40
8.0
240260 280 300 320 340 240260 280 300 320 340 240260 280 300 320 340
Parameter 4 (units) 9.0
10.0
ANDA (High Level) Later Risk Assessment

Strength
g CPP Low Low
Appearance/Description CPP CPP Low

Assay CPP Low Low
Moisture CPP Low Low
Uniformity Low CPP CPP
Stability Low Low CPP
PK/PD Low Low Low
Manufacturing Process CPP CPP CPP

• High risk areas identified at project start are now either:
• Low – experimentation showed no effect on QTPP
• CPP – experimentation showed an effect on QTPP
and Critical Process Parameter is controlled
23
9/23/2011
Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
NCE NDA Products - CMC

` New to the world
` API
` Form(s)
` Process for manufacture unknown
` Formulation
` P k i
Packaging
24
9/23/2011
505b2 NDA Products - CMC

` Knowns
` API
` Form(s)
` Process for manufacture
` Some analytical methods may be applicable
` Unknowns – New to the World
` Formulation
` Packaging
QbD Process Flow
505b2 Oral Solid Product

NDA Case Study
25
9/23/2011
NDA Quality Target Product Profile

Attribute Target
Dosage Form and Size Product Y, Maximum Size of XX dimensions

Target
Strength XX, XX, XX and XX mg Product
Appearance Colors defined by Marketing Profile
Identity API Name Definition
Assay 90-110% of Product
Intended
Uniformity Meets USP Use and
Degradation Products/ List impurities and/or degradation products and pre-
Impurities known limits definition
of Quality
Targets
Dissolution Timepoint 1: NMT XX% released (clinical
Timepoint 2: XX% - XX% released relevance,
Timepoint 3: XX% - XX% released efficacy,
Timepoint 4: NLT XX% released safety)
Stability XX months expiry
PK/PD List in vivo criteria
NDA Flow Down Map
Prior
Process
Know-
Outline
ledge
Operations of Prior
to Knowledge
intended (drug
drug substance,
substance process,
or drug unit ops,
(
(could
ld b
be Ri k
Risk
to identify
Critical
Quality
Attributes
Drug Delivery Technology, Jan 2010, Vol.

10 No 1
26
9/23/2011
NDA (High Level )Risk Assessment
Unit Operations
Formulation Container
Composition 1 2 3 4 5 6 7 8 Closure System
Dosage Form Low Low Low Low Low Low Low Low Low Low
Strength Low Low Low Low Low Low Low Low Low Low
Appearance Low Low Low Low Low Low Low Low Low Low
Identity Low Low Low Low Low Low Low Low Low Low
Assay Low Low Low Low Low Low Low Low High Low
Uniformity Low High Low Low Low Low Low Low Low Low
Degradation Products Low Low Low Low High Low Low Low Low High
Dissolution High Low Low Low Low High High High High Low
Stability High Low Low Low High Low High Low Low High
PK/PD High Low Low Low Low High High High Low Low
Manufacturing Process High High High High Low High High High Low Low
Analysis Pointed to Manufacturing

Process
Process
Ten overall sources of risk to the drug product: Develop-
ment
` Formulation
F l ti Composition
C iti ` Unit
U it O
Operation
ti 5
Overview of
Quality by
` Unit Operation 1 ` Unit Operation 6 Design key
actions and
` Unit Operation 2 ` Unit Operation 7 decisions
taken to
` Unit Operation 3 ` Unit Operation 8 develop
New
` Unit Operation 4 ` Container Closure Scientific
Knowledge,
¾Process Steps
System
p 1-3 have the highest
g risk to the p
product p
progressing
g g
e.g. DoE,
PAT Risk
PAT,
(based on prior knowledge, experience, etc.) Assessment
and Risk
¾ More thorough understanding needed earlier rather than later Control
¾Formulation fixed based on in vivo performance requirements
¾Other Process steps are relatively straightforward
¾ Can be looked at in more detail at a later date (lower priority)
¾Container closure system has been explored
¾ Data in-process (stability)
27
9/23/2011
NDA Detailed Risk Assessment

Evaluation of Unit Operation 1 Evaluation of Unit Operation 2
Parameters Parameters
1 2 3 4 5 6 1 2 3
Assay Low Low Low Low Low Low Assay Low Low Low
Uniformity High High Low Low Low Low Uniformity Low Low Low
Degradation Degradation
Products Low Low Low Low Low Low Products Low Low Low
Sulfate/Sulfamate Low Low Low Low Low Low Sulfate/Sulfamate Low Low Low
Dissolution Low Low Low Low Low Low Dissolution Low Low Low
Stability Low Low Low Low Low Low Stability Low Low Low
PK/PD Low Low Low Low Low Low PK/PD Low Low Low
Manufacturing Manufacturing
Process Low High High High High High Process High Low High
Evaluation of Unit Operation 3 • All three unit operations are

Parameters linked together
1 2 3 4 5
Assay Low Low Low Low Low • Used DOE as an efficient
Uniformity Low Low Low Low Low way to screen through
Degradation Products Low Low Low Low Low
Sulfate/Sulfamate Low Low Low Low Low
parameters and focus on the
Dissolution Low Low Low Low Low few of high importance
Stability Low Low Low Low Low
PK/PD Low Low Low Low Low
Manufacturing Process High Low High High High
What is DoE?
` DoE is “a structured, organized method for
determining the relationship between factors (X’s)
affecting a process and the output of that process
(y).” (ICH Q8)
` Process = {unit operation, formulation, assay}
` X’s = controllable (e.g., time, temp, amount of a
component) and uncontrollable (e.g., instrument,
operator, media lot) factors
` y=response
response variable
ariable
28
9/23/2011
Goals of DoE
` Efficient experimentation - versus “one factor at a
time”(OFAT)
` Reduced number of runs
` Covers wider space
` Hidden replication
` Effective experimentation - versus “one
factor at a time” (OFAT)
` Mitigates impact of artifacts such as run order and
experimental clustering
` Acknowledges main effects and interactions
Types of Designs
` Screening designs
` Used to identify significant factors
` Used to verify ruggedness
` Response surface designs
` Used to optimize a process
` Used to model a process
` Special designs
` Simplex – iterative optimization
` Mixture – constrained factors
` R b t – stability
Robust t bilit tto noise
i ffactors
t
` Split-plot – experimental units split into two dimensions
` Optimal – model is specified
29
9/23/2011
Plackett-Burman Screening Design Used
- +
Factor 1 200 300
Factor 2 1500 2500 • 9 factors each at 2
levels giving 12
Factor 3 300 500 runs
Factor 4 0 60 • Study of main
effects only
Factor 5 43 53 • No interactions
Factor 6 50 80 • No curvature
Factor 7 800 1600

Factor 8 200 500
Factor 9 2 8
Data Collection
` Responses:
` Measured material attributes from in-process material
from Unit Operations 1,
1 2,
2 and 3
` Recorded dependent process information
` Calculated process yield
30
9/23/2011
Analysis Example for Usable Product from

Unit Operation 3
Factor 6(800,1600) -15.02878 2.056689 -7.31 0.0053*
Factor 1(200,300) -7.172118 4.659808 -1.54 0.2214
Factor 2(1500
2(1500,2500)
2500) -1.596386
1 596386 2.088476
2 088476 -0.76
0 76 0 5003
0.5003
Factor 9(49,53) -2.208199 3.272166 -0.67 0.5481
Factor 5(50,80) -1.308466 2.174117 -0.60 0.5897
Factor 3(300,500) 1.2461104 2.582938 0.48 0.6625
Factor 7(200,500) -0.767327 1.938503 -0.40 0.7187
Factor 8(2,8) -0.729208 2.054873 -0.35 0.7462
Factor 4(0,1) Zeroed 0 0 . .
90
• Factor 6 had a significant
80
negative effect on the
70
usable yield
Usable (%)
60
• The higher the value of
Factor 6, the lower the
50
usable yield
40
700 900 1100 1300 1500 1700
Factor 6
Linear Fit
Overall Design Outcome
Unit Operation 1: Unit Operation 2: Unit Operation 3:

Factors with significant effects (blue) were identified for each unit operation.
One factor (red) could not be evaluated in this design due to equipment
constraints.
31
9/23/2011
Narrowing Down Factors to 4 for a RSM

Design
` Factor 1- a significant factor for all three unit
operations
` Factor 4 - a significant factor for all three unit
operations
` Factor 5 - a significant factor on attributes from
Unit Operation 1 in-process material and is likely
related to Factor 1 and Factor 4
` Factor 7 – a significant factor for numerous
product attributes
Translation to RSM
- +
Factor 1 200 250
Factor 2 2000
Factor 3 500
Factor 4 0 20
Factor 5 48 52
Factor 6 70
Factor 7 800 1600
Factor 8 500
Factor 9 6
32
9/23/2011
Analysis Example for Unit Operation 2

Response
Factor 1(48,52) -0.143333 0.015699 -9.13 <.0001*
Factor 1*Factor 4 -0.135 0.027191 -4.96 0.0001*
Factor 7(800,1600)
7(800 1600) 0 0516667 0.015699
0.0516667 0 015699 3 29
3.29 0 0046*
0.0046
Factor 4*Factor 5 -0.0775 0.027191 -2.85 0.0116*
Factor 1*Factor 1 0.0426667 0.021062 2.03 0.0598
Factor 5*Factor 7 -0.05 0.027191 -1.84 0.0846
Factor 1*Factor 5 -0.04 0.027191 -1.47 0.1607
Factor 1*Factor 7 -0.04 0.027191 -1.47 0.1607
Factor 5(180,220) -0.019167 0.015699 -1.22 0.2398
Factor 4(0,20) -0.000833 0.015699 -0.05 0.9583
• Analysis gives a response surface

• Includes interactions
• Includes curvature
• Two main effects and two 2-factor
interactions were significant
• Can use many models together to
predict future behavior of the process
Mathematical Optimization was Performed to

Give Desired Responses
` Important goal was to have a high yield with minimal

waste
` All response surfaces generated were used to identify
processing parameters to meet this goal
` Final Outcome:
` Factor 1 Æ 200 (low)
` Factor 4 Æ 52 (high)
` Factor 5 Æ 0 (low), but formulation dependent
` Factor 7 Æ 1200 (center point)
` These parameters were used to manufacture small
scale material and were used to give starting points for
the commercial process.
33
9/23/2011
Objectives

` QTPP
` Process Mapping
ANDA product
NDA product
Comparison Summary
` Major QbD Focus ANDA NDA
API √
Excipients √
Formulation √ √
Manufacturing √ √
Packaging √ √
34
9/23/2011
Conclusions
` Independent of the type of submission, QbD
principles can and are being applied in
bio/pharmaceutical development.
development
` Risk management tools provide a means for
determining the focus and how QbD is applied
throughout the development program.
` Higher risk, more complex technology = more
evaluation of p
process steps
p and materials ((CPP,
CMA) and the determination of CQAs.
` The use of multiple tools allows the information to be
analyzed in different ways, providing new insights.
` Extra Slides
35
9/23/2011
Introduction to ICH Q8, Q9, Q10

` ICH Q8 – Pharmaceutical Development
` Describes the suggested content for the 3.2.P.2
((Pharmaceutical Development)
p ) Section of a
regulatory submission in the CTD format.
` Annex to the guidance describes the principles of
Quality by Design.
` ICH Q9 – Quality Risk Management
` Provides principles and examples of tools for quality
risk management that can be applied to different
aspects
p of p
pharmaceutical q
quality.
y
` ICH Q10 – Pharmaceutical Quality System
` Establishes a new ICH tripartite guideline describing
a model for an effective quality management system
for the pharmaceutical industry.
ICH Q8 - Highlights
` The aim of pharmaceutical development is to
design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product.
` Quality should not be tested into products, it
should be built in by design.
` Greater understanding of the product and its
manufacturing process,
process through the
implementation of quality by design, can create
a basis for more flexible regulatory
approaches.
36
9/23/2011
ICH Q9 - Highlights
` QRM is a systematic process for the
assessment, control, communication, and
control off risks to quality off a drug product
across the product lifecycle.
` Two primary principles of QRM:
` The evaluation of the risk to quality should be based
on scientific knowledge and ultimately link to the
patient.
` The level of effort… of the QRM process should be
commensurate with the level of risk.
ICH Q10 - Highlights

A model for a pharmaceutical quality system that can be
implemented throughout the different stages of a product
lifecycle.
Implementation should result in achievement of three main
objectives:
Achieve Product Realization – establish, implement and
maintain a system that allows delivery of products with
appropriate quality attributes
Establish and Maintain a State of Control – develop and use
effective monitoring and control systems for process
performance and product quality
Facilitate Continual Improvement – identify and implement
appropriate product or process quality improvements
37
Abstract
Pharmaceutical companies are increasing their use of outsourcing
of manufacturing processes as a strategy for remaining competitive
in the global marketplace. This has placed greater emphasis on
process management at Contract Manufacturing organizations. Two
parties are now involved and it is critical that process knowledge
and understanding is developed and communicated back and forth
between the two parties. Quality by Design (QbD) is a disciplined
A Quality by Design Based Approach to and systematic approach for effectively developing and
Process Design, Control and Improvement communicating the needed process understanding. QbD provides
the common language needed to enhance the outsourcing process.
Ronald D. Snee This presentation will introduce the building blocks of QbD with a
focus on how the needed process understanding is developed to
IVT’s 3rd Annual Bio/Pharmaceutical Conference on enable effective process development, transfer, improvement and
Quality by Design control. The concepts, methods and benefits involved will be
San Francisco, CA introduced and illustrated with pharmaceutical case studies and
September 14-16, 2011 examples.
1 Snee Associates, LLC 2 Snee Associates, LLC
Agenda Today’s Environment
{ Outsourcing to CMOs is on the increase
{ Today’s Environment { Some companies want to develop partnerships to reduce
{ QbD – What, Why and the Building Blocks the number of CMOs utilized
Design Space, Process Control and Risk Management { Partnerships are more easily praised than practiced
{ Developing Process Understanding Viewed as a continuing, never ending process
{ Experimental Strategies for Process Design Common language
Common method of working together
Identifying the Critical Control Parameters (CCP)
Development of trust
Experimentation – Right Data in the Right Amount at the
{ Process understanding is critical to success
Right Time
Process design, improvement and control
{ QbD Monitoring System for
Communication and collaboration
Process Performance and Product Quality
{ FDA updated Process Validation Guidance (Jan 2011)
{ QbD Enables Successful Tech Transfer Elaborates on QbD techniques for process development,
{ Summary risk analysis and process control

Contract Manufacturing and Risk Desired State for
Pharmaceutical Manufacturing
{ The price paid by the Pharma
Company to the CMO is a “A maximally efficient, agile, flexible pharmaceutical
function of the risks involved $$ manufacturing sector that reliably produces high quality
Technology Transfer will be drug products without extensive regulatory oversight.”
done rapidly and smoothly Janet Woodcock, Director
FDA Center for Drug Evaluation and Research
Manufacturing will be stable Risk
and capable Quality by Design – An Effective Approach
Systematic approach to product and process development
{ Risk is a function of process • Begins with predefined objectives
understanding - Ability to: Risk • Emphasizes product and process understanding and
Predict process performance process control
• Based on sound science and quality risk management
Move technical information From ICH Q8(R1) Step 2
Process
between the parties
Understanding Quality by Design is about
Need An Approach to Increase Process Understanding Building Quality into Products and Processes
Linked and Sequenced
{ Identification of Critical to Quality Attributes (CQA) Process
Capability
{ Raw Material Variation Characterization Process
Control
{ Identification of Critical Process Parameters (CPP) Process
Critical Quality Model
{ Characterization of Design Space Attributes (Ys) Y=f(X) Design
{ Process Capability, Control and Robustness Space Risk
{ Analytical Method Capability, Control and Robustness Critical Process Process Level
Parameters (Xs) Robustness
{ Risk Analysis and Management
{ Life Cycle Management of the System
Raw
On-Going Checking and Enhancement Materials
Continued Process Verification (Xs)
Failure Modes and Effects Analysis
QbD Develops Process Understanding
“Process” = Process and Analytical
Design Space
Region Where Product Will Be in Specs
Design Space
Product Is
Predicted
to Be
Within Specs
Control Point
(105, 11.5)

Design Space – Variation, Process Understanding, and Risk Reduction
A Fundamental Element of QbD
Analyze
The multidimensional combination and interaction of Process Variation
input variables (e.g., material attributes) and process
parameters that have been demonstrated to provide
assurance of quality. Processes Process Enhanced Compliance
Vary Understanding Reduced Risk
Knowledge Space ICH Q8
10 November 2005
Design Space
Process Understanding Reduced Process Variation
is Required to Create the
Control Control Design Space Enhanced Prediction of
Space Q Space Z Process Performance
Analyzing Process Variation Leads to
{ Increased Process Understanding
{ Reduced Process Variation
{ Reduced Risk 12 Snee Associates, LLC
Predicting Process Performance
Check List for Process Understanding Controlled Variables (Xs)
• Press speed
{ Critical variables (Xs) that drive the process are known • Compression forces
{ Critical uncontrolled (Environmental) variables that • Pre-compression forces
Y = f (X)
affect the process output (Ys) are known and: • Punch separation
Process has been designed to be insensitive to these Process Inputs (Xs) Process Outputs (Ys)
uncontrolled variations (robustness) • Raw Materials • Thickness
• Energy Compression
{ Measurement systems are in place and the amount of Process • Hardness
• Tooling • Friability
measurement variation is known
• Weight
{ Process capability is known • Yield
Uncontrolled Variables (Xs) • Waste
{ Process failure modes are known
• Ambient Temp and Humidity • Dissolution
{ Process control procedures and plans are in place • Shift
{ You can accurately predict process performance • Operators
• Machine
QbD Provides Methods and Tools for • Raw Material Lot
Developing Process Understanding • Powder Flow Characteristics
Using Quality by Design to
Improve Dissolution Performance
Case Study – Product in Late Stage Development Strategy of
New formulation in development for 8 years – validation
not complete
Using QbD product successfully launched in 1 year Experimentation
Design of Experiments (DOE) identified
Variable with largest effect was previously unknown
Critical interactions between 4 raw material variables
• Strategy:
and 5 process variables The science of planning and directing an activity
New measurement method identified need to tighten raw • What strategy do you adopt when using
material specs
experimentation to improve a process?
Quality by Design • What critical issues do you consider and
• Increases Process Understanding Enabling Timely
Process Optimization and Control pay attention to?
• Enables You to Obtain the
Right Data at the Right Time in the Right Amount

Developing the List of Candidate Variables (Xs)
Historical
Process Map C&E Matrix FMEA
Data
Reducing
Experimentation Risk List of
Candidate
Ensuring that We Don’t Miss Any Tribal Knowledge Xs
Important Variables • Organization

• Process Experience
• Literature Experimentation
• Screening
• Characterization
• Optimization including
Robustness Studies

Diagnosis of the Experimental Environment
Situation
{ Number of factors (X’s)
{ Begin experimenting with a large number of variables:
{ Type of factors (X’s):
Reduce the Risk of missing one or more key
variables Quantitative (temperature, pressure, feed rate)
{ Need a strategy for experimenting in this environment Qualitative (reactor type, catalyst, team)
that minimizes the amount of experimentation { Type of output variables (Y) – continuous or discrete?
{ An effective Strategy: { Can the factors be studied over their full ranges?
Diagnose the experimental environment { Resource constraints – time, funds($$), people
Decide the quality of information needed { Quality of prediction required:
Select the appropriate experimental design Identify “key drivers”, find “sweet spot”, define
Conduct the experiment design space or make predictions?
{ Is the available scientific theory useful:
Has a theory been developed for all responses?

Comparison of Experimental Environments
Experimental Strategy Building Blocks
Characteristic Screening Characterization Optimization
No. of Factors More than 6 3-6 2-5 Product and Process

Analytical Control and
Process
Methods Capability
Desired Critical Factors Understand how Prediction Xs and Ys
Reduced Risk
Information System Works Equation, Enhanced
Optimization, Compliance
Process
Design Space Model Design
Experiments
Space
Y=f(X)
Model Form Linear or Linear and Linear, Interaction
Main Effects Interaction Effects and Curvilinear
Effects Strategy of
Experimentation
Experiment Plackett- Burman Full and Response Surface • Screening
• Characterization
Design Fractional- Fractional • Optimize including
Factorials Factorials Robustness Studies

Fermentation Optimization Study
Comparison of Initial and Optimized Conditions
Initial Screening Optimized
Fermentation Conditions Design Conditions
Variable Raw Coded Raw Coded Raw Coded
Optimization Study FeCl3 0.1 -1 0.1 -1 0.1 -0.2
Strategy of Experimentation Inoculum 1 -1 2 1 2.1 1.2

Vol
• Current Performance: Enzyme Activity = 3762
OD 578 0.8 -1 0.8 -1 1.1 0.4
• 12 Variables are considered “important”
Induction
• Questions: Time 5 -1 7 1 6 0
Measured
• What variables are affecting Enzyme Activity? Activity 3762 4924 5790
• Can We Increase Enzyme Activity
Enzyme Activity Increased 54%!

Optimizing Multi-Component Mixtures
Use Strategy of
An Example Formulation Experimentation Approach
Ingredient Amount (%) { Approach similar to process
API 5 – 50 variable DOE
Filler 5 – 65 Designs, models, graphics
Binder 0.2 – 12 { Strategy of Experimentation
MCC 5 – 35 applies – Screen,
Disintegrant 0–5 Characterize, Optimize
Lubricant 0.5 – 1.0 { Large number of
Water 2-5 components can be
optimized
How Do We Find { Lower and upper bounds on
• Optimal Formulation? components can be Life Cycle Management and Continuous Improvement
• Formulation Design Space? Continued Process Verification
addressed
Product Quality Lifecycle Implementation (ISPE) Stable Manufacturing Process
Average
Process Variable
Time or Sequence
{ A process in a state of statistical control consistently

produces product that varies within the process
control limits; typically
Upper Limit: Process Average + 3(Process Std Dev)
Lower Limit: Process Average – 3(Process Std Dev).
{ Process that is in a state of statistical control as
Each batch of tablets is being produced
Berridge, etal 2009 Batches of tablets are produced over time.
Capable Process
{ Consistently produces
product that is within
specifications for all
product parameters.
{ Process capability Reducing Process Risk
analysis compares the Improving Process Stability and Capability
process variation to the
lower and upper
specification limits Statistical Process Control
{ Broadly used measure of Process Capability Indices
process capability is the
Ppk index

Common Causes of Variation Special Causes of Variation
If only common causes of variation are present, the
process output is stable over time and is predictable If special causes of variation are present, the process
output is not stable and is not predictable
Common Causes:
Present all the time Special Causes:
Influences all process outputs Due to outside influences
Require process changes to reduce Affect some of the process outputs
Minimum variation process is likely
to exhibit
Can cause data to form non-normal
patterns

Shewhart Control Chart Tablet Weight – Stable Process – Two Presses

Upper Control Limit (UCL) 1.08
UCL=1.07360
1.07
Average
1.06
_
X=1.05489
Process Variable
1.05
Lower Control Limit (LCL) Individual Value
1.04
Time or Sequence LCL=1.03619
1.03
Control Limits Are Not Specification Limits! 1 19 37 55 73 91 109 127 145 163 181

Assessing Process Stability
{ Q: When Should I worry about process stability?
A: When Long-Term process variation is too high
102 { Q: How high is too high?
UCL=101.818
101 { A: Long-Term variation becomes a concern when it represents more

than 20% of the total variation
100
Total Variation = Long-Term Variation + Short-Term Variation
99 _
X=98.682 { This guideline is based on the assumption that
98 Well-controlled process will detect a shift of 1.5 short-term
Individual Value
97 standard deviations
96
LCL=95.546 Process Stability Long-Term Variation
95 Not a Problem < 20%
1 14 27 40 53 66 79 92 105 118
Batch May be A Problem 20 – 30%
Corrective Action Needed > 30%

Schematic - Between and Within Variation
3 Batches, 2 Samples per Batch
Long-Term (LT) Variation Analysis
1.08
Within-Batch LT Variation = 18% LT Variation = 44%
(p=.000) (p=.001) UCL=1.07360
Short-Term
1.07
Variation
Between-Batch 1.06
_
Long-Term X=1.05489
Variation
Individual Value 1.05
Batch
Mean 1.04
LCL=1.03619
1.03
1 19 37 55 73 91 109 127 145 163 181

102 Measuring and Reducing
UCL=101.818
101
Process Risk Using
100
99 _
X=98.682
98 • Short-Term (Cp and Cpk)
LT Variation LT Variation
Individual Value
97 =6% =23%
(p=.41) (p=.14) • Long-Term (Pp and Ppk)
96
LV Variation LCL=95.546
95 = 64%
1 14 27 40 53 66 79 105
92 (p=.001)118
Batch

Measuring Process Capability
Capability versus Performance Cp Index Compares Process Variation to Spec Limits
• Process Capability is the

variation the process would
Process
exhibit if only common cause
Performance Tolerance
Process
variation were present:
Capability
“The variation in the
process if the angels ran
the process”
• Process Performance is the
total variation experienced by
the customer; includes
common cause, structural, and
special cause variation:
USL – LSL
“The variation when we Cp
mortals run the process”
Cpk Index Compares Process Variation to Cpk Index Compares Process Variation to
Difference Between Process Average and Specs Difference Between Process Average and Specs
Average – LSL
USL – Average Cpk = = 0.33 Poor
Cpk = = 1.33 Good!! 3 (Short-term Standard Deviation)

Traditional Performance Indices Levels of Process Capability
Marginally Capable
Two traditional measures of process performance: LSL USL
LSL
Cp = 1.0 USL
Poor
USL – LSL
Pp = Capability
6 (Long-term Standard Deviation) Cp < 1.0
Where: 40 45 50 55 60 65 44 46 48 50 52 54 56 58
LSL = Lower Specification Limit

USL = Upper Specification Limit Robust Process
LSL USL
Cp = 2.0
Ppk = Min (USL – Average, Average – LSL)

44 46 48 50 52 54 56

Sampling to Assess Process Capability Process Management System Use of Data
Depends on Process, Business Need, and Objectives Process Control, Improvement and Design Integrated
Time Frame Practical Statistical Customers Process

Significance Significance Design/Redesign
Short Term Short Term Variation n > 30

Process Process
Sampled (ex: 30 Days, The Process
Performance Improvements
measured daily)
Data
Long Term Total Range of n > 60
Process Variation Process
Feedback Improvement
Sampled (ex: 90 Days, Adjustments Feedback
Projects
measured daily)
Periodic Process
Capability Indices are Highly Variable when Reports &
Information to Analysis and Improvement
Estimated from Small Samples System
Management Reviews

Periodic Reviews of Process Performance
A Team Sport Individual Batch Monitoring System
Review Team Timing Individual

Batch
{ Process Operators { Daily/Hourly Production
{ Area Manager and { Weekly

Direct Reports Process Process
Data Process
{ Site Manager and { Monthly Models
Adjustment
Direct Reports Y=f(X)
{ Business Manager and Monitoring Tools
{ Quarterly Periodic
Direct Reports •Control Charts
Data Analysis •Capability Analysis
and •Variance
Review Components
•Histograms
•Pareto Charts

Process Adjustment - Example
Process Adjustment Model
Process Model Y=26 + 0.4x – 0.003x**2
Process Model Y=f(X) Process Model Y=f(X)
Current
Current (X, Y) Performance
Performance =38
Deviation Target
Deviation
Target from Target =34
from Target
38-34=4
Required Required
Change in X Change in X
= -16

Batch Production Monitoring System DMAIC Process Improvement Framework
Batch
Production Sense of Lean Six Sigma
Over Time Tools
Urgency Results ($$)
Batch Process Process Data Control

Quality Data Adjustment Models
Y=f(X)
Improve
Im
Periodic
Monitoring Tools Data Analysis Process Analyze
•Control Charts and Improvement
•Capability Review Leadership
Analysis Measure Teamwork
•Variance Stakeholder Building
DMAIC
Components Project Management
•Histograms Define
•Pareto Charts 53 Snee Associates, LLC 54 Snee Associates, LLC
Tracking Special Cause Variation to Sources of Special Cause Variation
Identify Systemic Problems
Controlled Variables
• Temperature
Special Causes – Some Examples • Pressure
{ Raw material lot variation • Flow rate
• Catalyst concentration
{ Differences between pieces of equipment
Tablet presses Process Inputs Process Outputs
• Raw materials Manufacturing • Yield
Bioreactors • Water • Waste
Process
Test instruments • Energy • Capacity
• Downtime
{ Sources of Human Intervention • Production rate
Operating teams Uncontrolled Variables
Lab analysts • Ambient Temperature and Humidity
• Shift
{ Production lines • Team Typical Sources of
• Operators Special Cause Variation
{ Day of week • Machines

BioPharm Process Yield Improvement Tablet Content Variation Study
Daclizumab Fermentation Yield
Lot 1 Total Grams
Time Series Plot of % ACTIVE INGREDIENT
5.3
Here we see a step 1100 UCL=1083

1000 Lot 2 5.2
change in yield 900
5.1
800 Mean=799.9
What is the cause?
700
5.0
600
Grams
Raw Material Lot
500 LCL=516.5
4.9
Variation 400
Lot 3
300 4.8
Better Raw Material
% ACTIVE INGREDIENT
200
Subgroup 0 10 20 30 40 50 60 4.7
Specs Required
A:Batch 62 72 84 94 104
4.6
1 12 24 36 48 60 72 84 96 108
Used DMAIC to Identify Key Drivers of Process Yield Batch
Raw Material Lot Variation Had the Largest Effect

Tablet Content Variation Study Tablet Content Variation Study
Results Reported by Analysts A, B, C and D Analyst B Has the Least Amount of Variation
Time Series Plot of % ACTIVE INGREDIENT Dotplot of % ACTIVE INGREDIENT vs ANALYST
5.3
C
C
5.2
A
B
A B
5.1 CC
B B B
A B B A
A BA B BB B B BBB BBB BB BB B B B
AB B B BBB B
5.0 B A A BB B B B BB B B B B B B
AA BB B B B B D
B B C A B B C
A B BB B D B
A B A BB B A A DD B
4.9 D
B C D ANALYST
A B B BB B B B
4.8 A C
A B CC
% ACTIVE INGREDIENT
A A D D
A
A A 4.68 4.77 4.86 4.95 5.04 5.13 5.22
4.7
A A A % ACTIVE INGREDIENT
A
4.6
1 12 24 36 48 60 72 84 96 108
Batch

Production Process
On-Time Delivery vs Day of the Week
Box Plot of Yield vs. Team
2200
Best On-Time Delivery

Occurs on Fridays
2100
Yield
2000
1 2 3 4
Team
Team 4 – The Most Experienced Team - Has the Highest Yield

Reducing Special Cause Variation
Special Cause List Process
Continued Verification of Process Model
• _____________________ Y=f(X)
• _____________________
• _____________________ Assumptions and Strategy
• _____________________
• _____________________ { The model will predict well as long as
• _____________________
No new variables become important. Sometimes a “non-
significant” variable becomes important because its
range increases beyond what it was when the model was
created
Pareto Analysis by The process remains within the design space of
Process Type predictor variable (Xs) used to generate the model
Process to be
Improved
# Deviations
{ Monitor the prediction residuals to detect deterioration in
the prediction accuracy of the model
Type of Process
Residual = Observed Y – Predicted Y
Improvement DMAIC { Monitor the predictor variables (Xs) to detect a shift of the
process outside the design space region of the data used to
Implemented and Improvement build the original model
Confirmed Process

Model Verification Example
Process Model Verification Formulation Study
Objective
{ Monitor control chart of prediction residuals – • Construct a model to predict formulation performance as a
difference between model predictions and observed function of the levels of an additive and the 3 components in the
process performance over time formulation.
Control limits: Lower = 0 - 3S, Upper = 0 + 3S • Use the model to calculate the amount of additive to add to
S is Standard Deviation of the residuals for the model produce a specified performance of a formulation with a given
being maintained composition
{ Monitor control charts of model predictors (Xs). Control • Formulation model created from data on 18 blends that cover the
limits for Variable X are the average of X, plus and following ranges. Residual standard deviation = 0.036
minus 3 standard deviations of variable X
{ Out-of-control signals in all charts which may be due to Variable Low High Average Std Dev
One or more new variables becoming important Additive .07 .18 .125 .0183
Process moving outside the range of the data used A 0 .30 .15 .05
to create the model
B .37 .70 .535 .055
{ Consider updating the model using the data obtained
since the model was constructed C 0 .15 .075 .025

Formulation Model Prediction Accuracy
Formulation Study Model Prediction Residuals
Y Y
Batch Additive A B C obsd pred Difference
I Chart of Y-Ypred
1 0.0923 0.0741 0.6975 0.1361 10.35 10.32 0.03 UCL=0.108
0.10
2 0.1035 0.0846 0.6774 0.1345 10.80 10.75 0.05
3 0.1389 0.1244 0.6075 0.1292 12.20 12.22 -0.02 0.05
4 0.1793 0.1765 0.5211 0.1231 14.07 14.12 -0.05 _

0.00 X=0
5 0.1924 0.1936 0.4929 0.1211 14.72 14.8 -0.08
Individual Value -0.05
6 0.105 0.05 0.735 0.11 10.83 10.79 0.04
7 0.137 0.1 0.643 0.12 12.20 12.15 0.05

-0.10
LCL=-0.108
8 0.175 0.2 0.485 0.14 13.93 13.97 -0.04
1 2 3 4 5 6 7 8
Observation
Difference = Yobsd - Ypred

Formulation Model Prediction Data
Model Space Check
Formulation Model Verification
Additive Component A
I Chart of Additive I Chart of A
Summary
0.20 1 0.30 UCL=0.3
0.18 UCL=0.1800
0.25 { Model prediction residuals were all within the control
0.16
0.20
0.14 _
limits indicating that the regression model predicted
_ 0.15 X=0.15
X=0.125
0.12 well
0.10
Individual Value
Individual Value
0.10
0.05 Two of the prediction points (5,6) were slightly outside
0.08
LCL=0.0700
0.00 LCL=-0.0000
0.06 the region of the data
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Observation Observation
{ The model is predicting well. There is no need to
Component B Component C update the model at this time
I Chart of B I Chart of C
0.75 1 0.16
UCL=0.15
0.70 UCL=0.7 0.14
0.65 0.12
0.10
0.60
0.08 _
0.55 _ X=0.075
X=0.535
0.06
0.50
Individual Value
Individual Value
0.04
0.45
0.02
0.40
LCL=0.37 0.00 LCL=-0.0000
0.35
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Observation Observation

Tips and Traps
Operating Effective Process Monitoring Systems QbD Enables Successful Tech Transfer
{ Process understanding - A deep knowledge of the variables “ A process is generally considered to be well understood
that drive the process exists when:
{ Magnitudes of the measurement variation are known. (1) All critical sources of variability are identified and explained
Gage studies measure method repeatability and reproducibility (2) Variability is managed by the process, and
Ruggedness studies assess method sensitivity to protocol (3) Product quality attributes can be accurately and reliably
variations predicted over the design space established for the materials
used, process parameters, manufacturing, environmental and
{ Systematic method to keep track of special cause variation to
other conditions”
determine if systemic problems are present.
FDA 2004
{ Two common problems
{ QbD Provides Strategy, Methods and Tools for Developing
Data are not analyzed routinely
When problems are identified, no action is taken.
Process Understanding
{ Regular management reviews are essential You Can’t Successfully Control, Improve or Transfer a
Process that You Don’t Understand

Technology Transfers
How Use of QbD Improves Tech Transfer
Need to be Managed at Two Levels
MProgram Level { Focus on quality, speed and reduced costs
(Managing Multiple Tech Transfer Projects) { Role definition at all levels enhances communication
Assess Training to build skills
Manage
and Design Implement and { Structure – Program level and project level
Define Realize
{ Tech transfer management systems:
Project selection and sequencing
NProject Level Management review
(Implementing a Single Tech Transfer) Communication
Strategy Transfer Approve Recognition and reward
Gap Develop
and and and
Analysis Plan
Goals Test Launch { Measurement system evaluation
{ Creating process understanding

73 74
Process Understanding is Beneficial to Both My Message
Pharma Companies and CMO
{ QbD is an effective method for
Pharma Company CMO Developing new products and processes
{ Reduced cost of tech transfer { Better estimate of tech transfer
and manufacturing costs Enabling effective technology transfer
More competitive quotes Optimization and improvement of existing processes
{ Rapid and smooth start-up { Rapid and smooth start-up { QbD produces process understanding that is
{ Predictable outcome – No { Predictable Outcomes – No fundamental to creation of
surprises surprises Design Space and sustaining performance
{ High product quality { High quality product and reduced Process control and improvement system
operating costs { QbD concepts, methods and tools provide a common
{ Sustainable product and { Sustainable product and process language and methodology for working together
process quality over time quality over time resulting in
Fewer investigations Fewer investigations Regulatory flexibility,
{ Satisfied customers { Satisfied client Improved process performance and compliance
{ Competitive Advantage { Competitive Advantage Enhanced bottom-line results for all parties involved

Some Further Reading
Alaedini, Pedram, R. D. Snee and B. W, Hagen (2007) “Technology Transfer by References on Design of Experiments
Design – Using Lean Six Sigma to Improve the Process”. Contract Pharma, June
2007, 4-9.
Box, G. E. P. , Hunter, J. S. and Hunter, W. G. (2005), Statistics for
ICH Harmonised Tripartite Guideline: Pharmaceutical Development, Q8(R2), Current
Step 4 Version, August 2009. Experimenters – Design, Innovation and Discovery, 2nd Edition,
Snee, R. D. (2007) “Lean Six Sigma and Outsourcing – Don’t Outsource a Process John Wiley and Sons, New York, NY.
You Don’t Understand”, Contract Pharma, October 2006, 4-10.
Hoerl. R. W. and Snee, R. D. (2002) Statistical Thinking: Improving
Snee, R. D. (2009) “Quality by Design: Four Years and Three Myths Later”,
Pharmaceutical Processing, February 2009. Business Performance, Duxbury Press, Pacific Grove, CA,
Snee, R. D. (2009) “Building a Framework for Quality by Design”, Pharmaceutical Chapter 7 and Appendix E.
Technology, October 2009, Online Supplement.
Moen, R. D., Nolan, T. W. and Provost, L. P. (1991) Improving
Snee, R. D. (2009) “Raising Your Batting Average” Remember the Importance of
Sequence in Experimentation”, Quality Progress, December 2009, 64-68. Quality Through Planned Experimentation, McGraw-Hill, New
Snee, R. D. (2010) “Experimental Strategies for Implementing Quality by Design”, York, NY.
Pharmaceutical Processing, April 2010, 12-16.
Montgomery, D. C. (2009) Design and Analysis of Experiments,
Snee, R. D. (2010) “Robust Strategies for Improving Upstream Productivity”,
BioPharm International, June 2010, 28-33.
7th Edition, John Wiley and Sons, New York, NY.
Snee, R. D. (2011) “Using Quality by Design to Enable CMO Manufacturing Process Snee, R. D., L. B. Hare and J. R. Trout (1985) Experiments in
Development, Control and Improvement”, Pharmaceutical Outsourcing, Industry – Design, Analysis and Interpretation of Results,
January/February 2011, 10-18.
Quality Press, Milwaukee, WI.
Snee, R. D. (2011) “Think Strategically for Design of Experiments Success”,
BioProcess International, March 2011, 18-25.
Questions and Comments
??????
For Further Information, Please Contact:
Ronald D. Snee, PhD
(610) 213-5595
Ron@SneeAssociates.com
www.SneeAssociates.com

The ICH Q10 Implementation Journey
Gary W. Denney
Director, Product R&D
Eli Lilly and Company
IVT QbD Conference

Sept 13-15, 2011
San Francisco, CA
Agenda
• Establishing
g a ICH Q10 Integrated
g Quality
y System
y
• Integrating QbD and Quality Systems
• QbD Implementation
• QRM and Knowledge Management
• QbD Benefits
B fit
• Discussion / Q&A
1
Pharmaceutical Quality System
Q10
Pharmaceutical Development
•Life Cycle
y Approach
pp
Q8
10 •Quality System Elements
•Life Cycle Approach 8
•Enablers
•Product knowledge 9 •QS for Control Strategy Execution
•Design space
•Verification
•Product & Process development
•Continuous Improvement
•Control Strategy Development
10
9
Quality Risk Management

8 Q9
•Risk to p
patient safetyy and product
p q
quality
y
•Development Criticality Assessments
•Manufacturing link CQA’s to controls,
monitoring & revalidation
•Enabler of Pharmaceutical Quality System
9
3
ICH Q10 Pharmaceutical Quality Systems
Product and Process Technology Commercial Product

Development Transfer Manufacturing Discontinuation
Management Responsibilities
Process Performance & Product Quality Monitoring System

CAPA System
Change Management System
PQS
Elements Management Review
Knowledge Management
Enablers
2
ICH Q10 Pharmaceutical Quality Systems
Objectives of ICH Q10
1. Achieve product realisation

2. Establish and maintain a state of control
3. Facilitate continual improvement
Establishing a ICH Q10

Integrated Quality System
3
Integrated Quality Systems
Quality System must be designed to…
• Meet global regulations

• Meet global regulatory commitments
• Capture product knowledge
• Capture process understanding
• Facilitate process execution
• Facilitate product testing
Continuous Improvement Loop
Quality by Design Quality in Execution Quality in Monitoring
Complaints
Manufacturing/
Development Distribution
4

Engineering
Standards
MANUAFACTURNG
QUALITY SYSTEM
Product R&D QS
Lilly Quality
Standards
10
5
Lilly’s Quality System Approach
Integrated Business
Standards Processes
Robust
Governance/ g
Organization
Management
Controls
11

Integrated standards provide the ‘who’ and ‘what’
•Clear
Clear requirements to
meet both compliance
and patient expectations Integrated
Standards
•Owned by Quality and the
business
Quality Standards covering
• Quality Systems
• Commercialization Contract Manufacturing
Commercialization, Manufacturing, Clinical Supply Manufacturing
• Facilities, Utilities, Maintenance, Equipment, and Computer Systems
• Materials
• Production
• Packaging and Labeling
• Laboratories
12
6
The functional standards provide the ‘how’

•Simple
Business •Effective
Processes •Efficient
•Agile
Defined processes established for these functions
supporting the business:
• Operation for Manufacturing
• Product Development
• Manufacturing Information and Computer Systems
• Engineering (including Maintenance)
• Manufacturing, Science & Technology
• Laboratories
13
•Management Involvement
Robust
•Escalation Governance/
•Decision Making Management
•Auditing Controls
Examples of Governance includes:

• Notification
ot cat o to Management
a age e t for o esca
escalation
at o oof issues
ssues
• Formalized decision making in committees
• Auditing program
• Monitoring, evaluation, and trending of activities (including Quality Plans
(corporate and site) and Annual product review)
14
7
•Right People
•Right Role
Organization
•Clear Accountability
•Right Span of Control
Examples of Organization includes:
• Defined personnel qualifications
• Formal and documented training
• Defined responsibilities for roles
• Monitoring and maintenance of personnel qualifications
• Appropriate and effective organizational structure
• Education & training
• Leadership
15
• Clear requirements
to meet both • Simple
compliance and • Effective
Effecti e
patient
• Efficient
expectations Integrated Business
• Owned by quality Standards Processes • Agile
and the business
Robust
• Management
g Governance/ • Right People
Organization
Involvement Management • Right Role
• Escalation Controls • Clear Accountability
• Decision Making • Right Span of
Control
• Auditing
16
16
8
External Environment External Internal
•Q8, Q9, Q10 implementation Environment Trends
•Batch Release/QP responsibilities
•Regulatory Enforcement
•Emerging Markets
Internal trends
•Deviations Integrated Business
•Recalls Standards Processes
•Agency observations
•Audit observations
Robust
Quality Improvement Initiatives Governance/

Organization
Management Organization
Standards
Controls
Business Processes
Management Controls
Organization
17
Integrating QbD
and Quality Systems
18
9
Quality Systems and QbD
“Product Commercialization” Lilly QS Policy

Lilly’s commitment to QbD associated with product and process development
and continuous improvement as part of the product lifecycle.
• Provides quality requirements for product commercialization which must
then be translated into appropriate systems, business processes, or
procedures
• Oversight for the product commercialization process
• Define the expectations for use of the concepts of ICH Q8,
Q8 Q9 and Q10
• Defined roles and responsibilities of the functions throughout the lifecycle
of the product
19
Quality Systems and QbD
“Product Commercialization” – Lilly QS Policy

• Product
P d P
Performance
f R
Requirements
i
• Process Design / Product Design
• Technology Transfer
• Lifecycle focus
• Continuous Improvement
• Quality Risk Management
• Knowledge Management
• Governance
20
10
QbD Business Processes
Single Process Map

• One process integrating all CMC activities and deliverables
• Product Development and Commercialization scope
• QbD deliverables integrated into gate reviews
• CSFs associated with individual gate reviews
g p
• Linkages/dependicies of activities transparent
p
• Recognizes drug development as a continuous process
21
QbD Business Processes
Single Process Map
CMC Milestones and Phases
QbD deliverables reviewed at applicable gates

(eg: CQAs, design space, CPPs, CS)
22
11
Quality by Design Leadership
Lilly’s
Lilly s Approach to QbD
• Establish an enterprise wide QbD vision
• Provide leadership and stewardship for QbD Implementation
• Provide a forum for cross-functional consulting on QbD
• Ensure Lilly representation for external QbD initiatives
• Ensure organizational QbD education
• Incorporate learning
23
QbD Education
QbD Curricula established:

• QbD and Product Commercialization Introductory
course
• Quality Risk Management – Introductory,
Advanced, Applied courses
• Technical Transfer course
• Pharmaceutical Control Strategy course
24
12
QbD Education
Integrated hyperlinked curriculum and knowledge map
25
QbD implementation
26
13
Level of QbD Adoption
27
Implementation Challenges
• External Challenges
• Internal Challenges
• Benefits
28
14
Internal Challenges
Small
Molecule
Large
DP
Molecule
API
Complexity of Small Qb
Molecule
the Business API D Large
Molecule
DP
Devices
29
Cross-Network Differences
All networks have nuances associated with the individual area
• Primary risk assessment tools may differ

• FMEA for Unit ops that are difficult to build scale down models
• First principles models when they are possible
• Perturbation analyses
• Ishikawa fishbone diagram
• Criticalityy definition and determination may

y differ
• Differ between networks, differ between scientists, difficult to
choose a single approach – should we even attempt?
30
15
Cross-Network Complexities
• Multiple networks within same company perceive elements

of Qualityy byy Design
g differently
y
• Risk analyses
• Criticality assessment
• CQA assignment
• Concept of scaleability and dependence
• Availability and use of models to represent design space
• Perceived value
• Telling a consistent story within the same application
31
Within-Network Complexities
• Varying levels of understanding between scientists

• V i d
Varying degrees off acceptance
t off strategies
t t i
• Management buy-in and support
• Differing opinions from support groups
• Quality
• Regulatory
• CMC Project management
32
16
Internal QbD Perspectives
Costs
• Is the upfront investment worth the potential gains
• Increased workload on project teams
• Determination of ROI
Adoption
• “We’ve done this all along”
• Limited or skeptical support at best
Cross network harmonization

• Consistent cross functional positions nearly impossible
33
Internal Quality Systems
Existing quality systems may require updating for QbD

implementation
p
• Criticality determination more systematic, may result in
fewer critical parameters
• Deviation systems may not include the appropriate
leveling based on enhanced information package
• PM systems specifically tied to parameter classification
my require updating
• Validation criteria/strategy needs to allow for both QbD
developed projects and existing legacy products
34
17
and
Knowledge Management
35

• Regulatory compliance issues are merely external
indicators for the breakdown of internal systems or poor
g
scientific understanding
• Innovation and science are “at the heart of the enterprise”.
A well defined control strategy for the product based on
science and understanding of risk is required (QbD)
• Education / Training - People need to know “why” and
“how” to do their jobs
• Sense of urgency and the ability to react when things go
wrong is key (feedback loops, management involvement &
responsibilities)
36
18
Weak Sustainability Strong
High High
Majority time & resources
8 10 spent on improving control
9 strategies, closing knowledge
gaps, which lends focus to
Majority of time Proactive
manufacturing excellence
Knowledge
and resources
Cost
Including; reduced cycle
spent times, improved yields ,
understanding Reactive
efficient qualification,
cause and effect validation, training
relationship
p in Elimination of
order to provide Level 3 Deviations and
Low assurance Factory Loss Low
Weak Strong
Robustness
37
QRM and Knowledge Management
6
Knowledge
4 Product 1
3 Product 2
Product 3
2
0
1 year 2 years 3 years 4 years 5 years 6years
38
19
Through an understanding of Quality Risk and Knowledge

Management effectiveness can be achieved in the
Management,
following areas:
¾Product and Process Knowledge ¾Validation
¾Resource management ¾Maintenance
¾Process and people capabilities ¾Cycle Times
¾Training ¾Auditing
¾Q lifi ti
¾Qualification ¾Reviews
¾Quality
39
Benefits of QbD
Implementation
40
20
The Path to QbD Implementation
Increased Investment to Start
(e.g., development costs,
pment & Manufacturing Costs
organizational planning,
new tool implementation) Meet Patient Needs
(e g reliable performance and supply)
(e.g., reliable performance and supply)
Current State
Transition
Decreased Expenses
• Empirical development approach (e.g., lower manufacturing
• Quality by testing & inspection and compliance costs,
• Frozen process with reactive changes familiarity with tools)
Desired State
Develop
• Quality by design development
• Flexible process & continuous improvement
Initial QbD Efforts QbD Fully Realized
QbD Implementation Progress
41
Benefits to QbD Implementation
QbD results in more efficient process development

efforts
• More efficient experimental programs
• Greater level of understanding of processes
• Focused efforts on highest risk elements
• Phase appropriate effort
• Leveraged prior knowledge forces institutional learning
• Institutional learning is driving internal consistency
• Periodic evaluation and risk assessment improves
documentation through lifecycle of development
42
21
Benefits to QbD Implementation
Registration documentation significantly easier to understand

• Development effort consists of more of a story
• Design
D i space mapping i clearly
l l d demonstrates
t t process
understanding
Regulatory Benefits
• Flexibility for process changes within design space
• Reduction in number of post approval supplements
Company Benefits
• Higher likelihood of best process first
• More thorough process understanding earlier
• Fewer failures and recalls, improved safety record
43
Lilly’s QbD Experience
Recognized as a long term commitment

Regulatory perspectives continually evolving
Increased scientific understanding of processes
and products has huge benefits
Transition to manufacturing environment can be a
challenge
Knowledge management still a challenge
44
22
ICH Q10 and QbD
Understand Use Provide an

the Appropriate Integrated
Science Risk Management Quality System
Serves the customer/patient
Ensures Compliance
Makes good business practice
45
Acknowledgements
Dr. Eugene Inman, VP Analytical Sciences R&D

Dr. Kevin Seibert, Senior Engineering Advisor
Susan Busse, Director QA, Global Quality Systems
46
23
47
24
Implementing QbD in the
Development of Generic Drug
Products
Shailesh K. Singh, Ph.D.,

September 15, 2011
Disclaimer: Opinion expressed in this presentation represents solely the views of the author
Presentation Outline
n Requirements for QbD in Generics
n Quality Target Product Profile
n Criticality and Critical Quality Attributes
n Therapeutical Equivalents
n Status of Question-based Review (QbR)
n Use of prior knowledge in generics
n Risk Assessments-identify the CPP’s and CMA’s
n Implementation of QbD
n Control Strategy
n Summary
3rd Annual IVT

2 September 15, 2011 2 Singh, Ph.D.
Shailesh K. Conference
Stages in implementation of Qbd in General
Target
Product profile • Target the Product Profile
CQA’s • Determine the Critical Quality Attributes (CQA’s)
Risk assessment • Link input material attributes and process parameters

to CQA’s and perform risk assessment
Application of
Design space • Develop a design space PAT Tools
Control strategy • Design and implement a control strategy
• Manage product lifecycle, including continual

Lifecycle
management improvement
3rd Annual IVT
3 September 15, 2011 Shailesh K. Singh, Ph.D. Conference
The QbD Approach for Generics
Target Product nDefine the Quality Target Product Profile

Profile
(QTPP)
CQAs nDetermine the Critical Quality Attributes

(CQA)
Risk nLink material attributes and process

Assessment parameters to CQAs and define Critical
Material Attributes and Critical Process
Parameters (CMA, CPP)
Control
Strategy nDesign and implement a Control Strategy
3rd Annual IVT

Conference
QbD Approach as applied in Generics

(QTPP) Critical Quality Attributes Quality Risk Assessment
(CQA)
9 Assay (efficacy)
9 Impurities (safety)
9 Content Uniformity (efficacy)
9 Dissolution (efficacy)
CPPs & CMAs

identified
Experiments
Control Strategy Trospium XR 60mg Commulative Dissolution Profile - Apparatus IV
100
90 INNOVATOR L/N 0702997
80
NB574A-11
70
% R elease
60
50
40
30
20
10
0
0 2 4 6 8 10 12
Time (hours)
*Adapted from GPhA FDA QbD Workshop, May 2010, “Quality by Design for ANDAs: An Example for Immediate Release Dosage 3rd Annual IVT
Forms” – Draft Example QbD Immediate Release Dosage Forms Conference
What are the general Expectations
(generics)?
*for generics – adapted from GPhA FDA QbD Workshop, May 2011, “Define Quality by 3rd Annual IVT
Design for Generic Drugs”, Lawrence Yu, Ph.D. presentation Conference
Quality Target Product Profile (QTPP) –
Beginning with the end in mind
n Natural extension of the Target Product profile for product quality
n Prospective summary of the quality characteristics of the drug product taking into
account the safety, efficacy (and manufacturability) of the drug product
n 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)
n Consideration should also be given to:

Clinical usage Setting
Supply chain requirements
Special region/market requirements (e.g.) Japanese requirements for
appearance
3rd Annual IVT
Conference
QTPP: RLD labeling issues
n Different dosage forms have specific information contained in the RLD

Labeling
For e.g. Administration of dosage form via a specific type of feeding tube for
pediatric and dysphagic patients
Administration of split or crushed tablet (draft guidance just issued by FDA)
Sprinkle formulation requires to meet a bead size criteria (new guidance)
n ANDA Product design may be impacted
n ANDA product should match the performance of the RLD.
3rd Annual IVT

What Should be Included in Quality Target Product
Profile?
n Intended use in clinical setting (this includes RLD labeling)
Route of administration, dosage form (delivery systems), and container
closure system.
Natural extension of the Target Product profile for product quality
n Quality Attributes of drug product

Appearance, Identity, Strength, Assay, Uniformity,
Purity/Impurity, Stability, etc.,
n Active Pharmaceutical Ingredient release or delivery and attributes

affecting pharmacokinetic characteristics (Safety and Efficacy)
Dissolution
Aerodynamic performance
September 15, 2011 3rd Annual IVT

9 Shailesh K. Singh, Ph.D. Conference
Compliance Perspective: Equivalence By
Design
n End user (consumer) perspective for potential non-compliance
n Typical QTPP includes- API, Strength, Dosage form, Route of

Administration, Labeling, performance, Quality, Bioavailability, etc.,
n Physical and Organoleptic properties: Reference Vs Test formulation
Reference is beads Vs test is mini-tabs- there is a condition of use concern-

(published draft guidance)- Size of minitabs (if > 2mm) can result in loss of
efficacy for sprinkle study, etc.
Test tablet substantially larger than RLD; Same shape, size and color for all
strengths; Difficulty in swallowing fairly large tablets
Tablet score-Ease of splitting : Uneven breaking of tablets; crumbles upon
splitting; distribution of active
Taste, odor masking and tablet dust: Reference is non-functional coated
product Vs test is un-coated tablet
n New draft guidance will address some of these concerns
Adapted from “Equivalence by Design”, Vilayat Sayeed, Ph.D., Division of Chemistry III,
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011
3rd Annual IVT

Example of a Quality Target Product
Profile of MR Tablet
Adapted from “ Quality Target Product Profile with Examples”, Robert LionbergerI, 3rd Annual IVT
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 Conference
Summary: QTPP in Generic Drug Development
n QTPP is set-up in the beginning of development
n Knowledge gained during development may change some of the elements

For e.g. knowledge gained during development from IVIVR/IVIVC may change
the requirements
n QTPP is used to set the target for the development work
n Some elements of the QTPP may become part of the specification
n The Targets set forth should be quantitative ( could be number or range). It

should serve as a guide during development to determine how far or close
the test product is from this goal.
n QTPP is the starting point and is used as a starting point to identify what is
the drug product CQA

Criticality Analysis
n 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
3rd Annual IVT

Conference
Decision Tree to decide CQAs
Start
Brainstorm list of
Prior QTPP
Quality Attributes
Knowledge
(potential CQAs)
Quality No Is this a CQA Unsure Experimental

Attribute not (from a patient work to increase
a CQA perspective)? knowledge
Quality Attribute may not Yes

be a CQA but still be
critical from a business Critical Quality Attribute (CQA):
perspective e.g. tablet Apply suitable
thickness, appearance QRA tool to rank A physical, chemical, biological or microbiological property
CQAs or characteristic that should be within an appropriate limit,
range, or distribution to ensure the desired product quality.
List of CQAs
3rd Annual IVT

Conference
Critical Quality Attributes (CQA)
Identity; Assay;
Microbiology; UDU;
Mechanical & Physical
Manufacturability Drug Product CQA’s Props.; Description;
Purity; Dissolution;
Taste; Odor
Closely interlinked but not be identical
Identity; Assay;
Critical Quality Attributes Drug Substance CQA’s
Description; Purity;
Physical Properties
Raw Material CMA’s Material & Functional

Properties
Safety & Efficacy
3rd Annual IVT

15 Conference
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
3rd Annual IVT

Conference
Functionality of excipients
n What is Functionality-IPEC definition:

- A desirable property of an excipient that aids manufacturing and improves
the manufacture, quality or performance of product.
n The real function of the excipient must be known before deciding what
tests to do.
e.g. MCC can be used as a binder in tablets or as extrusion aid in a
spheronization process.
n How to access functionality & control it?
Functionality can only be accessed in context of finished product.
Is there a surrogate property of the excipient that will help predict its
requisite functionality for the end use property of product.
n Functionality tests rely on being able to simulate and predict the
performance of the material during manufacturing, packaging and the
product shelf life.
3rd Annual IVT

17 September 15, 2011 Conference
Criticality: Linkage between CPP & CQAs
n 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
n 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
3rd Annual IVT

Conference
Mapping the Linkage
Inputs: Outputs:
M1 CQA1
Critical
M2 CQA2 Quality
Attributes
Material Attributes
CQA3
P1
P2 Relationships:
CQA1 = function (M1)
P3 CQA2 = function (P1, P3)
Process CQA3 = function (M1, M2, P1)
Parameters
P2 might not be needed in the
establishment of design space
3rd Annual IVT
Conference
Therapeutic Equivalence and Pharmaceutical
Equivalence as applicable to Brand Drug
n Therapeutic Equivalents
- “… have the same clinical effect and safety profile when administered top
patients under the conditions specified in the labeling.”
n Pharmaceutical Equivalence
Same active ingredients
Same dosage form
Same route of administration
Identical in strength or concentration
Meet compendial or other applicable standards of strength, quality, purity, and
identity
May differ in shape, release mechanisms, excipients, packaging, expiration
date, etc.,
n The agency approves generic products on the basis of

- Pharmaceutical Equivalence + Bioequivalence = Therapeutic Equivalence
Clinical trials are required to establish Bioequivalence.
Adapted from “ Question-based Review and Updates”, Lane V. Christensen, Ph.D.,

Question Based Review (QbR) for
Generics
n FDA introduced in 2007 the Question-based Review (QbR) within the framework of
science and risk-based assessment of product quality.
n QbR contains the important scientific and regulatory review questions to –

Comprehensively assess critical formulation and manufacturing process
variables
Set regulatory specifications relevant to quality
Determine the level of risk associated with the manufacture and design of the
product.
n Currently the QbR questions will be revised in 2011 and a new system is planned to
be implemented from January 2013.
This will include enhanced understanding through the use of QbD
concepts that will help reduce the post market related issues
OPS MAPP 5016.1: that applies the principles of ICH Q8(R2), Q9, and Q10
to the CMC review process.
Adapted from “ Question-based Review and Updates”, Lane V. Christensen, Ph.D.,

3rd Annual IVT

When is prior knowledge usable?
n It is relevant to submission–
Clearly delineates similarities and differences
Properly links CQA’s with CMA’s and CPP’s
n It is justifiable/qualifiable
Through scientific rationale
Supported by relevant data
n Can fill the gaps/missing-links, as applicable

n Can be submitted to the agency for review with
submission
n Used as starting point for subsequent assessment
“Use of Prior Knowledge in QbD – IR and MR Examples”, Khalid M. Khan, M. S., R. Ph., CMC, Division of Chemistry III,
3rd Annual IVT

Conference
Prior Knowedge and Degree of Relevance
3rd Annual IVT
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 Conference
Use of prior knowledge
n Prior knowledge can reduce the number of experiments that need to be
studied for a given product and process.
n Due to the nature of the generic business, a number of standard
technology platforms are extensively used. Thus, there is extensive prior
knowledge and experience with these processes. These include
Direct compression/Roller compaction/ Wet granulation
Blending, milling, compression and film coating
Drug Layering/ DR or ER coating / Encapsulation
n Alignment of equipment used in these standard technology

platforms(from development to commercial scale) will provides further
assurance of predictable performance across manufacturing scales.
n There is a need to show specific examples of prior knowledge with

explanation of relevance to the current formulation and process.
n Currently, there is no formal mechanism to ensure that the use of such

prior knowledge receives FDA concurrence. The agency plans to create a
mechanism to address this issues via TC or meeting.
Use of Prior Knowledge in QbD – IR and MR Examples”, Khalid M. Khan, M. S., R. Ph., CMC, Division of Chemistry III,
3rd Annual IVT

Prior Knowledge in QbD: MR Example
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 3rd Annual IVT
Conference
Take Home : Prior Knowledge
3rd Annual IVT

Conference
Risk Assessments
Product Process Process Scale-up

& Tech Transfer Manufacturing
Development Development
ICHQ9
Phases Purpose: evaluation of Purpose: Correlation of Purpose: Differentiation of Purpose: Risk
linkage between QAs and PPs with QAs and/or CPPs from other PPs assessments for
Target Product Profile differentiation of CQAs manufacturing process
Initiation (TPP) from other QAs improvements
Inputs: TPP and prior Inputs: DOE results Inputs: DOE results and Inputs: manufacturing
knowledge (commonly bench/pilot scale process process knowledge
Risk obtained from similar knowledge
Assessment products and/or scientific
literature)
Outputs: DOE strategy Outputs: Additional or Outputs: Preliminary Outputs: various (could be
refined DOE strategies (if manufacturing control change control plans,
Risk Control necessary) and a strategy and refined refined control strategies,
(Plans & preliminary manufacturing design space revalidation, etc.)
design space
Outputs)
DOE results trigger next DOE results and Scale-up and Manufacturing experience
risk assessment bench/pilot scale demonstration batch triggers potential process
manufacturing experience results trigger potential and control strategy
trigger next risk process and control refinement
Risk Review assessment strategy refinement
DOE = Design of Experiments

3rd Annual IVT
(C)QA = (Critical) Quality Attribute Conference
(C)PP = (Critical) Process Parameter
Risk Assessment Tool Considerations
Product Process Process Scale-up

Manufacturing
Development Development & Tech Transfer
Platform / Prior Knowledge Specific Product Knowledge
General Risks Specific Risks
Qualitative Tools Quantitative Tools
More Simple Tools More Complex Tools
• Fishbone / Ishikawa • Fault Tree Analysis (FTA) • FMEA / FMECA

• PHA • HAZOP • HACCP
• Risk Ranking & Filtering
3rd Annual IVT

Conference
Risk Assessment in Development
Adapted from “ Risk Assessment in the IR & MR examples”,Helen Teng, Ph.D.,

3rd Annual IVT
29 Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 Conference
Example-Preliminary Risk Identification:
Ishikawa or Fish bone Diagram

30 Conference
Example of Risk Identification: P-I Grid
(Probability and Impact grid)
Set Thresholds
H IG H HIGH
RISK
P Urgent attention
R MED
O MEDIUM
B RISK
Regular review
LOW
LOW
RISK
Monitor
LO W MED H IG H
IM P A C T

31 Conference
Example-Risk Identification: IPO
Diagram for Coating
Controllable Parameters
Pan Speed Rate of addition

Atomization Air Pressure
Gun To bed Disctanc
Exhaust Air temp

Rate of addition
Inlet air Volume

Spray gun type
solids content
Feeder Speed
Inlet Air Temp

Mixer Speed
Coater Type
Mixing time
Spray Rate
Dew Point
Inputs Outputs
Tablet Yield (Compression) Coating Yield
Hardness (Compression) Moisture
Appearance(Compression) 1. Material transfer Dissolution profile
Friability (Compression) 2. Color suspension Tablet Weight
Tablet Shape 3. MaterialPreparation
transfer Appearance
Tablet Embossing 4. Coating Stability
Moisture (Drying and Hold Time, 5. Discharge Degradation
Tablet size
Raw Material (coating) Characteristics -
Wettability of Tablet Surface
Hygroscopicity of tablet (formulation)
Tablet dissolution
Tablet Defects
Key
Moisture
HIGH RISK
MEDIUM RISK
Dependent & Non-Controllable Parameters LOW RISK
3rd Annual IVT

32 Conference
Example- Risk Matrix(Filter) for Process
Risk Assessment Filter for Process Evaluation

Binder Milling/ Final
DP QA's Dispensing Preblending Granulation Drying Lubrication Compression Coating
Addition Screen Blending
Safety Efficacy
Dissolution *
Content Uniformity
Assay
Degradation Products
Moisture - Tablet
Manufacturability
Granule Hardness
Granule Particle size
Disintegration
Tablet Hardness
LOD of Granule
Flowability of Pre-blend
Flowability of Final Blend
Appearance (Picking sticking)
Polynmorphs
3rd Annual IVT

Conference
Risk Assessment : Summary
n Agency is does not recommend using any specific risk assessment tool
n A risk and science-based assessment is important to identify the

Parameters / attributes that are critical.
n The justification for each identified risk is most important and a clear
strategy should be summarized in the assessment process.
n The agency plans to publish a list of potential quality attributes and

process parameters that are critical for some of the standard technology
platforms. This process will help standardize the filing process.
Exceptions do exists.
Adapted from “ Risk Assessment in the IR & MR examples”,Helen Teng, Ph.D.,


Risk Assessment Process Applied to Product
Development
Develop
Design Space Identify Quality
& Attributes
Control Strategy and How Measured
(Risk Mitigation)
Experimentation
Risk
Product Assessment
&
Quality
Process Risk Assessment
Perform
Experiments Understanding
Identify and Prioritize
Process Parameters
Experimental
Prioritization Planning
Risk Assessment ID Experiments

Prioritize
Experiments Understand
CQA =f(CPP)
DOE PAT Modelling 3rd Annual IVT

Conference
Quality by Design
Product Development Knowledge
Level of Sophistication
1st
Principles
HIGH
MECHANISTIC
MODELS
EMPIRICAL
MODELS
MEDIUM
HEURISTIC RULES
LOW (HISTORICAL) DATA DERIVED FROM

TRIAL-N-ERROR EXPERIMENTATION 3rd Annual IVT
36 Dr. Ajaz Hussein
Conference
Role of DoE in QbD
3rd Annual IVT

Conference
37
Factorial DoE: Fraction & Resolution
Use of DoE e in QbD – IR and MR Examples”, Y. Peng., CMC, Office of Generic Drugs, GPhA/FDA QbD Workshop for 3rd Annual IVT
ANDAs, May 2011 Conference
Steps Involved in DoE Study
Use of DoE e in QbD – IR and MR Examples”, Y. Peng., CMC, Office of Generic Drugs, GPhA/FDA QbD Workshop for 3rd Annual IVT
ANDAs, May 2011 Conference
39
QbD Implementation Aspects - People
Multidisciplinary and cross-functional teams are a

key to making QbD a success
Quality by Design
Formulation
Operations Development
Regulatory Analytical
Affairs Development/PAT
Technology
Chemometrics
Quality
Statistics
Operations

QbD: Process Robustness (Enhanced
process understanding)
Capable Process
USL
UCL
LCL
Stable Process
LSL
n Enhanced Process Understanding is key

n Robustness is the ability of a process to demonstrate acceptable
quality and performance while tolerating variability in inputs
n Should be demonstrated in: Formulation, Process design,
established during: development - Scale-up- commercialization.
September 15, 2011 3rd Nov/Dec

Reference: Process Robustness – A PQRI White Paper. Pharmaceutical Engineering Annual IVT
41 2006. Conference
Implementation of QbD
Integral part of control strategy development and implementation

n Control Strategy: A planned set of controls, derived from
current product and process understanding, that assures
process performance and product quality. The controls can
include parameters and attributes related to
Drug substance and drug product materials and components,
Facility and equipment operating conditions
In-process controls, finished product specifications, and
the associated methods and frequency of monitoring and control
n Ensures input quality attributes and process parameters

are maintained within the approved design space(s)---thus
product should meet predefined quality standards (TPP)

Control Strategy
Target product Profile
Drug substance properties; prior knowledge
Proposed formulation and manufacturing process

Formulation understanding
Process understanding
Determination of
Cause – Effect relationships
(Risk Identification with subsequent Risk Analysis)
Risk-based classification
(Risk Evaluation)
Parameters to investigate (e.g. by DOE)
FORMULATION CONTROL PROCESS

DESIGN SPACE DESIGN SPACE
STRATEGY
BY UNIT OPERATION
September 15, 2011 F. Erni – EFPIA Working Group 3rd Annual IVT
State of Control Strategies
Adapted from “ Control Strategy in Generci Drug Development”, Youmin Wang, Ph.D.,

Basis for Control Strategy
Control Strategy
Adapted from “ Control Strategy in Generci Drug Development”, Youmin Wang, Ph.D.,
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 3rd Annual IVT
Control Strategy
It is not just Manufacturing Controls
Balanced control of quality attributes & design space
Gauge of process understanding or knowledge

Understanding of risk (NOR vs. PAR)
- Includes design space
- Include process controls (PAT)
- Include specifications
Serve as the basis for establishing post approval change management
n Ensures how process operates within design space-

Implementation at plant level (ICH –Q10)
n Raw material characterization

Summary
n Identified the differences in the QbD approach for Generics.
n Differences in how we look at QTPP, specifically the labeling
issues.
n Clear and concise way to identify critical and non-critical
parameters and attributes – Criticality-
n Risk assessment justification is key.
n Need to build a concurrence with agency on how to better use
prior knowledge, given the number of batches manufactured for
some of the standard technology platforms.
n Product and process understanding goals is similar for all type of
products
n QbD Goal is Enhanced Process Understanding. If suitable control
strategy is enabled than leads to regulatory flexibility and
reduction in
KNOW RISK KNOW REWARD
9/6/2011
QbD APPLICATION
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
COMPLIANCE BY DESIGN (CbD)
COMPLIANCE BY DESIGN (CbD)
and
COMPLIANCE MASTER PLAN (CMP)
A LIFECYCLE Approach
Paul L. Pluta, PhD
OUTLINE / OBJECTIVES
1. Why?
2. Quality by Design (QbD)
– Compliance by Design (CbD) comparison
3. Validation Master Plan (VMP)
– Compliance Master Plan (CMP) comparison
4. Lifecycle Approach
– Process Validation Lifecycle comparison
5. Implementation
6. Benefits and Problems
7. Discussion
1
9/6/2011
WHY CbD / CMP / LIFECYCLE APPROACH?
Development has been revolutionized by QbD ‐‐ an organized
approach with defined objectives and steps. Industry and
regulatory have strongly embraced and supported QbD.
Validation Master Plans (VMP) are successful and widely
V lid i M Pl (VMP) f l d id l
accepted documents useful to industry and regulatory.
The FDA Process Validation Guidance has introduced the lifecycle
approach to process validation.
Coincident with growth and success of QbD have been serious
GMP
GMP compliance incidents (heparin, glycerin, Viracept, J&J,
li i id t (h i l i Vi t J&J
Genzyme).
Can QbD, VMP, and lifecycle approaches be applied to
improve compliance?
3
CbD / CMP / LIFECYCLE OVERVIEW
QUALITY SYSTEMS
Development of system
– Objective and attributes of quality systems
j q y y
– Parameters to achieve objectives and attributes
– Variation affecting parameters
– Control of variation
Performance of system
Maintaining system
– Maintain and monitor system
– Improvement projects
Documentation
2
9/6/2011
QUALITY BY DESIGN
• Target product profile (TPP) and critical quality
attributes (CQA)
• Drug substance and excipient properties
• Formulation design and development
• Manufacturing process design and development
• Identification of critical process parameters (CPP)
and critical material attributes (CMA)
• Risk assessment and design space
Risk assessment and design space
• Scale up, identification of variables, and control
strategy
Red = Original QbD
5
COMPLIANCE by DESIGN
CbD is an organized approach to compliance with
quality systems. CbD has a defined structure with
objectives and associated content CbD continues
objectives and associated content. CbD continues
throughout the lifecycle of the quality systems.
CbD approaches quality systems as a development
project in the manner of QbD.
Can compliance be improved by using QbD concepts?
3
9/6/2011
COMPARISON –
COMPLIANCE BY DESIGN and QUALITY BY DESIGN
Objectives and critical compliance attributes (CCA)
– What are the goals of each quality system?
– What makes a quality system successful?
Critical compliance parameters (CCP)
– What factors may significantly influence the success of the quality system?
Input variation and control
– What variation in quality system operation is expected and how is it
controlled?
Ongoing maintenance and management
– How is performance monitored and maintained?
How is performance monitored and maintained?
Continuous improvement projects
– How can the quality system be improved?
CbD approach equivalent to QbD
Ongoing maintenance and management = Stage 3 process validation
Continuous improvements expected from ongoing monitoring.
7
VALDIATION MASTER PLAN
Sections discuss site validation categories
– Validation policy
– Equipment
– Facilities (HVAC)
Facilities (HVAC)
– Utilities
– Process
– Cleaning
Tables with document references (IQ, OQ, PQ)
Validation commitments and timelines
Regular updates (quarterly?) related to needs frequency
Regular updates (quarterly?) related to needs frequency
Note “chapters” of VMP
VMP is routinely requested by regulatory auditors.
4
9/6/2011
COMPLIANCE MASTER PLAN
CMP is an organized approach to documenting the CbD
methodology. CMP has a defined approach, structure, and
content CMP is a working document that is continually
content. CMP is a working document that is continually
maintained throughout the quality systems lifecycle.
Can compliance documentation be improved by use of VMP
concepts?
• Quality System
• Facilities and Equipment System
• Materials System
• Production System
• Packaging and Labeling System
• Laboratory Control System
• Training System
• Validation System
• Product Review System
• Stability System
• Product Complaint System
• Others
Red = FDA Quality Systems
Note “chapters” of CMP
10
5
9/6/2011
SYSTEM TITLE
• System and subsystem descriptions
S t d b t d i ti
– Objective and critical attributes
– Critical parameters affecting objective
– Input variables and control strategy
– Ongoing maintenance and management
• Continuous improvement project status
• References (includes project reports)
11
LIFECYCLE APPROACH
FDA Process Validation Guidance (January 2011)
Lifecycle Approach to Process Validation
• Stage 1. Process Design
– Includes QbD, PAT, risk management
• Stage 2. Process Qualification
• Stage 3. Continued Process Verification
Process validation always ongoing
P lid ti l i
Continuous improvements expected
12
6
9/6/2011
LIFECYCLE APPROACH
1. Understanding and planning
2 Performance
2.
3. Maintenance and monitoring
• System performance
4 Continuous improvement
4. Continuous improvement
Application to equipment, computer systems, etc.
13
LIFECYCLE APPROACH
Validation Evolution
1978 ‐‐ CGMP includes Validation
1978 CGMP includes Validation
1987 ‐‐ Development ‐‐ VALIDATION ‐‐ Control
2008 Æ 2011 Lifecycle approach

Continuum of understanding – validation – maintenance
UNDERSTANDING Æ VALIDATION Æ MAINTENANCE Æ IMPROVEMENT
14
7
9/6/2011
LIFECYCLE APPROACH
Recent speakers on various aspects of validation and
qualification have adopted the lifecycle approach to their
fields.
– Equipment
– Facilities
– Utilities
– Cleaning
– Computer systems
Can compliance be improved by use of lifecycle concepts of
Can compliance be improved by use of lifecycle concepts of
process validation?
Are quality systems designed, maintained, and monitored to
yield continuous system improvements?
15
LIFECYCLE APPROACH
ICH Q10. Pharmaceutical Quality Systems
• Pharmaceutical Development
• Technology Transfer
Technology Transfer
• Manufacturing
• Product Discontinuation
ICH Q10 focus ‐‐ product performance
throughout product lifecycle.
g p y
CbD focus ‐‐ quality systems performance throughout
quality system lifecycle.
16
8
9/6/2011
IMPLEMENTATION AND EXAMPLES
Overview and approach
Material System
• Multiple subsystems
Training System
• One system serves all site areas
One system serves all site areas
17
CbD / CMP / LIFECYCLE IMPLEMENTATION
1. Identify systems in the organization
– FDA systems (6) are major systems
– Addition “subsystems” are identified in FDA Quality System
– Other systems support multiple major systems
Other systems support multiple major systems
2. For an individual system:
– Identify complete business process
– Identify subsections
– Identify objectives , CCA, CCP, variation, controls for all subsections
– Gap analysis of subsections
– Risk analysis of subsections
3. Continuous improvement projects based on gap analysis,
3 Continuous improvement projects based on gap analysis
risk analysis, and ongoing monitoring
4. Documentation in CMP
5. Repeat for all systems based on risk.
18
9
9/6/2011
CbD / CMP LIFECYCLE IMPLEMENTATION
– Identify complete business process
– Identify system subsections
– Identify objectives and CCA, CCP, variation, and controls for all
subsections
– Gap analysis of subsections
– Risk analysis of subsections
– Initiate improvement projects
– Documentation
Above analysis and evaluation conducted by management,
each section staff, and QA ‐‐ with cross functional input
– Staff participation critical
– Cross‐functional input critical
Ex: Process experience, incoming test data, vendor audits
Ex: Process experience, deviations, CAPA, training
19
EXAMPLE: MATERIAL SYSTEM BUSINESS PROCESS
1. Identify approved vendors to source incoming materials
– Vendors approved by Vendor QA
2. Receive incoming materials
3. Store incoming materials – quarantine status
4. Submit samples for testing
5. Receive and evaluate test results
6. Transfer tested materials to materials to status areas
– Approved or Rejected. Materials on test remain in quarantine
7. Dispense approved materials to manufacturing and packaging locations
8. WFI, gas, and compressed air distribution
9. Received and store manufactured / finished products – quarantine
status
t t
10. Transfer tested materials to status areas
– Approved or Rejected. Materials on test remain in quarantine
11. Transfer approved materials to distribution center
12. Ship approved materials from distribution center to customer
20
10
9/6/2011
COMPLIANCE BY DESIGN
MATERIAL SYSTEM SUBSECTIONS
Incoming Materials ‐‐ Sourcing
Incoming Materials – Storage/testing/disposition
Incoming Materials
Drug dispensing
Water/gas/air testing/distribution
Finished Products – Storage/testing/disposition
Finished Products – Distribution
Finished products – Offsite distribution
Above customized to site organization
21
COMPLIANCE BY DESIGN ‐‐ MATERIAL SYSTEM
INCOMING MATERIALS ‐‐ SOURCING
System objective and critical attributes
• Obtain high quality materials (API, excipients, commodities) from QA‐approved vendors for eventual
dispensing to product manufacturing
Critical parameters affecting objective
• QA audit, investigate, and approve material suppliers
• Vendor procedure, process, and management changes
p ,p , g g
Input variables and control strategy
• Material variation
• Vendor outsource commodity items
• Approved supplier list
• Material specifications
• Material test data monitoring
• Non‐conforming materials received
Continuous improvement project status
1. Risk analysis of incoming materials. See Appendix for project description.
2. Supplier risk evaluation. See Appendix for project description.
Reference documentation
• Risk analysis of incoming materials. J. Doe, 1‐1‐10.
• Supplier risk evaluation. J. Smith 1‐4‐10
Appendix
1. Project Description: Risk analysis of Incoming Materials.
2. Project Description: Supplier Risk Evaluation.
22
11
9/6/2011
COMPLIANCE BY DESIGN ‐‐ MATERIAL SYSTEM
INCOMING MATERIALS – STORAGE / TESTING / DISPOSITION
• Storage of high quality materials (API, excipients, commodities) prior to dispensing to
product manufacturing. Materials stored according to recommended temperature.
Materials stored according to QA disposition (Approved, Quarantine, Rejected)
p g j
• Vendor storage recommendations
• Vendor expiration date recommendations
• Power supply to storage areas
• Storage recommendations per vendor checklist.
• Expiration date recommendations per vendor checklist.
• Alarm system for temperature limits
• Material inventory list ongoing
• Facility monitoring system
• Refrigeration backup generator
• Material requirements
23
TRAINING SYSTEM BUSINESS PROCESS
Functions, work centers, procedures (training modules), and personnel
Training system uses validated tracking software
Training system defines training categories
Function defines work centers
Function assigns procedures to work centers
‐ Procedures include training category and retraining frequency (risk based)
g
‐ Training modules written
‐ Training modules approved
Function assigns personnel to work centers
Functions, work centers, procedures, and personnel entered into tracking software
QA approval
1. Personnel trained according to category and frequency
2. Personnel training completion in tracking system
3. Training status reported by software
4 T i i
4. Training modules evaluated by trainees
d l l db i
24
12
9/6/2011
TRAINING CATEGORIES
Company information (general news, holidays)
Awareness of common procedures (ethics, analytical
methods, tablet machine parameters) –
th d t bl t hi t ) read and
d d
sign
Policies and procedures – (GMP) ‐‐ classroom
Performance (OtJ) training (HPLC, tablet machine
operation) qualification
SME qualification (expert designation)
External continuing education (scientific meetings)
25
COMPLIANCE BY DESIGN – TRAINING SYSTEM
• Provide effective training to site personnel
• Development of high quality training modules
• Selection of appropriate training category and retraining frequency
Selection of appropriate training category and retraining frequency
• Competency of training instructors
• Employee experience and learning motivation
• Work center recommendations on training category and retraining frequency
• Training module completion records
• Trainee evaluations
• Correlation of training modules and exception events
C ti
i t j t t t
1. Risk analysis of site positions. See Appendix
2. Training Module X development
• Risk analysis of site positions. J. Jones, 1‐1‐10.
Appendix
Project Description: Risk Analysis of Site Positions
26
13
9/6/2011
• Introduction and policy
• Quality System
• Facilities and Equipment System
• Materials System
• Production System
Production System
• Packaging and Labeling System
• Laboratory Control System
• Training System
• Validation System
• Product Review System
• Stability System
• Product Complaint System
Product Complaint System
• Others
Each system with subsections has description, objectives, CQA, CCP, variation,
control of variation, projects completed (improvements), commitments, etc.
CMP available to auditors
27
CbD / CMP / LIFECYCLE POSITIVES
• Organized and comprehensive focus on compliance based on risk to
the patient and the organization – Based on successful concepts
• System design ‐‐ Gap analysis
• Risk analysis
• Cross‐functional systems thinking
Cross‐functional systems thinking
• Consistent prioritized mitigation activities across functions – based
on risk
• Variation identification and control strategy
• Centralized tracking of commitments
• Continuous improvements based on systems monitoring
• Standardized audit expectations and documentation
• Organization commitment, transparency, and credibility
Organization commitment transparency and credibility
• Track organization accomplishments completed
• Strong message to employees
• Strong message to auditors
• Potential “credit” in audits for projects completed and new
commitments identified
28
14
9/6/2011
CPD / CMP / LIFECYCLE NEGATIVES
Difficult
• Getting organized is extremely difficult!
• Risk analysis is difficult
• Gap analysis is difficult
• Changes are difficult
Transparency
• Being open about gaps and deficiencies may have
regulatory and political risks
O ga at o a co
Organizational commitments
t e ts
• Headcount needed to correct deficiencies
Do the benefits outweigh the negatives?
29
OTHER THOUGHTS
ASTM E2500
• Addresses validation criticism by risk prioritization
• Pfizer using
FDA Comments
• Prosecution of responsible executives / management
• Transparency
p y
• Generally positive comments on QbD ‐‐ Concerns about implementation
• Site organization according to systems
ICH Q10 Pharmaceutical Quality System Elements
• Process performance and product quality monitoring system
• CAPA system
• Change management system
• Management review of process performance and product quality
Medical Devices
• Management controls
• Design controls
• CAPA
• Production and process controls
• Sterilization process controls
• Sampling plans instructions
30
15
9/6/2011
GETTING STARTED
1. Identify high risk areas
– Example: Sourcing of incoming materials
– Example: Aseptic core area training
2. Senior management discussion –
d risks to operation
k
3. Function management discussion – risks to operation
4. Identify receptive individuals in high risk area
5. Training of appropriate individuals
6. Start slowly
7
7. Communication Modify strategy as needed to insure
Communication. Modify strategy as needed to insure
success
8. Expand effort based on success
31
COMPLIANCE BY DESIGN AND COMPLIANCE MASTER PLAN
LIFECYCLE APPROACH ‐‐ SUMMARY
• CbD based on QbD, CMP based on VMP
• Lifecycle approach based on lifecycle approach to process validation
– Design, Perform, Monitor
• Identify quality systems: FDA, Quality Systems, support systems
• Identify business process of systems Æ system subsections
• Identify objectives and CCA, CCP, variation, controls, gaps, and risks
• Continuous improvement projects based on gap, risks, monitoring
• Documentation in CMP
• Positives: Organized and comprehensive focus based on risk to the patient and the
organization, strong message to employees and to auditors, “credit” in audits
• Negatives: Difficult, transparent, deficiencies identified
• Consistent with FDA direction (Process Validation, risk), ASTM E2500, and ICH Q8,
Q9, Q10
• Cost effective ‐‐ High risk activities emphasized and prioritized
• Implementation approach
32
16
9/6/2011
INTERACTIVE DISCUSSION
Comments on CbD
Comments on CMP
Comments on Lifecycle
33
REFERENCES
Pluta, Paul L. and Richard Poska. “Compliance by Deisgn (CbD)
and Compliance Master Plan (CMP). An Organized Approach
to Compliance.” J. GXP Compliance, V 14, #2, Spring 2010.
Pluta, Paul L., Richard Poska, and Timothy J. Fields. “Compliance
Pluta, Paul L., Richard Poska, and Timothy J. Fields. Compliance
by Design and Compliance Master Plan” Pharmaceutical
Technology, V35, #3, March 2011.
Nash, Robert A. “The Concept of Establishing a Compliance
Master Plan (CMP).” J. Validation Technology, V 12, #2,
February 2006.
Borkar M M A A Shirwaikar and P G Shilotri “Step
Borkar, M.M., A.A. Shirwaikar, and P.G. Shilotri. Step by Step
by Step
Approach to Quality System Implementation and Regulatory
Compliance.” J. GXP Compliance, V 9, #2, January 2005.
Yu, Lawrence X., et. al., “Quality by Design for Generic Drugs.”
PharmTech.com, October 2, 2009.
34
17
9/6/2011
COMMERCIAL
Book chapter authors
Pilot program
Pilot program
• System or subsection using CbD approach
Writers for JVT and JGXP
• Sample journals
• Brochure with example papers
• New features and ongoing features
35
PAUL L. PLUTA, PhD
Editor‐in‐Chief
• Journal of Validation Technology
• Journal of GXP Compliance
Adj
Adjunct Associate Professor
A i P f
• University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA
Editor and Chapter Author
• Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles. PDA and Davis Healthcare International (DHI) Publishing, 2009
• Cleaning and Cleaning Validation, Volume 2 . Applications of Basics and
Principles PDA and Davis Healthcare International (DHI) Publishing 2011
Principles. PDA and Davis Healthcare International (DHI) Publishing, 2011
(expected)
Contact: paul.pluta@comcast.net
36
18
9/23/2011

a QbD Approach
Daniel Song
Pfizer Inc
Sept. 15, 2011
Outline

expectation
t ti
Case study
1
9/23/2011

lifecycle.
significant waste

Integrate
g into p
lifecycle
2
9/23/2011
Right technique for


interactions

suitability

3
9/23/2011

y
product

Examples:
ssay The
Assay: epprocedure
ocedu e must
ust be ab
able
e to accu
accurately
ate y qua
quantify
t yad drug
ug

4
9/23/2011

(MODR)
Unexplored Space
Knowledge Space
Method Operable
Design Region
Target
Method
Conditions
O ti off the
Operation th method
th d within
ithi the
th MODR
5
9/23/2011
Technique Selection

Different
Diff t analytical
l ti l ttechniques
h i capable
bl off
ATP.
cost
Quality
Q lit Att
Attribute*
ib t * to
t be
b

accuracy required:
±1.5% N/A N/A ±1.5% ±10% ±10% ±10% ±2% N/A
Range required:
Testing environment
labs, etc.):

Resolution of PRI,
degradants,
No signal (i.e.
expcipients and
separation of
specified
dissolution media.
impurities from
each other.
6
9/23/2011

measurement.
software.
M
i

Sample Set
Yes No
ID. Known?
Color Key
RP
screening studies
Green:in silico
versus pH
points

Screening

Optimization
No
Meet Criteria? Yes

(Rs, TF, time)
7
9/23/2011

3
0
0 2 4 6 8 10 12 14
Log D
-1
-2
-3
-4 pH=2.7
pH

Sample Set
Yes No
ID. Known?
Color Key
Red: experimental
RP studies
screening modeling
Black: Decision
Column & pH
selection

Screening

Optimization
No
Meet Criteria? Yes

(Rs, TF, time)
8
9/23/2011

Identifyy method p
requirements.
9
9/23/2011

Full Process Map
Sub Process Map
(HPLC Analysis)
Sub Process Map

(Sample Prep)

Sample preparation
Chromatography

(OFAT) study
10
9/23/2011


risk assessment
assessment.
Sensitivity (LOQ)
Accuracy


MODR
Set TMC within MODR


the ATP criteria
11
9/23/2011

MODR .
Case Study
12
9/23/2011

impurities.
15%
Resolution:
Resolution
R l ti off critical
iti l pairs
i off d
degradants
d t ≥ 1.2
12
Accuracy:
Sensitivity (LOQ):
13
9/23/2011


(MP).
Comet program
8 HPLC columns
l


Flow Rate: 1 mL/min
Detection: 270 nm
0 90 10
2 90 10
20 82 18
30 45 55
30.1 90 10
35 90 10
14
9/23/2011

Development labs
QC labs
Stability labs
Chromatography
Sample preparations
noise parameters
Noise (column age)


St ti
Stationary Phase
Ph Type
T & Particle
P ti l Size

Gradient Profile
•% Organic Ramp 2
Detector Wavelength
Wavelength)
15
9/23/2011

1 Resolution (≥1
0.15 % level)
An LOQ standard
Column temperature
Column
C l b
batch
t h number
b
Injection volume
Detector wavelength
Detector type
reduced.
16
9/23/2011

3 10
7 Ramp 1
13 7 Ramp 1 13
Beginning Beginning
Organic (%) O
Organic
i (%)
0.1
TFA Conc in
MP (%)
22
at o 2
0.05
R Fl 1.
Graphical
e w
/
in L
m (m
Organic (%)
8
Beginning
0.
27 33 27 33 27 33 27 33
)
Ramp 2
View of the
278
TFA Conc in
0.1
Design of
MP (%)
Wave Length (nm)
DOE
e w2
0.05
at o 1.
/
in L
14
m (m
R Fl8
0.
27 33 27 33 27 33 27 33
)
onc in
MP (%)
0.1
TFA Co
22
at o 2
0.05
R Fl 1.
e w
/
in L
m (m
8
Organic (%)
0.
27 33 27 33 27 33 27 33
Beginning
)
Ramp 2
262
TFA Conc in
0.1
MP (%)
at o 2
14
e w
/
R Fl 1.
in L
0.05
m (m
8
27
0.
27 33 27 33 33 27 33

17
9/23/2011
TFA Ramp
Run Block ((°C)
C) min) (%) (%) Org. (%)
Org Vol. (µL)
Res. % RT (min)
1 L01 30 1.0 0.075 10 18 7 270 PDA 1 22.0 2.01 0.15 17.266
2 L1 27 1.2 0.100 7 14 3 278 PDA 2 12.3 2.59 0.15 24.439
3 L1 27 0.8 0.050 7 14 3 262 PDA 1 24.4 2.71 0.26 25.096
4 L1 27 1.2 0.050 7 22 10 262 PDA 1 32.6 1.82 0.26 15.051
5 L1 27 0.8 0.100 7 22 10 278 PDA 2 32.5 0.06 0.14 20.67
6 L02 30 1.0 0.075 10 18 7 270 UV 1 49.5 1.99 0.15 17.516
7 L2 33 0.8 0.050 7 22 3 278 UV 1 20.7 1.27 0.14 17.473
8 L2 33 1.2 0.050 7 14 10 278 UV 2 35.5 3.17 0.14 20.593
9 L2 33 0.8 0.100 7 14 10 262 UV 1 22.9 1.43 0.24 26.268
10 L2 33 1.2 0.100 7 22 3 262 UV 2 24.2 1.31 0.26 17.465
11 L3 27 0.8 0.050 13 14 3 278 UV 1 10.2 1.28 0.15 14.578
12 L3 27 1.2 0.050 13 22 3 278 UV 2 13.0 0.95 0.17 9.039
13 L3 27 1.2 0.100 13 14 10 262 UV 2 17.2 1.51 0.31 17.184
14 L3 27 0.8 0.100 13 22 3 262 UV 1 28.1 0.56 0.32 15.759
15 L03 30 1.0 0.075 10 18 7 270 UV 2 25.2 1.97 0.14 17.975
16 L4 33 0.8 0.100 13 14 3 278 PDA 1 3.6 1.42 0.13 20.604
17 L4 33 0.8 0.050 13 22 10 262 PDA 2 33.5 0.32 0.26 10.761
18 L4 33 1.2 0.100 13 22 10 278 PDA 1 17.0 1.03 0.14 10.918
19 L4 33 1.2 0.050 13 14 3 262 PDA 2 3.3 0.85 0.26 8.999
20 L04 30 1.0 0.075 10 18 7 270 PDA 2 16.5 2.04 0.14 17.724

d
degradant
b too
t far
f from
f 0.15%.
0 15%
ramp 1.
18
9/23/2011

Region (MODR)
Region of
resolution
95%
confidence
limit
Method operable
99%
limit
(MODR)

Region (MODR)
19
9/23/2011

Region (MODR)

within MODR
Range Studied
Target Acceptable
Parameter
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1 ~1.2
0.05 0.075 0.1 0.05 0.05 ~ 0.075

Wave Length (nm) 262 270 278 270 270 ~ 278
20
9/23/2011

Similar Column

were performed

Similar Column
Similar column:
Range Studied

Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 - 1.2
0.07
5
Wave Length (nm) 262 270 278 270 270 - 278
Original column:
Range St
Studied
died
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 ~1.2
0.07
0.05 0.1 0.05 0.05 ~ 0.075
Wave Length (nm) 262 270 278 270 270 ~ 278
21
9/23/2011

for Both Columns

g during
g the

for Both Columns
22
9/23/2011

for Both Columns
both columns.
Range Studied
Target Acceptable
Parameter
Setting Ranges
Low Mid High
27 30 33 30 27 - 33
0.8 1.0 1.2 1.0 1.0 - 1.2
Flow Rate (mL/min)
0.05 0.075 0.1 0.05 0.05 - 0.075
7 10 13 10 7 - 11
14 18 22 18 14 - 18
Detector Type
3 6.5 10 6.5 6.5 - 10
262 270 278 270 270 - 278
Wave Length (nm)

S
Same criteria
it i off the
th critical
iti l method
th d attributes
tt ib t
23
9/23/2011
Wave
Iminium Band
Run (mL/min) (%) (%) (%) DAD ((°C)
01 1.0 0.05 10 18 270 30 5 2.1 24 0.11 15.4
1 1.2 0.05 11 14 278 30 5 2.1 17 0.11 14.2
2 1 0.075 11 14 270 30 5 2.2 10 0.11 20.3
3 1 0.05 11 18 270 30 5 1.9 18 0.11 13.8
4 1 0.075 7 14 278 30 5 2.9 33 0.10 24.6
5 1 0.05 7 18 278 30 5 2.3 17 0.10 18.6
6 1.2 0.075 7 18 270 30 5 2.2 22 0.11 19.3
7 1.2 0.05 7 14 270 30 5 3.1 10 0.12 21.2
8 1.2 0.075 11 18 278 30 5 1.9 10 0.11 14.8
1
Q lit attributes
d ffor th
the assessment:
t
Accuracy:

24
9/23/2011

0 6 Hours
50/50% ACN/Water
0 ~ 12
nominal

Numbers of
Injection of
Preconditioning
(hours)
Sample
1 50/50 ACN/Water 6 3
3 50/50 ACN/Water 9 6
4 50/50 ACN/Water 0 3
5 50/50 ACN/Water 6 0
7 50/50 ACN/Water 3 6
8 50/50 ACN/Water 12 3
14 50/50 ACN/Water 6 3
25
9/23/2011


Number of
Pre-
Before Time S/N
Hours
Preconditioning
1 50/50 ACN/Water 6 3 16.5 1.89 18
2 Initial Phase 9 6 16.3 1.94 17
3 50/50 ACN/Water 9 6 16.2 1.96 17
4 50/50 ACN/Water 0 3 16.3 1.98 16
5 50/50 ACN/Water 6 0 16.4 1.99 19
6 Initial Phase 3 6 16.2 2.05 23
7 50/50 ACN/Water 3 6 16.2 2.07 24
8 50/50 ACN/Water 12 3 16.2 2.06 21
9 I iti l Ph
2.05 18
10 Initial Phase 0 3 15.9 2.06 21
11 Initial Phase 6 0 15.9 2.04 21
12 Initial Phase 6 3 15.9 2.04 24
13 Initial Phase 6 3 15.8 2.04 21
14 50/50 ACN/Water 6 3 16 2.06 20

TWG6
DOE Results:
time.
time
ACN/Water.
26
Slide 52
skipping
9/23/2011

DOE Conclusions:
For
F a column
l stored
t d iin iinitial
iti l mobile
bil phase,
h it


E
Experiment
i t - one factor
f t att a time
i t

27
9/23/2011

Column
initial #1 #2 #3 #4 #5 #6
1 x x x x x x x
1200 injections
1800 injections
3000 injections
120 injections
360 injections
600 Injections
2 x x x x x x x
3 x x x x x x x

1 0 127 1.74 15.4
1 120 99 1.75 15.4
1 360 89 1.75 15.4
1 600 42 1.74 15.2
1 1200 137 1.76 15.1
1 1800 72 1.79 15.1
1 3000 99 1.79 15
2 0 35 2.01 18
2 120 56 2.02 18
2 360 32 2 17.7
2 600 34 2.05 17.9
2 1200 46 2.05 17.6
2 1800 32 2.05 17.3
2 3000 42 2.14 17.2
3 0 30 1.76 17.5
3 120 38 1.82 17.7
3 360 49 1.95 17.9
3 600 49 1.87 17.7
3 1200 43 1.83 17.3
3 1800 68 1.96 17.1
3 3000 28 2.06 17.1
28
9/23/2011

j )

Conclusions

29
9/23/2011
interchangeably.
suitability check.
Acknowledgement

Kimber Barnett
30
9/23/2011
Backup slides
p range
31
9/23/2011

a QbD Approach
Daniel Song
Pfizer Inc
Sept. 15, 2011
Outline

expectation
t ti
Case study
1
9/23/2011

lifecycle.
significant waste

Integrate
g into p
lifecycle
2
9/23/2011
Right technique for


interactions

suitability

3
9/23/2011

y
product

Examples:
ssay The
Assay: epprocedure
ocedu e must
ust be ab
able
e to accu
accurately
ate y qua
quantify
t yad drug
ug

4
9/23/2011

(MODR)
Unexplored Space
Knowledge Space
Method Operable
Design Region
Target
Method
Conditions
O ti off the
Operation th method
th d within
ithi the
th MODR
5
9/23/2011
Technique Selection

Different
Diff t analytical
l ti l ttechniques
h i capable
bl off
ATP.
cost
Quality
Q lit Att
Attribute*
ib t * to
t be
b

accuracy required:
±1.5% N/A N/A ±1.5% ±10% ±10% ±10% ±2% N/A
Range required:
Testing environment
labs, etc.):

Resolution of PRI,
degradants,
No signal (i.e.
expcipients and
separation of
specified
dissolution media.
impurities from
each other.
6
9/23/2011

measurement.
software.
M
i

Sample Set
Yes No
ID. Known?
Color Key
RP
screening studies
Green:in silico
versus pH
points

Screening

Optimization
No
Meet Criteria? Yes

(Rs, TF, time)
7
9/23/2011

3
0
0 2 4 6 8 10 12 14
Log D
-1
-2
-3
-4 pH=2.7
pH

Sample Set
Yes No
ID. Known?
Color Key
Red: experimental
RP studies
screening modeling
Black: Decision
Column & pH
selection

Screening

Optimization
No
Meet Criteria? Yes

(Rs, TF, time)
8
9/23/2011

Identifyy method p
requirements.
9
9/23/2011

Full Process Map
Sub Process Map
(HPLC Analysis)
Sub Process Map

(Sample Prep)

Sample preparation
Chromatography

(OFAT) study
10
9/23/2011


risk assessment
assessment.
Sensitivity (LOQ)
Accuracy


MODR
Set TMC within MODR


the ATP criteria
11
9/23/2011

MODR .
Case Study
12
9/23/2011

impurities.
15%
Resolution:
Resolution
R l ti off critical
iti l pairs
i off d
degradants
d t ≥ 1.2
12
Accuracy:
Sensitivity (LOQ):
13
9/23/2011


(MP).
Comet program
8 HPLC columns
l


Flow Rate: 1 mL/min
Detection: 270 nm
0 90 10
2 90 10
20 82 18
30 45 55
30.1 90 10
35 90 10
14
9/23/2011

Development labs
QC labs
Stability labs
Chromatography
Sample preparations
noise parameters
Noise (column age)


St ti
Stationary Phase
Ph Type
T & Particle
P ti l Size

Gradient Profile
•% Organic Ramp 2
Detector Wavelength
Wavelength)
15
9/23/2011

1 Resolution (≥1
0.15 % level)
An LOQ standard
Column temperature
Column
C l b
batch
t h number
b
Injection volume
Detector wavelength
Detector type
reduced.
16
9/23/2011

3 10
7 Ramp 1
13 7 Ramp 1 13
Beginning Beginning
Organic (%) O
Organic
i (%)
0.1
TFA Conc in
MP (%)
22
at o 2
0.05
R Fl 1.
Graphical
e w
/
in L
m (m
Organic (%)
8
Beginning
0.
27 33 27 33 27 33 27 33
)
Ramp 2
View of the
278
TFA Conc in
0.1
Design of
MP (%)
Wave Length (nm)
DOE
e w2
0.05
at o 1.
/
in L
14
m (m
R Fl8
0.
27 33 27 33 27 33 27 33
)
onc in
MP (%)
0.1
TFA Co
22
at o 2
0.05
R Fl 1.
e w
/
in L
m (m
8
Organic (%)
0.
27 33 27 33 27 33 27 33
Beginning
)
Ramp 2
262
TFA Conc in
0.1
MP (%)
at o 2
14
e w
/
R Fl 1.
in L
0.05
m (m
8
27
0.
27 33 27 33 33 27 33

17
9/23/2011
TFA Ramp
Run Block ((°C)
C) min) (%) (%) Org. (%)
Org Vol. (µL)
Res. % RT (min)
1 L01 30 1.0 0.075 10 18 7 270 PDA 1 22.0 2.01 0.15 17.266
2 L1 27 1.2 0.100 7 14 3 278 PDA 2 12.3 2.59 0.15 24.439
3 L1 27 0.8 0.050 7 14 3 262 PDA 1 24.4 2.71 0.26 25.096
4 L1 27 1.2 0.050 7 22 10 262 PDA 1 32.6 1.82 0.26 15.051
5 L1 27 0.8 0.100 7 22 10 278 PDA 2 32.5 0.06 0.14 20.67
6 L02 30 1.0 0.075 10 18 7 270 UV 1 49.5 1.99 0.15 17.516
7 L2 33 0.8 0.050 7 22 3 278 UV 1 20.7 1.27 0.14 17.473
8 L2 33 1.2 0.050 7 14 10 278 UV 2 35.5 3.17 0.14 20.593
9 L2 33 0.8 0.100 7 14 10 262 UV 1 22.9 1.43 0.24 26.268
10 L2 33 1.2 0.100 7 22 3 262 UV 2 24.2 1.31 0.26 17.465
11 L3 27 0.8 0.050 13 14 3 278 UV 1 10.2 1.28 0.15 14.578
12 L3 27 1.2 0.050 13 22 3 278 UV 2 13.0 0.95 0.17 9.039
13 L3 27 1.2 0.100 13 14 10 262 UV 2 17.2 1.51 0.31 17.184
14 L3 27 0.8 0.100 13 22 3 262 UV 1 28.1 0.56 0.32 15.759
15 L03 30 1.0 0.075 10 18 7 270 UV 2 25.2 1.97 0.14 17.975
16 L4 33 0.8 0.100 13 14 3 278 PDA 1 3.6 1.42 0.13 20.604
17 L4 33 0.8 0.050 13 22 10 262 PDA 2 33.5 0.32 0.26 10.761
18 L4 33 1.2 0.100 13 22 10 278 PDA 1 17.0 1.03 0.14 10.918
19 L4 33 1.2 0.050 13 14 3 262 PDA 2 3.3 0.85 0.26 8.999
20 L04 30 1.0 0.075 10 18 7 270 PDA 2 16.5 2.04 0.14 17.724

d
degradant
b too
t far
f from
f 0.15%.
0 15%
ramp 1.
18
9/23/2011

Region (MODR)
Region of
resolution
95%
confidence
limit
Method operable
99%
limit
(MODR)

Region (MODR)
19
9/23/2011

Region (MODR)

within MODR
Range Studied
Target Acceptable
Parameter
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1 ~1.2
0.05 0.075 0.1 0.05 0.05 ~ 0.075

Wave Length (nm) 262 270 278 270 270 ~ 278
20
9/23/2011

Similar Column

were performed

Similar Column
Similar column:
Range Studied

Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 - 1.2
0.07
5
Wave Length (nm) 262 270 278 270 270 - 278
Original column:
Range St
Studied
died
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 ~1.2
0.07
0.05 0.1 0.05 0.05 ~ 0.075
Wave Length (nm) 262 270 278 270 270 ~ 278
21
9/23/2011

for Both Columns

g during
g the

for Both Columns
22
9/23/2011

for Both Columns
both columns.
Range Studied
Target Acceptable
Parameter
Setting Ranges
Low Mid High
27 30 33 30 27 - 33
0.8 1.0 1.2 1.0 1.0 - 1.2
Flow Rate (mL/min)
0.05 0.075 0.1 0.05 0.05 - 0.075
7 10 13 10 7 - 11
14 18 22 18 14 - 18
Detector Type
3 6.5 10 6.5 6.5 - 10
262 270 278 270 270 - 278
Wave Length (nm)

S
Same criteria
it i off the
th critical
iti l method
th d attributes
tt ib t
23
9/23/2011
Wave
Iminium Band
Run (mL/min) (%) (%) (%) DAD ((°C)
01 1.0 0.05 10 18 270 30 5 2.1 24 0.11 15.4
1 1.2 0.05 11 14 278 30 5 2.1 17 0.11 14.2
2 1 0.075 11 14 270 30 5 2.2 10 0.11 20.3
3 1 0.05 11 18 270 30 5 1.9 18 0.11 13.8
4 1 0.075 7 14 278 30 5 2.9 33 0.10 24.6
5 1 0.05 7 18 278 30 5 2.3 17 0.10 18.6
6 1.2 0.075 7 18 270 30 5 2.2 22 0.11 19.3
7 1.2 0.05 7 14 270 30 5 3.1 10 0.12 21.2
8 1.2 0.075 11 18 278 30 5 1.9 10 0.11 14.8
1
Q lit attributes
d ffor th
the assessment:
t
Accuracy:

24
9/23/2011

0 6 Hours
50/50% ACN/Water
0 ~ 12
nominal

Numbers of
Injection of
Preconditioning
(hours)
Sample
1 50/50 ACN/Water 6 3
3 50/50 ACN/Water 9 6
4 50/50 ACN/Water 0 3
5 50/50 ACN/Water 6 0
7 50/50 ACN/Water 3 6
8 50/50 ACN/Water 12 3
14 50/50 ACN/Water 6 3
25
9/23/2011


Number of
Pre-
Before Time S/N
Hours
Preconditioning
1 50/50 ACN/Water 6 3 16.5 1.89 18
2 Initial Phase 9 6 16.3 1.94 17
3 50/50 ACN/Water 9 6 16.2 1.96 17
4 50/50 ACN/Water 0 3 16.3 1.98 16
5 50/50 ACN/Water 6 0 16.4 1.99 19
6 Initial Phase 3 6 16.2 2.05 23
7 50/50 ACN/Water 3 6 16.2 2.07 24
8 50/50 ACN/Water 12 3 16.2 2.06 21
9 I iti l Ph
2.05 18
10 Initial Phase 0 3 15.9 2.06 21
11 Initial Phase 6 0 15.9 2.04 21
12 Initial Phase 6 3 15.9 2.04 24
13 Initial Phase 6 3 15.8 2.04 21
14 50/50 ACN/Water 6 3 16 2.06 20

TWG6
DOE Results:
time.
time
ACN/Water.
26
Slide 52
skipping
9/23/2011

DOE Conclusions:
For
F a column
l stored
t d iin iinitial
iti l mobile
bil phase,
h it


E
Experiment
i t - one factor
f t att a time
i t

27
9/23/2011

Column
initial #1 #2 #3 #4 #5 #6
1 x x x x x x x
1200 injections
1800 injections
3000 injections
120 injections
360 injections
600 Injections
2 x x x x x x x
3 x x x x x x x

1 0 127 1.74 15.4
1 120 99 1.75 15.4
1 360 89 1.75 15.4
1 600 42 1.74 15.2
1 1200 137 1.76 15.1
1 1800 72 1.79 15.1
1 3000 99 1.79 15
2 0 35 2.01 18
2 120 56 2.02 18
2 360 32 2 17.7
2 600 34 2.05 17.9
2 1200 46 2.05 17.6
2 1800 32 2.05 17.3
2 3000 42 2.14 17.2
3 0 30 1.76 17.5
3 120 38 1.82 17.7
3 360 49 1.95 17.9
3 600 49 1.87 17.7
3 1200 43 1.83 17.3
3 1800 68 1.96 17.1
3 3000 28 2.06 17.1
28
9/23/2011

j )

Conclusions

29
9/23/2011
interchangeably.
suitability check.
Acknowledgement

Kimber Barnett
30
9/23/2011
Backup slides
p range
31
Profiting From Quality by Design
Analyzing QbD Impact on Product Lifecycle Costs
Stephen M. Tyler
Director, Global Quality Systems
Global Pharmaceutical Operations
Overview
• Why is it important to invest in QbD?

• What are the financial benefits of QbD?
• One model for establishing QbD Profitability
•Q&A
Profiting From Quality by Design.pptx Company Confidential 2

© 2011 Abbott
Investing in Quality by Design
Overview
QbD is a systematic approach to development that begins with

predefined objectives and emphasizes product and process
understanding and control based on sound science and quality
risk management (ICH Q8(R2)).

© 2011 Abbott
Business Case for Pharma Industry
$ Billions

© 2011 Abbott
#
* Source: http://www.in-pharmatechnologist.com/Processing-QC/Pfizer-aggressively-pursuing-cost-saving-real-time-release
# Source: http://www.firstwordpharma.com/forward/emailref?path=node/830916

© 2011 Abbott
This is not a discussion of

financial calculations.
This is a holistic product
lifecycle approach to
understanding the role of
QbD in improving and
sustaining pharmaceutical
product profitability.

© 2011 Abbott
Financial Benefits of QbD
Hard and Soft Savings Potential

© 2011 Abbott
QbD Profitability
Cost of Poor Quality

© 2011 Abbott
QbD Profitability
90
80
Total Quality
Related Costs
70
Failure
60
Quality Related Costs

50
40
30 Appraisal
20
10 Prevention
Quality Awareness and Improvement

© 2011 Abbott
QbD Profitability
Iceberg source: http://www.qimpro.com/Cost_of_Poor_Quality.php

© 2011 Abbott
QbD Profitability
Cost of Poor Quality – Product X
Implementation of PRODUCT X COPQ ‐ Rate of Diverted Resources

Labor Hours per Day (HPD) ‐ Nonconformance
process 45
improvements using 40 Legacy Processes

Average HPD spent on NCRs = 9.54
QbD principles
resulted in a 74% 35
decrease in labor 30
hours spent on QbD Improvements

25
nonconformances. Implemented
Average HPD spent on NCRs
20 2010 AVG HPD = 4.5
Assuming 2011 AVG HPD = 2.5 YTD
$100/hour and 240 15
work days/year 10
equates to annual
5
hidden cost
savings of 0
01/02/07
03/02/07
05/02/07
07/02/07
09/02/07
11/02/07
01/02/08
03/02/08
05/02/08
07/02/08
09/02/08
11/02/08
01/02/09
03/02/09
05/02/09
07/02/09
09/02/09
11/02/09
01/02/10
03/02/10
05/02/10
07/02/10
09/02/10
11/02/10
01/02/11
03/02/11
05/02/11
~$170,000

© 2011 Abbott
QbD Profitability
Robust Manufacturability

© 2011 Abbott
QbD Profitability
Robust Manufacturability

© 2011 Abbott
QbD Profitability
QbD & New Product Development

© 2011 Abbott
QbD Profitability
QbD & New Product Development
Total
Savings
$1.09MM

© 2011 Abbott
QbD Profitability
Effective Risk Management

© 2011 Abbott
QbD Profitability
Effective Risk Management – Risk Analysis

© 2011 Abbott
QbD Profitability
Effective Risk Management – Risk Analysis
High Medium Low

© 2011 Abbott
QbD Profitability
Effective Risk Management – Coating Risk Assessment
KEY
A Already studied
B Planned pre-RSL
C Planned post-RSL
D  Studies not planned
X  identified after risk assessment
19
Profiting From Quality by Design.pptx Company Confidential
© 2011 Abbott
QbD Profitability
Regulatory Flexibility

© 2011 Abbott
QbD Profitability
Regulatory Flexibility : CASE STUDY
This project was conducted before ICH Q8 was finalized

• Design space aspects are not necessarily new
• Approaches are evolving
Process Product
Focuses on the extrusion part of the BCS Class IV Drug - tablet dosage
process form required
This is the most critical process for Poorly soluble pharmacokinetic
this product enhancer in formulation
Provides a molecular dispersion of Degradation products form with heat
poorly soluble API
• Drug and enhancer dispersed in a
hydrophilic polymer via extrusion
• Milled extrudate compressed into
tablets

© 2011 Abbott
QbD Profitability
Regulatory Flexibility: CASE STUDY
Powder Schematic of Extrusion Process

feed
Twin Screws
Heated Barrel
Die
Drive
Extrudate
Assembly
Conveying

© 2011 Abbott
QbD Profitability
Critical to Quality Attributes (CQA) for this Product:
Process
Controlled
GMP
Controlled

© 2011 Abbott
QbD Profitability
Process Parameters & Ranges for Extrusion at Pilot Scale
Critical

© 2011 Abbott
QbD Profitability
Experimental Approach to Identify Ranges for CPPs

© 2011 Abbott
QbD Profitability
Critical Process Parameter Ranges for Extrusion

(Set Points are Approximately mid-point of the range)
Non-Critical Process Parameter Target Process Conditions for Extrusion

© 2011 Abbott
QbD Profitability
Presenting Information in the CTD Dossier

© 2011 Abbott
QbD Profitability
Regulatory Flexibility: QbD Key Scientific Elements and ‘Flow’…
…for this Case Study:
Product /
Target Product /
Prior Process Control Regulatory
Product Process
Knowledge Design Strategy Flexibility
Profile Dev.
Space
• Bioavailable Conducted Screening Identified • CPP ranges Use of

Tablet (i.e., preliminary risk studies followed CPPs, their • In-process protocols
molecular assessment to by DOE studies acceptable controls for describing
dispersion of help focus ranges and a clarity and experiments
API in experimental mathematical moisture and acceptance
polymer) studies model criteria for
• Safe (i.e., describing the future changes
major relationship
degradation
product below
specified limit)
* Adapted from EFPIA Flow

© 2011 Abbott
QbD Profitability
Summary
A holistic equation for determining QbD profitability:
Manufacturability QRM Regulatory R/D QbD

Savings Enablers Savings Costs Profitability

© 2011 Abbott
Contributors
Janet Andre
Nancy Christensen
Liam Feely, PhD.
Steven Laurenz
Yanhui Hu

© 2011 Abbott
Contact Information
Stephen M. Tyler
Director, Global Quality Systems
Global Pharmaceutical Operations
Stephen.Tyler@abbott.com

© 2011 Abbott
QbD in Small Molecule Drug Substance
Process Design – Reduce Redundant Analytical
Testing by Design Space Mapping
Robert A. Forbes, Ph.D., Sr. Research Scientist, Analytical Sciences Research and Development
Bryan C Castle,
Castle Ph
Ph.D.,
D Director
Director, Analytical Sciences Research and Development
Arzoxifene Hydrochloride--decision not to
submit for marketing authorization
Indications: Osteoporosis & Breast Cancer Risk Reduction
Route of Administration: Oral 20 mg Tablet HCl
O
N
O
OCH3
HO S
Arzoxifene HCl
Project Terminated end of Phase III: August 18, 2009*

• Arzoxifene met its primary endpoint--significant reduction of the risk of vertebral fracture
and invasive breast cancer in postmenopausal women
• But no statistically significant difference from placebo in key secondary endpoints (non-
vertebral fractures, clinical vertebral fractures, cardiovascular events and cognitive
function)
• Ad
Adverse events
t included
i l d d venous thromboembolic
th b b li events,
t hot
h t flushes,
fl h and
d
gyenecological events, more frequent than placebo
*Lilly Press Release, August 18, 2009
15-Sep-2011 IVT’s 3rd annual Bio/Pharmaceutical Conference on 2
B. Castle & R. Forbes Quality by Design (QbD)
Arzoxifene Commercial Synthetic Route
Step 1 O
1)
Et2 N Cl 1) Br
O
O S OMe O
O S OMe THF, Et3N, Et2 N S
2) aq. NaS2O3, Na2CO3 O OMe
2) aq. washes Et2 N
379361 2491419
starting material 2491420
Step 2 1) H2O2 Br
H2SO4 , sulfolane O
2491420
2) aq. NaHSO3, AcOH
Et2 N
O S
O
OMe Manufacturing Site 1
3) EtOAc ReX
2492986
O N
Step 3 O O N
N
O
1) 315699starting material O O
1) H2
2492986 O Pd/C, O
DMF, KOt-Bu O S OMe H3PO4 O S OMe
Et2 N O 2) aq. KOH Et2 N
2) 1-butanol
3) aq. NaCl / NaOH washes 2492987
2492988
O N
1)KOH
Step 4
2) con HCl O
O N 3) iPrOH washes
O O S OMe
HCl *HCl
353381 Arzoxifene Free base
water, MeOH S
HO OMe 353381
Arzoxifene HCl
Manufacturing Site 2
Guides for QbD of the Drug Substance Process and Controls
ICH Q111 on Approaches to Development
Traditional approach
•ID potential CQAs associated with drug substance so that those characteristics having
p
and impact on p
product q
quality
y can be studied and controlled
•Defining an appropriate manufacturing process
•Defining a control strategy to ensure process performance and drug substance quality
E h
Enhanced
d approach,
h also
l iincludes
l d
•A systematic evaluation, understanding and refining of the manufacturing process,
including:
• Identifying
y g through
g e.g.,
g p prior knowledge,
g experimentation
p and risk assessment, the material
attributes and process parameters that can have an effect on drug substance CQAs
• Determining the functional relationships that link material attributes and process parameters to
drug substance CQAs
•Using the enhanced approach in combination with quality risk management to establish
an appropriate
i t control
t l strategy
t t which
hi h can, for
f example,
l include
i l d a proposall ffor a d
design
i
space and/or real-time release testing
1 ICH Q11, Development and Manufacture of Drug Substances, 19-May-2011, Step 2 version
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Step_2/Q11_Step_2.pdf

Guides for QbD of the Drug Substance Process and Controls
FDA1 on Drug Quality

•Quality
Quality, safety
safety, and efficacy are designed or built into the product
•Quality cannot be adequately assured merely in-process and finished-product
inspection or testing
•Each
E h step
t off a manufacturing
f t i process is i controlled
t ll d to
t assure that
th t the
th finished
fi i h d
product meets all quality attributes including specifications
1 FDA Guidance for Industry, Process Validation: General Principles and Practices, Jan 2011, Rev 1
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf

QbD: Ensuring DS Quality via a Robust Control Strategy
control of impurities in starting

What goes in materials, reagents and solvents
processing conditions,
isolation/purification points,
What goes on
critical process parameters,
ranges, assay control points
Wh t comes outt
What verification of success with final
drug substances assays
Knowledge = Control = QbD

Traditional Approach to Initial Specification Setting
Process for Arzoxifene Intermediates
Post primary stability campaign, there was a debrief to determine

which tests are needed
• Cross-functional team: site QA, manufacturing sciences and technology (MST),
quality control lab (QCL); process development chemist, --engineer, and --analytical
Initial specifications were developed based upon process history

• Impurities that have been observed above 0.10% designated as specificed impurities
• Acceptance limits based on rejection efficiency studies, analytical variability, and
process capability
Specifications were reviewed and approved by:

• Cross-functional team
• By the leadership team
• Manufacturing Site Quality Assurance
Methods were finalized and validated/transferred

Step 1 Potential Impurities
O Br
Et N
Cl
Et O O
O S NBS O S OMe
S OMe
HO OMe Et N
Et N
379361 Et 2491419 Et 2491420
O
O S OMe
Et N
HO S OMe 2491419
NB Et
S
379361
B
Br
HO S OMe
430206
Rejected during crystallization

HO S OMe
379361
15-Sep-2011 IVT’s 3rd annual Bio/Pharmaceutical

B. Castle & R. Forbes Conference on Quality by Design (QbD)
Arzoxifene Step 1 Primary Stability Campaign Lots
0.024
0.022
0.020
0.018
0.016
0 014
0.014
Lot 4
A219133
0.012 Lot 3
AU
A217078
0.010
Lot 2
A217072
0 008
0.008
0.006
Lot 1
A213606
0.004
0.1% std
0 002
0.002
0.000
Blank
-0.002
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00
Minutes

Step 1 Specifications—Traditional Approach
Analytical
Test Procedure Acceptance Criteria
Identification / Assay / Purity Tests
Identity HPLC The relative retention time ratio between the sample and
(B11315) the standards must compare qualitatively for a positive
result
l for
f identity.
id i
Assay Not less than 97.5 %
Total Impurities Not more than 1.0 %
LSN 2491419 Not more than 0.50 %
Largest Unspecified Not more than 0.15 %
Impurity
Other Tests
Physical Appearance1 Visual It is a practically white to yellow to light brown solid.
1
“Physical Appearance” is equivalent to the ICH term “Description.”

Step 2—Potential Impurities
Br Br
Br
H 2 O2 H 2O2
O O
O O S OMe O S OMe
O S OMe Et N O O O
Et N Et N
Et Et
Et 2491420 2492986 2495649
H 2O2
Unreacted
O
Et
N O Br
Et
Br
OH
S
O
24
91
O S OMe
4
Br
20
OMe
Et N O
O Et 2521689
O S OMe
Et N
Et 2491420
Br
Br
O
O S OMe
Et N O
Et
2521691

Typical Arzoxifene Step 2 Primary Stability Campaign Lots
Lot 3
Peak Results
2492986
0.010 Nam e RT Are a %
1 LSN2521689 4.40 0.05
LSN 2
2 LSN2526306 7.72 0.11
LSN 2491420
0
0.008 3 LSN2521691 9.69 0.13
4 LSN2495649 9.92 0.06
521691
26306
5 LSN2491420 12.59 0.34
95649
21689
0.006
LSN 252
LSN 25
L
LSN 249
LSN 252
AU
0.004
Lot 5
0.002 Lot 4
Lot 3
Lot 2
Lot 1
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00
Minutes
Br
O
O S OMe
Et N
Et 2491420

Step 2 Specifications—Traditional Approach
Analytical
Identification Tests
Identity HPLC Retention time compares to standard
(B11342)
Br
OH
Assay Test O
O S OMe
Assay HPLC Not less than 96.5% Et N O
Et 2521689
Purity Tests
Br
Br
Specified Impurities HPLC
O
LSN 2521689 (B11342) Not more than 0.40% O S OMe
Et N O
E
Et
LSN 2521691 Not more than 0.50% 2521691
Br
LSN 2495649 Not more than 1.3%
O
LSN 2491420 Not more than 1.0% O S OMe
O O
Et N
Anyy unspecified
p Impurity,
p y, Et
N t more th
Not than 00.15%
15% 2495649
excluding LSN 2526306 Br
Other Tests O
O S OMe
Physical Appearance Visual Practically white to yellow solid Et N
Et 2491420
Cl
O OMe
O S
N
O (Converts to desired product)
2526306

Arzoxifene Free-Base step 3 Reaction Byproducts
O N
O N
O N O N
N O
O O
N
O OCH3
HO O
315699 O OCH3 HO S
Br O HO S
H2 KOH
O OCH 3 HO S
O O OCH3 S OCH3
OMe OCH3 S HO
S N O
O S N O
N O O
O 353381
2492988 (unreacted)
2492987 467739
2492986 (unreacted)
O N
KOH O N
Br
O OMe O
S H2 O
N O Br OH
O OCH3 O2
N O S
O OCH 3
O S
N 2492988 O
2491420
KOH
O
OH S
Br
OCH 3 472701
HO S
430206
O-
O N+
OCH 3
HO S
615901

Arzoxifene Free-Base step 3 Products from
Impurities in the Step 2 RXN Starting Material
H2 Br
Br 315699 KOH
OCH3
O OCH3 HO S
O S 430206
N
2491420
O
OCH3 H2 KOH
315699
N O S
2491419 OCH3
HO S
379361
O
OCH3
N O S
O
2828615
O N
H2 KOH
315699
Br OH
O OH
O OMe
O S
N OCH3
O S
2521689 HO
2537460
O N
H2 KOH
315699
Br Br
O O Br
OCH3
O S
N O OCH3
HO S
2521691
2528468
Note: No impurities carry forward from 315699 (PEP) starting material

Typical Arzoxifene Free-Base Primary Stability Campaign Lots
0.050
615901
2528468
379361
472701
430206
467739
0.045
Lot 11
0.040
Lot 10
0.035
Lot 9
0.030 Lot 8
Lot 7
AU
0.025
Lot 6
0.020 Lot 5
Lot 4
0.015
Lot 3
0 010
0.010
Lot 2
0.005 Lot 1
0.10% Standard
0 000
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00
Only 615901 and 2528468 above limit of disregard. Note that 379361 over-responds ~2X

Results of initial specification setting activity: Free-Base specifications
Analytical
Test Procedure Specification Rationale
Identity HPLC Retention time of the main peak in the Identification required. HPLC peak
(B07528) sample HPLC chromatogram must retention time match sufficient for an
compare with the reference standard. intermediate.
Assay Test
A
Assay (Potency)
(P t ) HPLC N t less
Not l th
than 92
92.0%
0% Hi t i l process capability,
Historical bilit mass
(B07528) balance, control of residual solvents and
sidechain.
Purity Tests
O N HPLC Not more than 0.15% Specification of NMT 0.15% at API and
(B11474) low rejection capability of Form V process
O OH (10%)
OCH3
HO S
LSN2537460
OH HPLC Not more than 0.50% High rejection capability of Form V
(B11474) process (90%)
O
O
OH S
LSN472701
HPLC Not more than 0.50% Specification of NMT 0.25% at API and
OCH3
(B11474) good rejection capability of Form V
HO S process (80%)
LSN379361
Any Unspecified HPLC Not more than 0.10% Control for API specification of NMT
Impurity (B11474) 0.10% for unknowns/unspecified
impurities.
Other Tests
Physical Appearance1 Visual
It is a practically white to yellow to brown Required test. Set based upon historical
solid batches.
1
Note: Several potential impurities were controlled via the “Any unspecified impurity” limit.
Specifications Were Established for Arzoxifene
HCl Process Using Traditional Approach
In order to support
pp timing g for p
process validation campaign
p g
activities analytical methods were transferred to the
manufacturing sites
• Methods fully validated vs.
vs ICH standards (including robustness)
• Methods transferred to QCLs using collaborative study protocol
In parallel,
parallel our organic chemistry and engineering
partners were engaged in quality by design activities
for the final synthetic route
• Efforts were delayed due to need to change API crystal form
based upon pivotal BE study
• S th ti route
Synthetic t (protecting
( t ti group)) alsol changed
h d llate
t iin
development due to manufacturability issues
Benefits of a QbD submission
Higher level of assurance of product quality for patient
• Design quality in versus testing for compliance to specifications
• Increased understanding leads to better and more robust processes
• Process for better identifying and managing risks
More efficient regulatory oversight

• Streamline post approval manufacturing changes and regulatory processes
• Process changes within the design space (DS) don’t need to be reported
• Fewer questions on submission potentially leading to faster approval?
Cost saving and efficiency for industry

• Increase efficiency of manufacturing process (higher yields, less waste)
• More flexibility to adjust process (within DS)
• Opportunity to reduce testing (in-situ? intermediates? final product?)

Potential down-side of a QbD
submission
The Design-Space becomes a regulatory commitment
• A classical
l i l submission
b i i iincludes
l d only l a hi
high
h llevell process d
description
i ti with
ith a
small subset of parameters included
• During QbD risk assessment, ALL process parameters are examined for
potential impact
¾ Most parameters are found to have little impact (low-risk)
¾ A small subset are found to be critical or medium-risk
¾ If the design space must include the low-risk parameters, this would be a dramatic increase in the
number of regulatory commitments
Management of changes that impact the Design Space

• Movement of the set-point for a MRP toward failure limit can make it a CPP
• If the number of CPPs or MRPs change, the design space should be re-mapped
¾ 30-experiment DOE + 2 to 4 bracketting experiments
On-going
g g assurance that equipment
q p capability
p y does not change?
g

Arzoxifene Hydrochloride—CQAs
Drug Substance Link to the Drug Product Rationale
Critical Quality Critical Quality Attributes
Attributes
Identity Identification Ensures drug product
performance, safety and efficacy
Crystal Form Identification Ensures drug product
Potency Potency Ensures drug product
Purity Purity Ensures drug product safety
safety.
Particle Size Release Profile The particle size distribution of

Distribution the drug substance controls
dissolution kinetics of the
molecule in vivo and ensures
appropriate dissolution time
based upon the current unit
formula.
W t
Water P t
Potency, Id
Identification
tifi ti E
Ensures d
drug product
d t
performance, safety and efficacy.
• The quality of the intermediates will not affect : API physical properties, identity, or water content.
• API Potency and purity can be impacted by levels of byproducts in the intermediates
• Thus impurity level was the response to assess impact on drug substance CQAs for DS mapping
for intermediate steps.
15-Sep-2011 IVT’s 3rd annual Bio/Pharmaceutical Conference on
QbD Approach for Arzoxifene HCl
Restrict the size of the design space to
ensure all outcomes of the combined
variables result in acceptable quality product
(meets FPC or CQA for API)
Conduct a design of
Identify critical process experiments
i t (DOE) using
i
parameters (CPPs) and all high (CPPs) and
other parameters with the medium-risk parameters
potential to have interaction
effects (medium-risk
parameters))
p
Conduct two final experiments at

the worst case DOE point
combined with all the other
parameters at their proposed
worst case settings
g ((and best
case settings) as a final check to
establish the design space for all
the parameters
22
Design
g Space
p Concepts
p
Definition of Limts for a Medium Risk Parameter
-6σ +6σ
Upper Spec Limit
CQA
Lower Spec Limit
Target Parameter
Lower Lower Upper set-points
Upper
Failure PAR Lower Upper Failure
PAR
limit limit DS DS limit
limit
limit limit
Lower limit Upper limit
for risk for risk
assessment assessment
For more info see: K. Seibert , et. al, J. Pharm. Innov. (2008) 3:105-112.

Arzoxifene HCl Input Materials
Table 3.2.S.2.3.2-3 Specifications for Compound 379361,
Analytical
Test Method Acceptance Criteria
Assay HPLC NLT 96.0%
Total Impurities HPLC NMT 1.2%
Anyy Unspecified
p Impurity
p y HPLC NMT 0.10%
% Tight
g control of
Specified Impurities: HPLC unspecified impurities
4578151 NMT 0.70%
Limits based upon
1535462 NMT 0.40%
rejection data
Volatiles LOD NMT 1.0%
NLT = Not less than NMT = Not more than
OH
1 OMe
The chemical structure of Compound 457815 is: S .
2 OH
The chemical structure of Compound 153546 is: HO S .
Table 3.2.S.2.3.2
3.2.S.2.3.2-4
4 Specifications for Compound 315699,
Analytical
Test Method Acceptance Criteria
Assay HPLC NLT 96.0%
Total Impurities HPLC NMT 1.0%
Any Unspecified Impurity HPLC NMT 00.10%
10% Tight control of
Specified Impurities HPLC unspecified impurities
1
027195 NMT 0.50%
433294 2
NMT 0.15%
Limits based upon
NLT = Not less than NMT = Not more than
rejection data
1 HO OH
The
h chemical
h i l structure off Compoundd 027195 is:
i .
N O
2 N
The chemical structure of Compound 433294 is: O

Arzoxifene HCl Step 1 Design Space
Table 1-2. Arzoxifene Hydrochloride Step 1 Design Space Limits for MRPs
Tightened
Operation Parameter Target 6σ Lower Limit Upper Limit vs. PAR? Risk
DMAP (eq) 0.1 0.006 0.08 0.12 No Med
Protection Reaction TEA (eq) 1.05 0.063 1.0 1.1 Yes Med
Dec-Cl (eq) 1.05 0.063 1.0 1.1 Yes Med
2491419 Wash Water volume (vol) 3 0.18 2 4 No Med
Bromination NBS (eq)
( ) 1.07 0.0642 1.02 1.12 Yes Med
The worst case combination of the MRPs was: DMAP (eq) at the high set-point,
and Dec-Cl (eq), TEA (eq), Water (vol), NBS (eq) all at the low set-points; in
conjunction with all other low risk process parameters (LRPs) at set-points
expected to increase impurity levels.

B. Castle & R. Forbes
Conference on Quality by Design (QbD)
Step 1 QbD Results—Worst Case Conditions
O
O S OMe
Et N
Et 2491419
3.87%
Does not meet
specification limt of
NMT 0.5%
The isolated intermediates made from the bracketing studies typically contained
maximal amounts of pprocess byproducts,
yp , and thereby
y served as worst-case
examples of intermediate purity.

Table 2-1. Arzoxifene Hydrochloride Step 2 Design Space Limits for MRPs
Tightened
Operation Parameter Target 6σ Lower Limit Upper Limit vs. PAR? Risk
Sulfolane ((vol)) 6.0 0.36 5.5 7 No Med
Sulfuric Acid (vol) 3.0 0.18 2.75 3.25 Yes Med

Reaction
H2O2 Amount (eq) 1.02 0.06 0.97 1.07 Yes Med
Reactor Tempp ((°C)) -10 12 -15 2 Yes Med
1st Crystallization Water Add Rate (vol/hr) 2.16 1.06 2.0 5.0 Yes Med

B. Castle & R. Forbes
Conference on Quality by Design (QbD)
Step 2 QbD Results—Worst Case Conditions
0.025 OM e
LSN2492986
OM e
Br O Br OM e
S
0.020 OM e
O Br O
S
O Br S
LSN2526307
N O
OMe Br S O
0.015 O
O O
N O O
LSN2491 420
OM e O N
AU
Br O OH N
A
S
0.010
LSN2495649
LSN2521691
Br O
S
LSN2521689
OH
LSN2526306
0.005 O
O
N
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

Minutes
Step 2 Lot 2526307 2521689 2521691 2495649 2491420

WH4-D2008-088 <0.05% 0.32% 0.14% 0.24% <0.05%
WH4-D2008-091 <0.05% <0.05% 0.06% <0.05% 0.19%
WH4-D2008-092 0.78% 0.24% 0.16% 0.73% 0.10%
WH4-D2008-096 1.28% 0.15% 0.26% 0.41% 0.21%
Limit NMT 0.15% NMT 0.40% NMT 0.50% NMT 1.3% NMT 1.0%
OMe OMe OMe

OMe OMe
HO Br
New impurity
Observed Br S
O Br S
O Br S
O
B
Br S
Br O O
(deprotected product) S
O O O O
OH O O O O
N N N N
Table 3-1 Arzoxifene Hydrochloride Step 3 Design Space Limits for MRPs
Target 6σ Lower Upper Tightened Risk
Operation
O ti P
Parameter
t Li it
Limit Li it
Limit vs. PAR?
Coupling Reaction
PEP (eq) 1.09 0.065 1.03 1.15 Yes Med
KOtBu (eq) 1.05 0.06 1.0 1.1 Yes Med
Reaction Temperature (°C) 50 12 38 62 Yes M d

Med
Hydrogenation Reaction
pH Target 2.0 0.6 1.4 2.6 Yes Med
Reaction Temperature (°C) 110 12 98 122 Yes Med

Deprotection Reaction
KOH (eq) 55
5.5 03
0.3 52
5.2 58
5.8 No Med
Reaction Temp (°C) 108 12 102 114* No High

* Thermodynamic limit of boiling point is reached before limit of six sigma range

Arzoxifene Free-Base Bracketing Study Lot
(worst-case coupling reaction conditions)
0.024 Peak Results

Nam e RT Are a %
0.022
1 379361 7.43 0.21
0.020 2 2528468 7.63 0.08
0.018 3 472701 7.88 0.04

4 467739 8.65 0.13 Å NMT 0.10%
0.016 5 430206 9.98 0.10 Å NMT 0.10%
9361
0.014 6 11.01 0.05
379
7 2799691 13.07 0.13 Å NMT 0.10% New impurity
AU
0.012
0.010
Observed
0.008
39
91
2528468
8
46773
430206
6
279969
0.006
0.004 472701
0.002
0.000
-0.002
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00
Minutes
S S 18 03 0 091 S S
Impurities exceeding specification limits were also observed in other PAR and DS study samples

Mechanism for Formation of New Impurity in
Arzoxifene Free-Base Bracketing Study Lot
N O N
O Br N
O
Br 315699 O OMe
(Base)
O N O S
OMe O O O
S O
N O H2
O OCH3 OCH3 KOH
- S O S OCH3
O O S
2492986 O O
452661 O
OCH3
S OCH3
N O
O S
Long addition HO
2799691
times for the

2492986 starting
material allow time
for deprotection to
occur

Interpretation of QbD Results
Results of QbD experiments for all three steps did not meet the
specifications established using the traditional approach
• Impurities that were not specified needed to meet the NMT 0.10% any
unspecified impurity limit
Options for proceeding forward:

1) Establish several new CPPs and/or CIPCs and control the process to meet
the specification limits
2) Generate data to support revision of the specifications such that product of
all PAR experiments meet specifications (provided that the API made from
the intermediates meets CQA’s)

Forward Process Worst-Case Step 1 to Step 2
OMe
OMe
Br O
S
Br S
O OMe OMe
O Br
N
O
OMe O
O
Br O Br S N
OMe S O
828615
OH
O
S
O
O
28
O
Br O O
S N
N
O
O
N
O
O
N
New Impurity
Observed
Step 2 Lot 2828615 2521689 2521691 2495649 2491420
MM7-H70350-053 0.22% 0.13% 0.07% 0.09% 0.41%
Limit NMT 0.15% NMT 0.40% NMT 0.50% NMT 1.3% NMT 1.0%
% Rejection
S
Step 1L
Lot 2491419 S
Step 2L
Lot 2828615
Step 1 to Step 2
RJ2-H70246-093 3.77% MM7-H70350-053 0.22% 94%

Fate of 2828615 Impurity in Step 3
H2 O KOH
315699 OCH 3
O
OCH 3 N O S OCH3
N O S HO S
O
2491419
379361
2828615
Already a
specified
ifi d iimpurity
it
0.5 wt% of 2828615 was spiked into a step 3 reaction and the
isolated free-base contained 0.21% of compund 379361 (Spec.
limit = NMT 0.5%)

Revised Arzoxifene Step 1 Specifications
Analytical
Identification / Assay / Purity Tests
Identity HPLC The relative retention time ratio between the sample and
(B11315) the standards must compare qualitatively for a positive
result for identity.
Assay Not less than 97.5 94.0 %
Total Impurities Not more than 1.0% (No Limit)
LSN 2491419 Not more than 0.5 4.0 %
Largest Unspecified
ifi d Not more than
h 0.15
01 %
Impurity
Other Tests
Physical Appearance1 Visual It is a practically white to yellow to light brown solid.
1

Forward Process Worst-Case Step 2 to Step 3
0.025 OM e
N2492986
OMe
Br O Br OM e
S
LSN
0.020 OMe
O Br O
S
O Br S
LSN2526307
N O
OMe Br S
O
0.015 O
O O
N O O
91420
OMe O N
AU
Br O OH N
S
0 010
0.010
LSN249
LSN2495649
LSN2521691
Br O
S
LSN2521689
OH
LSN2526306
0.005 O
O
N
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

Minutes
0.024 Pe ak Res ults

0.022 Nam e RT Area %
0 020
0.020
1 615901 6.89 0.06 New impurity is
0.018
2 379361 7.44 0.17 Å NMT 0.5% rejected
0.016
0.014 3 2799691 13.25 0.06

379361
AU
0.012
3
0 010
0.010
0.008
0.006
2799691
615901
0.004
0.002
0 000
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

Minutes

Free-Base from Step 2 Spiked with New Impurities
S ik d att 1
Spiked 1.5
5 wt%
t% Spiked at 0.5
0 5 wt%
Br
O O
OCH 3 OCH 3
N O S S
N O
O O
2828615 2526307
LY353381
0.024 Pe ak Res ults
Corre cte d
0.022 Nam e RT
Area%
OCH 3
0 020
0.020
HO S 1 379361 7.16
7 16 0 21
0.21 Å NMT 0.50%
0 50%
0.018 379361 2 472701 7.50 0.06
379361
3 467739 8.59 0.09
0.016
4 430206 9.70 0.15 ÅNMT 0.25%
0.014
(new spec)
Br
AU
0.012
OCH3
0.010 HO S
430206
30206
0.008
0 006
0.006
43
472701
1
467739
0.004
0.002
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

Minutes

Revised Arzoxifene Step 2 Specifications
Analytical
T t
Test P
Procedure
d A
Acceptance
t C
Criteria
it i
Identity HPLC The retention time of the main peak must compare
(B11342) qualitatively with that of the reference standard when
run under the same conditions.
Assay Test
Assay HPLC Not less than 96.5 94.5%
(B11342)
Purity Tests
Specified Impurities HPLC
LSN 2526307 (B11342) Not more than 1.50% Note: Method was also revised to
resolve these two impurities for
LSN 2828615 (B11342) Not more than 0.50% accurate quantiation
LSN 2521689 (B11342) Not more than 0.40%
0 40%
HPLC
(B11342)
HPLC
(B11342)
HPLC
(B11342)
Any unspecified Impurity, HPLC
Not more than 0.15%
excluding LSN 2526306 (B11342)
Other Tests
LSN 2492986 Physical Visual Practically white to yellow solid
Appearance1
1
Spike Impurities in Arzoxifene Free-base to Produce API
0.025
Free-base
0 020
0.020 0 50%
0.50%
(Spiked)
2799691
0.50%
0.015
467739
0.25%
AU
0 010
0.010 0.25%
615901
430206
0.005
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

Minutes
0.025
Arzoxifene HCl
0.020
0.015
0 010
0.010 0.11%
0.06%
467739
615901
0.005
0 000
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

Minutes
Revised Arzoxifene Free-Base Specifications
Analytical
Test Procedure Specification
Identity HPLC The retention time of the main peak in the sample HPLC
(B07528) chromatogram must compare with that of the reference
standard when run under the same conditions.
Assay Test
Assay (Potency) HPLC Not less than 92.0%
(B07528)
Purity Tests
Specified Impurities
LSN2537460 Not more than 0.15%
LSN379361 HPLC Not more than 0.50%
0 50%
LSN472701 (B11474) Not more than 0.50%
0 50%
Any Unspecified Impurity HPLC Not more than 0.10%
(B11474)
Other Tests
1
Ph i l Appearance
Physical A Vi l
Visual I is
It i a practically
i ll white
hi to yellow
ll to brown
b solid
lid
1

Conclusions—Part
Conclusions Part I
With the QbD approach (enhanced approach) new
impurities and higher levels of impurities are observed in
intermediates versus the traditional approach
• Thus is it likely that more impurities may need to be specified for
i t
intermediates,
di t leading
l di to t the
th need d for
f an expanded
d d analytical
l ti l control
t l
strategy
• “What is good for manufacturing is not always good for the lab.”
PAR/design space studies should be completed prior to

analytical method finalization, specification setting, and
method validation/transfer
• Broader methods, capable of detecting a larger set of impurities
• More robust specifications
• Method revision after transfer is more difficult
Do we need intermediate specifications at all?
Completion
p of the mapping
pp g resulted in a final design
g space
p
in which all possible combinations of all process parameters
(high, medium and low risk) result in drug substance that
meets the critical quality attributes
When each of the intermediate steps are operated within

the design
g space,
p , the byproduct
yp impurities
p in the
intermediates will not exceed levels found to be rejected in
subsequent processing steps.
Why do we need to test when the quality is designed in?

3.2.S.2.4 Controls of Critical Steps
and Intermediates
Intermediates made from the bracketing studies contained maximal amounts of
impurities and served as worst-case examples of intermediate purity. When
forward processed, the resulting drug substance met its CQA’s.
As a result, the risk that byproducts will be present in an intermediate at levels that
will cause the final drug substance to fail to meet the critical quality attributes is
extremely low.
Therefore the quality of the intermediates has been ensured by robust process
design, and routine testing against specifications in not needed.
The final design space includes one CPP and one CIPC for the arzoxifene HCl
manufacturing process:
Table 3.2.S.2.4
3.2.S.2.4-1
1 Arzoxifene Hydrochloride Critical In-Process
In Process Controls
Step Critical Process Parameter Critical Specification
Step 3 Deprotection Reaction Temperature % LSN2492988 remaining in-situ by
HPLC
Step 4 Milling Feed Rate Particle size by Laser-Light Scattering

Conclusions—Part
Conclusions Part 2
When the process is run within the design space the purity of the drug
substance is assured
• There is no need for specifications and testing of intermediates
• The quality of the input materials (starting materials) is controlled by tight specifications
Final release testing on the drug substance versus a full set of

specifications is done as additional assurance of quality
Ongoing assurance of process capability through Post Approval Lifecycle

Maintenance
• Product & Process Knowledge Management
• Product Stewardship
• R ti P
Routine Process & P
Product
d tP Performance
f M
Monitoring
it i
• Equipment Qualification & Monitoring
• Deviation Management
• Change Management

Alternative Approaches?
EFPIA* Mock S2.6
EFPIA S2 6 for “Illustrain
Illustrain Hydrochloride
Hydrochloride” Draft Discussion Paper
Thus the formal control strategy comprises:
Registered description of the manufacturing route and process (M3

(M3.S.2.2)
S 2 2)
which includes Design Space and for CPPs
Description of Manufacturing Process For Illustrain hydrochloride

• Description of the manufacturing process for stage 1 (Representing the compliance commitment taken
from S.2.2)
• In process controls for completion reaction of stage 1 (residual olefin <0.5%)
• Description of the manufacturing process for stage 2 (representing the compliance commitment taken
f
from S.2.2)
S 2 2)
– In process controls for loss on drying of stage 2 (NMT 5.0% w/w)
• Description of the manufacturing process for stage 3 (representing the compliance commitment taken
from S.2.2)
– Control strategy and risk review for stage 3
– Design space (yellow shaded) in which residual benzyl chloride level is less than 0.5%
• Description of the manufacturing process for Stage 4 (Representing the compliance commitment taken
from S.2.2)
– Design space to control particle size distribution for Stage 4
*European Federation of Pharmaceutical Industries and Associations (EFPIA)
Registered specifications for raw materials particularly the starting
materials SM1 and SM2,, mandelate salt and illustrain hydrochloride
y
• Specification for starting materials
• Specification for mandelate salt
• Specification for illustrain hydrochloride


Acknowledgements
Matt Earley
Mary Kay McCauley
Vickie Horsleyy
Tim Aldridge
Jacek Wanczura
Kim Nordholz
Michael Sanford
Erin Copeland
Sally Dotterer
Ian Sherlock
Kevin Seibert
Phil Hoffman
H ff
Doug Kjeil
Brian Fahie
IVT’s 3rd annual Bio/Pharmaceutical Conference on 48

Quality by Design (QbD)
The Quality Risk Based Approach
Bernard
B dMMcGarvey,
G Ph.D.
Ph D
Siegfried Schmitt
PAREXEL Consulting
IVT Conference
Sept , 2011
San Francisco, California.
1
Introduction………
Bernard McGarvey, Ph.D.
Engineering Advisor
•Previous experience in risk analysis and process safety
•Engineering representative for QbD and QRM
•Helped develop the Lilly QRM process, QRM training.
•Leader of the Lilly QRM Community Of Practice (COP)
•Owner of the Lilly QRM internal collaboration web site.
•Participated in several internal process risk assessments

as well as several quantitative risk assessments
2
1
Let’s get warmed up…….
“A person (A) is walking down the street and meets

another person (B) he/she has not seen for many years.
They strike up a conversation
conversation, during which person (A)
asks person (B) if he/she has any children. Person (B)
replies that her/she has two children, one of whom is
a girl.
Question: What is the probability the person (B)

has two girls?
(Assume 50/50 chance that a baby will be a boy/girl).
Slide Intentionally left blank
2
Slide Intentionally left blank
The Pivotal Role of Risk Management
“The revolutionary idea that defines the

boundary between modern times and the past is
the mastery of risk: the notion that the future is
more than a whim of the gods and that men and
women are not passive before nature”
Bernstein – “Against the Gods – The remarkable

story of risk”
3
Notable Quotes on Risk Management
“Good Risk Management fosters vigilance in times of calm and

instills discipline in times of crisis.” Dr. Michael Ong
“Progress always involves risks. You can't steal second base and
keep your foot on first." Frederick B. Wilcox
“One thing that makes it possible to be an optimist is if you have a

contingency plan for when all hell breaks loose.” Randy Pausch
“Risk is like fire: If controlled it will help you; if uncontrolled it will rise
up and destroy you.” Theodore Roosevelt
"Take calculated risks. That is quite different from being rash."

George S. Patton
QRM is Central to QbD
Definition of QbD in ICH Q8
“A systematic approach to development that

begins with predefined objectives and
emphasizes product and process
understanding and process control, based
on sound science and quality risk
management.”
4
Principles of QRM
Two primary principles of QRM are
• The evaluation of the risk to quality should be based on

scientific knowledge and ultimately link to the
• The level of effort, formality and documentation of the

quality risk management process should be
commensurate with the level of risk
QRM is NOT!!!!!!!!!!!!!!!!!!!!!!!
• A justification for not doing the required work.
• A justification for poor quality products and/or processes.
• A justification for not complying with regulatory requirements.
• A check the box exercise.
• A single event in the product lifecycle.
10
5
So – what is Risk anyway!
“Risk can be defined as a measure of the probability and

severity of adverse effects.”
Haimes – “Risk Modeling, Assessment, and Management”
Risk Management Activities
1. Assessing risks
2. Judging the acceptability of those risks.
3. Mitigating those risks that are deemed unacceptable.
4. Documenting the entire activity.
11
And why is risk management such a difficult

activity???
1. Risk involves uncertainty.
2. The task is cross-disciplinary.
3. It involves trade-offs.
4. It typically involves high impact/low probability events.
5. It involves immediate investment with long term, invisible, and

uncertain returns.
6. It is very susceptible to personal biases.
7. You will always have to settle for non-zero risks.
12
6
Consider the following scenario………
The Slick Oil Transportation Company owns a fleet of oil tankers that it uses
for transporting crude oil products around the world. You have just been
informed that one of the company’s tankers that was carrying Naphtha was
involved in a collision
collision. It was towed into a nearby port and most of Naphtha
was transferred to another ship. The damage was severe enough that the
tanker must be moved to a shipyard where it can be cleaned and the damage
surveyed and repaired. The port fire authorities and local fire departments
have said that the ship’s tanks must be inerted before it can be moved to the
shipyard. The current procedure says that the ship should be inerted with
Nitrogen. However, just to prove that Murphy’s Law is valid, unforeseen
circumstances have led to a scarcity of Nitrogen and so it will not be available
for at least a week. The procurement department has located a sufficient
supply of Carbon Dioxide cylinders nearby and if this could be used, the
tanker could be moved immediately. Since the use of carbon dioxide is not
indicated in the current procedure, using it will mean that a temporary change
will need to be approved.
13
The case for proceeding…………….
•There is no record of a tanker ever blowing up while sitting in

port.
•You cannot find a regulation that says you cannot use CO2 as a
bl k ti agent.
blanketing t
•The current procedure does not explicitly exclude the use of
CO2.
•CO2 is as good a blanketing agent as Nitrogen.
•Every day the tanker remains un-utilized costs the company
$250,000.
•The port authority is calling you constantly to find out when the
port slot that the tanker is occupying will be available for another
tanker.
•Your interim review is up in two weeks and if you get an
exemplary rating from your (bottom-line, cost conscious) boss
you qualify for a bonus.
14
7
The case for not proceeding……….
•You cannot find any precedent for using carbon dioxide as an

inerting agent.
•In discussions with an external consultant, you have identified a
t t that
test th t can be
b performed
f d in
i 7 days
d which
hi h will
ill give
i ad definitive
fi iti
answer to the safety question.
•While the test only costs $50,000, waiting the 7 days will cost the
company $1,750,000.
•The potential loss to the company from an incident would be many,
many times $1.75M.
•Your final performance review for the year is in two weeks and you
are well aware that your most recent performance carries most
weight in these reviews. At your interim review earlier in the year
you were told that while your technical capabilities and attention to
detail were excellent, you sometimes had trouble making decisions
where the available information was open to interpretation.
15
So what would you do……………..
Uncertainty of payback Certainty of mitigation costs
16
8
Slide Intentionally left blank………
17
18
9
19
Risk Model – how to think about risk
This is based
on the
hazard/harm
model from
ISO 14971
20
10
Risk Model Examples
Bacteria
Bacteria in a
Vial
Bacteria enters
patient.
This is based on the hazard/harm model from ISO 14971

21
Risk Model – What about your examples….
This is based
on the
hazard/harm
model from
ISO 14971
22
11
The “Swiss Cheese” Model
Reason, J. BMJ 2000;320:768-770
23
What do we mean by Risk to the

Patient………..
Consider the following………….
Prior to placing a new product on the market, a risk analysis has shown
th t the
that th risk
i k that
th t a patient
ti t will
ill b
be h
harmed
db i l usage iis 10-88.
by a single
In its first year on the market the product is used 1,000,000 times by
patients (100,000 patients, each patient uses it 10 times).
After 5 more years on the market, the sales have grown and now the
product is used by 1,000,000 patients (each patient still uses the
product 10 times p
p per yyear).
) The p
product/process
p has not been modified
in any way over the 5 years.
Question: Based on your notion of risk to the patient, has the risk to the
patient increased between year 1 and year 6?
24
12
This slide intentionally left blank……
25
One view………………………
Risk is measured as risk to an individual patient taking

the
h product
d
In both cases the risk based on this view is the same

in both cases
Risk to a patient per annum is 10-88*10

10 = 10-77
26
13
Second view………….
Risk is measured as risk to all patients over a given time period

(1 year)
With this view, the risk has increased 10 fold
Year 1: Risk is measured as 10-8*106 = 10-2 = 1 patient harmed

every 100 years.
Year 6: Risk is measured as 10-8*107 = 10-1 = 1 patient harmed

every 10 years.
Which view is more correct?
27
QRM along the product life cycle:

Process Development
Initial Perform
Control Strategy
gy Risk Assessment
Identify Gaps in Modify

Proposed Control Strategy Control Strategy
Manage Define CQAs

Residual Risk and CPPs
28
14
QRM along the product life cycle:
Manufacturing
Execute Control Strategy
Product and Process Monitoring Quality System Monitoring
CAPA / Improvements
Change Management
Note: Use an existing risk assessment if available. If a risk assessment does not
already exist, then it may be created as the quality system elements are implemented.
29
Knowledge Management for QRM – the

Problem!
Microsoft Word
Microsoft Office
Excel 97-2003 Worksheet
Microsoft Office
Excel
Flowchart
30
15
Knowledge Management for QRM
•A risk assessment is a model of a product/process.
•Therefore
Th f it represents
t a significant
i ifi t quantity
tit off product/process
d t/
knowledge.
•It must be documented.
•Initially most companies will use simple approaches such as

spreadsheets and word or pdf documents.
•An integrated software solution for managing risk assessments

has many advantages for long term knowledge management.
31
Knowledge Management for QRM
All Risk Assessments Securely

Stored in Central Database
Risk Assessments
Role-Based Multi-User
Collaboration via the Web
Collaboration
Real-time Risk Distribution and

Top Risk Reports & Dashboards
Reports &
Dashboards
Global Search, Libraries and
Cross Study Queries of Historical
Knowledge Knowledge
Repository
Workflow for Approval &
Recommendation Tracking
Workflow
32
16
A Process for Quality Risk Management
Bernard
B dMMcGarvey,
G Ph.D.
Ph D
Siegfried Schmitt
PAREXEL Consulting
IVT Conference
Sept , 2011
San Francisco, California.
1
Quantitative Methods in Risk Assessment
“The revolutionary idea that defines the boundary

between modern times and the past is the mastery
of risk: the notion that the future is more than a whim
of the gods and that men and women are not
passive before nature”
Bernstein – “Against the Gods – The remarkable

story of risk”
1
A Potential QRM Process
1. Decide to Use Formal QRM

2. Develop the Risk Question
3. Form a QRM Team
4. Identify the Requirements (CQAs)
5. Determine Potential Harms and Severity
6. Develop a Process Flow Chart
7. Identify Unit Operations With Greatest Risk
8. Determine Process Steps With Greatest Risk
9. Determine Level of Risk Associated With Existing Controls
Recommend Actions and New Controls
10. Determine Level of Residual Risk and Risk Acceptance
3. The ICH Q9 Approach
2
3. Applied QRM Process Example
1. Decide to Use Formal QRM
2. Develop the Risk Question
3
3. F
Form a QRM Team
T
4. Identify the requirements (CQAs)
5. Determine Potential Harms and Severity
6. Develop a Process Flow Chart
7. Identify Unit Operations With Greatest Risk
8. Determine Process Steps With Greatest Risk
9. Determine Level of Risk Associated With Existing Controls
Recommend Actions and New Controls
10. Determine Level of Residual Risk and Risk Acceptance
How this Process fits in with ICH Q9
3
3. Prioritization can be Built into the QRM Process
The QRM Funnel
Formal QRM?
CQAs
Unit Operations with

Greatest Risk
Process
Steps with
Greatest
Level of Detail Risk Scope
I
Increasing
i Failure Decreasing
D i
Modes
With
Greatest
Risk
3. QRM Decision Process
QRM trigger from Business Requirements Yes

(e.g., Process Development)
No
QRM required
i d by
b Quality,
Q li H&S, H&S Yes
Environmental Policies or SOPs
No
Process utilizes a New Technology or Yes
Operational Paradigm
No
Operations for which one has experience but Yes
the process is problematic
No
O h reasons ffor using
Other i a fformall QRM process Yes
(e.g., complex, large impact)
No
Pursue Formal
Do Not pursue “formal” QRM** QRM
**But we still document our rationale so that it is evident that we did do a risk assessment. 8
4
3. The Risk Question
What is the purpose of a risk question?
Why is a good risk question so important?
How do we write a good risk question?

Start by asking a series of sub-questions:
• Wh
Who and/or
d/ whath t is
i impacted?
i t d?
• What is the focus of our analysis?
• Why are we conducting the analysis?
Risk Question Better Risk Question

Whatt iis th
Wh the risk
i k tto patient
ti t What product features should
safety? be altered to differentiate three
different product dosage
strengths?
What is the risk to our What risks must be mitigated to

manufacturing
f t i timeline?
ti li ? source ethyl acetate from only
one vendor?
10
5
3. QRM Tools
• Brainstorming -- an informal analysis tool that is used to identify hazards and harms. It can be
used at any point in the QRM process.
• Fishbone (Ishikawa) Diagram -- a diagram used to associate multiple possible causes with a
g effect. Major
single j branches represent
p major
j causes, and minor branches represent
p detailed causal
factors.
• PHA -- useful when limited information is available. The PHA, or Preliminary Hazard Analysis
relies heavily on prior knowledge from subject matter experts and similar products.
• FMEA -- used to evaluate potential failure modes for systems, products, or processes and
their effects. It is also useful to identify additional controls required to mitigate risks.
• FTA -- a diagram used to identify root causes of a potential failure. You need full knowledge of a
complete system in order for this tool to be effective.
• HACCP -- best used to identify and manage risks associated with physical, chemical and
bi l i l hazards,
biological h d including
i l di microbiological
i bi l i l contamination.
i i It is
i only
l effective
ff i when h allll the
h
critical control points of a system are identified and understood.
• Risk Assessment Matrix -- used to qualitatively determine the level of risk associated with an
activity before applying any risk management strategies.
11
3. Note on the QRM Tools
•Just because a method uses “numbers” does not imply it is a

quantitative technique – must look at where the numbers came
from.
•Most of the tools utilized in the QRM process are documentation

tools
•They do not directly contain the justification for the “numbers”.
•This justification must be provided using other methods such as

risk modeling, process modeling, designed experiments, etc..
•Recording this linkage (the rationale for the numbers) is extremely

important.
12
6
Form a QRM Team…………..
• Team should be appropriately cross-functional

• 5-8 team members (full-time)
• How long should the team meet?
• Long meetings can be difficult due to loss of energy levels
• Core Team and extended membership
• Ensures people’s time is used as productively as possible
• Managing disagreements
• Can sometimes use a high/low scoring to keep the process
moving along
13
Identify Requirements (CQAs)
Patient
Patient
Requirement Product Design CQAs/QAs
Requirements
Categories
Efficacy Dose Control Accurate Dose Potency (Assay)
Efficacy Dose Control Accurate Dose Uniformity of Dose
No microbial
Safety Closure System Integrity Microbial Purity (Sterility, Endotoxin)
contaminants
Minimal foreign
Safety particulate Foreign Particulate Control Particulate Matter
contamination
14
7
Determine Potential Harms & Severity
Preliminary Hazard Analysis (PHA)
15
Example – Solid Oral Dosage Form
16
8
Process Flow Chart
Ensures we have all agreed on what is out as much as

what is in!
17
Identify Unit Operations with Greatest Risk
Risk Assessment Matrix
Key: Low Medium High 1
18
9
Identify Process Steps with Greatest Risk
Solid Oral Dosage Product
19
Could also use a Fault Tree
Potency Out of
Specification
Reaction
Temperature
Too High
Heating Control Incorrect Setpoint Cooling Control

Valve Fails Open entered Valve Fails
20
10
Determine Level of Risk
Associated with Existing Controls
Failure Mode Effects Analysis (FMEA)
21
Typical Columns in an FMEA
• Process Step: A descriptive name for the process step that is being assessed (drying, milling, heating,
crystallizing,….)
• Function: The purpose of the step being assessed (the more precise the definition of the function, the easier it is to
identify the failure modes).
• Dry product until LOD reaches 1%
• Stir contents for 1 hour between 78 and 82 Deg C
• Add reactants at 10 kg/min +- 0.5 kg/min
• Requirement/CQA: already defined
• Failure Mode: Any failure to meet the purpose of the process step
• LOD never reaches 1%
• Temperature goes above 82 Deg C
• Temperature goes below 78 Deg C
• Reactant addition rate is above 10.5 kg/min
• Impact: What impact will this failure mode have on the CQA. This drives the severity of the failure mode
• LODs above 1% may impact the purity of the product
• Temperatures above 82 deg C may create an impurity
• A slow reactant rate may allow an impurity to form.
22
11
Typical Columns in an FMEA
• Failure Cause: What are the basic causes that will lead to the failure mode.
– A failure of the air heater may slow down the drying rate.
– A failed coolant flow control valve may cause the temperature to rise.
– A iincorrect entry off a set point
An i might
i h cause the
h addition
ddi i rate to be
b below
b l 9.5
9 5 kg/min.
k / i
• Control: This is a control system (or part of a control system) that prevents the failure mode from occurring or
prevents the failure cause leading to the failure mode.
– Maintenance is used to reduce the risk of a valve failing.
– Second person verification may be used to detect the entry of an incorrect set point.
• Severity: A measure of the possible consequences of a hazard (based on impact to a CQA).
• Occurrence: A measure of how likely a failure cause can occur.
• Detection: The ability to discover or determine the existence, presence or fact of a hazard during routine
manufacturingg and the ability
y to correct or impact
p the consequences
q of a hazard,, prior
p to leadingg to harm.
• RPN: The product of Severity, Occurrence and Detection (S x O x D)
• Recommended Action(s): An action that should be taken if the risk is deemed unacceptable.
• Action(s) Taken: Description of actions taken.
23
3. FMEA: A Word Regarding the use of Risk

Priority Number (RPN)
• RPN used to be the major mechanism to assess risk acceptability
• RPNs were compared to a threshold
• This method is less favored today
• The automotive guidelines for FMEA specifically states:
• “The use of an RPN threshold is NOT a recommended practice for
determining the need for actions.”
• Note that it is not the use of RPNs that are considered the issue, just
the use of the threshold to assess acceptable risk.
• Other approaches have been used:
•If Severity >= n, then this entry must be addressed irrespective of the
occurrence and detection.
• Leave
L outt detection
d t ti and d jjustt llook
k att the
th product
d t off severity
it and
d
occurrence.
• A Risk Grid approach can be used to determine risk acceptance
(this is consistent with the automotive guidelines).
24
12
Relationship Between FMEA and RCA
• FMEA (risk analysis) is used to anticipate failures and add

mitigation before a failure occurs.
• Root Cause Analysis (RCA) is used to identify failure causes

after a failure (incident/event) has occurred.
• If risk analysis was performed and implemented correctly,

unanticipated incidents would not occur.
• When an incident occurs we should be able to look back at the

risk analysis (FMEA) and learn how we got it wrong so we can
i
improve th
the nextt time.
ti
• Therefore being able to relate FMEA and RCA is important.
• Compare the Causal Factor method to do RCA and FMEA.
25
FMEA and RCA
FMEA RCA
Failure Mode Product mix up

p Incident
Incorrect label
Failure Cause Causal Factor
Attached to drum
Reminder of what Causal Factors are:
Equipment failure(s), human error(s), or component failure(s) that

directly caused the incident, or allowed it to occur, or allowed the
consequences to be worse
26
13
A word regarding detection
• Detection can be a useful part of a control strategy.

• However, if not used judiciously, it can lead to over dependence on
detection as a means to control the quality of the process.
• This will lead to processes where quality is tested in (detected)
rather than being built into the process!
• Consequently, use the Poka-yoke approach for mistake proofing.

That is:
• Prevention first.
• Then, detection.
• In the FMEA context

• First reduce Severity (if possible)
• Then reduce Occurrence
• Then improve Detection
27
Recommended Actions and New Controls
Unit Recommend Action(s S O D R

S O D R
Process Operation Requirement/ Failure ed Action(s) ) Taken E C E P
Failure Mode Impact Controls E C E P
Step or CQA Cause V C T N
V C T N
Function
28
14
Example for an automobile…..
29
4. Assessing the Effectiveness of a

Control
1. Is it a Prevention Control vs a Detection Control?
2 Is it managed?
2.
3. Is it practical?
4. Is it being used?
5 Does the control introduce new failure modes?

5.
6. Do we have any evidence of overall effectiveness?
30
15
4. Prevention Control vs Detection
Control?
1. Imagine a PAT device that measures the weight of
product in every vial after it has been filled.
2. If the weight measurement is used to decide if the

weight is Out Of Specification and to then to discard
the vial, we have a Detection control (system).
3. If the weight measurement is used in a feedback

control loop to adjust the addition system if the
weights drifts up or down, we have a Prevention
control (system).
4. Which approach is better?

31
4. Is it Managed?
1. This means that there is a specific expectation in our

quality management systems to execute the control.
2. If the control is manual, is it in a procedure?
3. If the control is automatic, was it validated and is it re-

checked every so often?
4. Are the measurement systems managed (e.g. defined

calibration procedure)?
5. How much credit can we take for a control that probably

happens but does not have a specific expectation?
32
16
4. Is it Practical?
1. This means that is it reasonable to expect that the

control can be executed the way it was intended..
2. How many things can an operator monitor at the same

time. Is the procedure easy to follow?
3. Can an automated control react quickly enough?
4. Does a detection control look at a large enough sample

of the process?
5. Would it be easy to see if the control has not been done

correctly?
33
4. Does the control introduce new failure

modes?
1. This checks to see if a control has any unintended
consequences (e.g. high false rejects).
2. Do we assume that the control will always behave as

designed?
3. Does the control introduce any unsafe behaviors?
4. Could we become over-dependant on the control?
5. Do we have too many alarms/manual interventions in

our controls? Each on its own might be OK, but what
about the entire set?
34
17
4. Is it being used?
1. This checks to see if a control is actually being used.
2. Do we have anyy feedback that a control was used?
3. Could the control be “turned off” and we would not know

it?
4. Have we heard comments that a certain control is

difficult to use/of no value?
5. Does the control create more activities that might not be

seen as value added?
35
4. Do we have any evidence of overall

effectiveness?
1. This checks to see if we have any evidence of the
effectiveness of this control.
2. Are there any measures of false accepts/false rejects?
3. Do we have systems in place to regularly check the

effectiveness of a control?
4. Does our Root Cause Analysis process link back to the

controls?
5. How are we doing with deviations/losses/etc…
36
18
Length Available
for Crimping Frequency LSL Freq USL Freq
0 0 0.01 0 0.033 0
0.00040404 0 0.01 3335 0.033 3335
0.000808081 0
0.001212121 0 4000
0.001616162 0
0.002020202 0 3500
0.002424242 0
0.002828283 0 3000
0.003232323 1
0.003636364 1 2500
0.004040404 1
0.004444444 1 Frequency
2000
0.004848485 2 LSL
0.005252525 0 1500 USL
0.005656566 4
0.006060606 4 1000
0.006464646 4
0.006868687 8
500
0.007272727 15
0.007676768 14
0
0.008080808 17
0 0.005 0.01 0.015 0.02 0.025 0.03 0.035 0.04 0.045
0.008484848 26
0.008888889 28
0.009292929 29
0.00969697 54
0.01010101 58
0.010505051 101
0.010909091 83
0.011313131 141
0.011717172 149
0.012121212 194
0.012525253 223
0.012929293 257
0.013333333 361
0.013737374 398
0.014141414 430
0.014545455 556
0.014949495 611
0.015353535 728
0.015757576 881
0.016161616 951
0.016565657 1070
0.016969697 1207
0.017373737 1320
0.017777778 1633
0.018181818 1637
0.018585859 1862
0.018989899 1959
0.019393939 2151
0.01979798 2388
0.02020202 2493
0.020606061 2642
0.021010101 2751
0.021414141 2962
0.021818182 3083
0.022222222 3085
0.022626263 3271
0.023030303 3220
0.023434343 3324
0.023838384 3335
0.024242424 3327
0.024646465 3191
0.025050505 3255
0.025454545 3174
0.025858586 3063
0.026262626 2895
0.026666667 2928
0.027070707 2653
0.027474747 2464
0.027878788 2347
0.028282828 2143
0.028686869 2071
0.029090909 1861
0.029494949 1690
0.02989899 1502
0.03030303 1406
0.030707071 1200
0.031111111 1034
0.031515152 936
0.031919192 796
0.032323232 732
0.032727273 575
0.033131313 555
0.033535354 447
0.033939394 394
0.034343434 302
0.034747475 253
0.035151515 205
0.035555556 187
0.035959596 129
0.036363636 133
0.036767677 91
0.037171717 81
0.037575758 62
0.037979798 37
0.038383838 35
0.038787879 29
0.039191919 26
0.03959596 16
0.04 51
9/1/2011
The benefits and pitfalls of QRM
Siegfried Schmitt
Principal Consultant
© 2011 PAREXEL International |
Agenda
Ch ll
Challenges tto iimplementing
l ti QRM
The relationship between QRM and Quality by Design
1
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Detecting risks
A real example: A company designs and intends to

manufacture a blood glucose meter for diabetics.
Detecting risks
It can get complicated
2
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Engaging senior management
Resource allocation
Management appraisal and responsibilities
Defining the acceptable risk threshold
Quality Risk Management Maturity Level
PDA TR 44 Volume II draft (www.pda.org)
3
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Maintaining consistency of the implementation

across the entire organisation
Who performs risk assessments?

What is the purpose of risk management?
Some real examples:

•FDA inspection risks in Pakistan and Mexico
•Clinical material supply
pp y chain controls in Albania and Canada
What you cannot / must not do
Never reach a conclusion - real example: 5 years of risk

assessments without a single close-out
Conclude that a mandated regulation can be ignored - real

example: removal of Qualified Person release in Europe
4
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Benchmarking and competitive advantage
Benchmarking and competitive advantage
5
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Application to acquisitions and mergers
Application to supplier management
6
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Application to supplier management
The regulatory framework
7
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Knowledge Management & Process Control
8
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How to apply it to a new drug?
Classic approach: study a few process parameters, look at

the results, perform a risk analysis and define the control
strategy - anything missing?
Finding the right balance
9
9/1/2011
Reference
http://www.parexel.com/services-and-capabilities/consulting/strategic-compliance/
10
8/31/2011
The concept of QRM and its integration into the

quality management system
Siegfried Schmitt
Principal Consultant
© 2011 PAREXEL International |
Agenda
• Defining
D fi i Q Quality
lit LLevels
l and
dQQuality
lit MMetrics
ti
• The elements of the Quality System that define QRM
• Identifying the players - not just the Quality Unit
• From quality metrics to compliance dashboards
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8/31/2011
Introduction
Siegfried Schmitt, Ph.D.

Principal
p Consultant
PAREXEL Consulting
Siegfried.Schmitt@parexel.com
+44 7824 592401
•First applied
pp risk management
g in the late 80s in p
production
•Established quality systems for global operations for both,
medical devices and pharmaceuticals
•Technical editor of the PDA Technical Report on
“Implementation of QRM for Commercial Pharmaceutical and
Biotech Manufacturing Operations"
Everyone has implemented QRM - right?
Quality Risk Management pre-

determines acceptable risk levels
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8/31/2011
Defining Quality Levels and Quality Metrics
Oops... [www.who.int]
Defining Quality Levels and Quality Metrics
Is this a regulatory requirement?
Not explicitly:
The standard operating procedure (SOP) on Quality Risk
Management should define how the management system
operates and its general approach to both planned and
unplanned risk management.
management It should include scope
scope,
responsibilities, controls, approvals, management systems,
applicability, and exclusions. [www.mhra.gov.uk]
3
8/31/2011
A Real Example
A company manufactures biological products. Their process

controls will identify non-conforming product with near 100%
accuracy.
They destroy around 1/3 of their batches due to non-
conformances.
How would you describe their Quality Risk Management

System?
Understanding the present and the future
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8/31/2011
The elements of the Quality System that define QRM
Quality risk management encompasses far more than just risk

assessment:
It must be integrated into the quality system to support the
decision making process - and it can't be just an afterthought
It takes support from top management to establish a quality
risk management program. Top management needs to
approve the necessary resources, which include
infrastructure, communications and training
[The Gold Sheet December 2009]
Infrastructure includes:
•Quality standard
•A dedicated quality risk management organisation
•Business processes
•A libraryy of risk assessments
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8/31/2011
Communications systems are needed for:
•Reporting risks and accepting them

•Discussions with regulators
•Organisational change management
Training is required for:
•People at all levels of the organisation

•Not just the people doing the risk assessments but also
management
•Process and tools
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8/31/2011
Identifying the players - not just the Quality Unit
Identifying the players - not just the Quality Unit
[Gregg Claycamp PDA / FDA Quality System Conference]
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8/31/2011
There’s Quality and there’s the Business
Is it acceptable to link quality risk management with cost

saving measures?
The expectation of QRM is to assess risks to the medicinal
product and patient and manage these to an acceptable level.
It is appropriate for companies to assess their control systems
to implement the optimum controls to ensure product quality
and patient safety. If this can be achieved in a more cost
effective manner while maintaining or reducing risk to the
product and patient then this is acceptable. However
inappropriate risk assessment and mitigation in order to
achieve cost savings is not appropriate. [www.mhra.gov.uk]
The Quality Organisation
What is the task / purpose of the quality organisation?

Is the organisation aligned with the processes or vice-versa?
8
8/31/2011
From quality metrics to compliance dashboards
Should sites have a formal risk register and management

process?
Yes, a risk register (or equivalent title document) should list
and track all key risks as perceived by the organisation and
summarise how these have been mitigated. There should be
clear reference to risk assessments and indeed a list of risk
assessments conducted should be included or linked to the
register. A management process should be in place to review
risk management - this may be incorporated into the quality
management review process. [www.mhra.gov.uk]
Risk based compliance approach - top (Quality Manual) down

(site quality index)
Implementation of knowledge management - quality
information centre and repository
Management oversight - quality dashboards
Continuous improvement - standardised metrics
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8/31/2011
Compliance Risk
Compliance Risk is the combination of System Design &

System Performance
FDA Compliance
program Guidance Quality Systems
Manual - 7356.002
Management
Document Control * Lot Release *
Controls *
Deviation
Change Control * Validation *
Management / CAPA*
Quality System
Regulatory Agency
Training * Adverse Events
Submissions
Annual Product Technical
Audits
Review Complaints
F iliti &
Facilities
Facilities Equipment Environmental
Equipment System
Packaging &
Packaging & Labeling
Labeling System
Materials System Materials Management
Production Production
Laboratory Control
Out of Specification Stability Testing Testing
System
Quality System Risk Quantification
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8/31/2011
Companies need to measure performance

Competitiveness depends, amongst other criteria, on meeting
performance metrics
Selection, measurement and control of metrics is critical for
success
Metrics are dependent on scope:
• Number of products
• Monetary value of goods
• Number of countries / locations supplied
Metrics must be baselined, i.e. measurable
Compliance dashboard
Deliver
Staffing Q lit
Quality
y in full
Delivery Cost
Goals
on time
Training Safety Documents
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8/31/2011
Compliance
The fundamental purpose of performance

measurement is to encourage behaviour
that achieves the goals of the organisation
Reference - https://store.pda.org/bookstore
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8/31/2011
Reference - https://store.pda.org/bookstore
13

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8/12/2011

Quality by Design for the Development

` Quality by Design Highlights

` Quality by Design Highlights

A New Quality Paradigm

` Science and risk-based

Benefits of Quality by Design

Factors for Success

Value Proposition/Management Support

Timelines and Resources to Support QbD

Quality Target Product Profile and

` QTPP defines targets for product development

Knowledge Management System

` Quality by Design Highlights

Quality Target Product Profile

` Needs to be derived from the Target Product Profile

Working Outside of the R&D Bubble!

TPP Collaboration and Multiple Touch

Research and Clinical Development

` Marketing: A document describing how the intended

Source: Tebbey, Rink, Journal of Medical Marketing, Vol. 9, 4, 301-307

Finding Common Ground

Quality Target Product Profile

Yu, Understanding Pharmaceutical QbD presentation

Modified Release Solid Oral Product

Modified Release Solid Oral Product

Process Mapping: Ishikawa Fishbone

Hitoshi Kume, Statistical Methods for Quality

Ishikawa Fishbone Diagram – Helpful

Hitoshi Kume, Statistical Methods for Quality

Ishikawa Fishbone Diagram Example

Blending Milling Tableting

Meets Assay Specification

Process Mapping: Flow Down Map

Softgood Softgood Raw Material: Active pharmaceutical ingredient (API),

Hardgood Raw Material: Typically packaging components such

Flow Down Map Example

Process Map Definitions

Inputs Unit Operation Critical Outputs

Process Map Example

Benefits of Process Mapping Tools

Some Quality Risk Management Tools

USL Risk Register – Probability and

3 6 9 12 15 Medium 2 Non-critical quality attributes may not be

Example USL Risk Register

Qualitative “Stop Light” Tool Example

Cause & Effect Matrix

0 No Effect No Effect No Effect No Effect Total Weight

Class Exercise continued

` Quality by Design Highlights

ANDA Products - CMC

QbD Process Flow

ANDA Oral Solid Product Case

ANDA Quality Target Product Profile

Quality Target Product Profile: A prospective summary of

ANDA Flow Down Map

ANDA Risk Assessment Overview

ANDA Early Qualitative Risk

• Some aspects of the formulation are known at the

Analysis Pointed to Formulation and

ANDA Early Risk Assessment - Blending

ANDA Data Modeling

ANDA Packaging DoE

Benefits of analytical QbD and regulatory

Method validation and transfer a ‘check box’ exercise

Analytical Target Profile (ATP)

Method Operable Design Region (MODR)

Method Control Strategy

Prospective summary of the requirement of a measurement

Purity: The procedure must be able to quantify specified and

Evaluation of critical method attributes

Opportunities for Continuous Improvement

Analyte’s properties understanding

Include sample preparation and measurement