Validation RISK Criticality

Session 3
Validation, Risk and

Criticality
Presented by Trevor Schoerie
14 May, 2014
Validation, Risk and Criticality
“GAMP 5 – Risk Based ……”

“We talk about QRM every time we meet!”
• In process validation we want to

understand and control the variation
not the risk.
• The “drug” benefit vs risk should
have already been determined,
(hopefully).
Slide 2 © PharmOut 2014

“Process Variation”
1. Sample Variation
Is the sample representation of the batch?
2. Analytical Variation?
Blinded samples in lab = STD DEV
3. Process Variation – normally associate
Real process variation

This session
Using Risk to determine no of batches
Risk vs criticality

How we get to validation…..
No concurrent release of validation batches
• New Chemical Entity *Stage 1 data
• Generic manufacturer
• Contract manufacturer
• New manufacturing site – Tech. Transfer
• Country where validation is a new
requirement
• Expansion of regulations, i.e. export to
Australia
No retrospective validation
Typical validation NCE – Stage 2a/b?
Real life
Start
Registration /
QbD
How many PPQ batches?
FSE Training
QTPP Qualified Completed
Process PVMP
Description
CQAs/ Approved
PV
CPPs Analytical Protocols
Methods
Design SOPs &
Reports Batch
Records

Knowledge vs # of PV batches
Comprehensive Prior Knowledge may support fewer PV batches
Prior Knowledge Process Design PV
Limited Prior Knowledge may require more PV batches
Prior
Process Design PV
Knowledge

This depends on the risk and the following elements:
Based on science, experience and

justified (documented).
Based on statistics.

Step 1: Risk Level Acceptable
Risk Assessment of Product
Knowledge & Process
Understanding Stage 1
Assessment
Step 2:
Risk Assessment of Control
Strategy
Step 3:
Determine Overall Residual
Risk Stage 2
Activities
Prepare PPQ Batches
Step 4: Compare results to
Translate Overall Residual Acceptance Criteria
Risk into # of PPQ Batches
Reference ISPE
Risk Assessment of Stage 1
Product Knowledge Process Understanding
• Analytical understanding • Depth of understanding
of product structure unit operations
• Mechanistic • Level of knowledge of
understanding of product process response to input
profile variability
• Contextual understanding • Process predictability
of CQA’s • Understanding of scale
Control Strategy
Can use: • Application of
• Risk Charts process/product
• Relative level of understanding to
risk based on production controls Assess each CQA
RPN • Control of raw material
• Other QRM tools inputs
• Equipment capability vs
process requirements

Step 1: Risk Assessment of Product
Knowledge
Identification of CQA and impact of CQA

variation on patient:
• Level of understanding of product attributes
(i.e. how a particular attribute affects patient
safety & efficacy)
Product Characterisation:
• The strength of the link between the CQA
and clinical performance

Product Knowledge Risk Ranking
Product Relative Risk Ranking

Knowledge Characteristics of ranking assignments
Factor Low Risk Medium Risk High Risk
Identification of • Physiochemical/ • CQAs identified and • Product
CQA and impact biological, justified specifications
of CQA variation pharmacokinetic • Physiochemical/ established from
on patient knowledge, and QbD biological, development trial
approach used to pharmacokinetic and error
design the formulation properties identified • Impact of variation
of drug product • Some exploration of known only from
• Impact of variation on impact of variation evaluation of
bioavailability explored incidents
& understood
Product • Analytical method has • Analytical method • Product
Characterisation direct measurable development based characterisation
linkage to clinical on mechanism of measures quality
performance action for the against established
• Complete product therapeutic agent but empirical limits
linkage to clinical
performance

Process Understanding Risk Ranking
Process Relative Risk Ranking

Understanding
Factor
Characteristics of ranking assignments
Low Risk Medium Risk High Risk
Degree of -First principles -Casual knowledge: that -Descriptive
process understanding: based on based on what causes knowledge: derived
understanding/ an understanding of interrelationships only from observation,
unit operation prevailing mechanisms and between variables reflecting basic facts
rationale
Process -Models based on first -Use of models derived -Primitive models
predictably and principles from basic physical, reflecting only basic
modelling -Extension of empirical and chemical, biological or understanding of
mechanistic models microbial mechanisms of process and scale
-Highly predictable process observed phenomena effects
and scale-up -Sufficient knowledge to -Process predictability
employ PAT methods, if is questionable
applicable and desired
Table continued on the next slide

Process Understanding Risk Ranking
Process Relative Risk Ranking

Understanding
Factor
Low Risk Medium Risk High Risk
Process Response -Design space identified -Well-defined criticality -Partially defined,
to input variability using multivariate data and for process based on primarily through
statistical methods multivariative univariate
-Impact of material experiments experimentation
attributes on product -Impact of material -Impact of materials
quality explored extensively attributes on product attributes to product
in development quality explored to some quality are minimally
-Material specific CQAs degree explored
identified and well -Material specific CQAs -Materials specific CQAs
understood or no material identified-full range of not identified
specific CQAs variability not explored in
development
Effects of scale -Highly predictable-data -Predictable-data across -Unpredictable-Scale
across different scales can scales can be projected impact
be projected.

Knowledge & Process Stage 1
Understanding Activities
Assessments of
Product Knowledge
Step 2: and Process
Risk Assessment of Control Understanding
Strategy
Step 3:
Risk Stage 2 Activities
Prepare PPQ Batches
Compare results to
Step 4:
Acceptance Criteria
Translate Overall Residual

Step 2: Risk Assessment of Control
Strategy
Raw Materials • How the specifications were developed.
Specifications
Equipment Capability
• How easily the requirements for the process are
vs. Process accommodated by the manufacturing equipment.
Requirements
Experience with • How consistently the process has performed

Process Performance historically and during development studies.
Monitoring capability • How the process is monitored and variability is

& detectability detected

Control Strategy - Risk Ranking
Control Source of Relative Risk Ranking

Strategy Potential
Factor Variability and/or
Uncertainty Low Risk Medium Risk High Risk
Raw Material -Different suppliers; -Specifications of -Limited -Specifications are
Specifications different material attributes justification of not justified.
manufacturing impacting product specifications of -Compendial or
processes, quality based on material attributes supplier limits
-Material attributes development data accepted without
test method further
-Different batches investigation
-Basis for material
specification
-Specification wider
than experience


Strategy Potential
Factor Variability and/or
Uncertainty Low Risk Medium Risk High Risk
Equipment -Capability of -Comparison of -Comparison of -Comparison of
Capability vs. equipment to parameter control control ranges parameter control
from
Process -Control operating -Ranges from -Equipment -Ranges from
Requirements parameters within equipment qualification with equipment
acceptable ranges qualification with process qualification with
process requirements process
requirements indicates marginal requirements
indicates all capability to meet indicates a
parameters are requirements for a significant number
well within limited number of of parameters are
equipment control process similar to
capabilities and parameters equipment control
supported by capabilities
qualification data


Strategy Potential
Factor Variability
and/or Low Risk Medium Risk High Risk
Uncertainty
Experience -Variation -Underlying cause(s) for -Variation is managed -Variation has
with process observed variation is understood empirically, but been observed,
performance -Scaling & addressed (or underlying causes are but has not been
to date effects variation not observed not well understood successfully
Consistency during manufacture) -Some understanding managed
of past -Impact of scale is well of scaling issues -Impact of scale
performance understood -Minor departures changes has not
-Process has from expected results been explored
consistently performed that were investigated -Unexplained
as expected and satisfactorily failure has been
explained experienced
Monitoring -Ability of -Attributes measured in -Attributes measured -Attribute
capability & monitoring real time at a sensitivity off-line (after batch measurement
detectability tools & where performance completion) at a accuracy is
methods to variability is likely to be sensitivity where inadequate
detect observed performance is likely
variation to be observed

Stage 2
Knowledge & Process
Understanding
Stage 1
Activities
Step 2: Assessments of
Risk Assessment of Control Product Knowledge
Strategy and Process
Understanding
Step 3:
Prepare PPQ Batches
Compare results to
Step 4:
Acceptance Criteria

Step 3: Determine overall residual risk
The residual risk level reflects the confidence in

performance of the commercial process:
Residual Risk Description
Level
Severe Multiple factors have high risk ratings
(5)
High Few factors have high risk ratings or all have
(4) medium risk rating
Moderate Medium risk level for multiple factors or high risk
(3) level for one factor
Low Medium risk level for a few factors, the others are
(2) low risk
Minimal Low risk level for all factors
(1)

Knowledge & Process
Understanding
Stage 1
Assess
Step 2:
Risk Assessment of Control
Strategy
Step 3:
Prepare PPQ Batches
Compare results to
Step 4:
Acceptance Criteria

Step 4: Translate overall residual risk
into the number of PV Batches
1. Based on rationales and experience

2. Target Process Confidence and Target Process
Capability
• Statistical-includes measures of variability &
confidence level
3. Expected Coverage
• Statistical-includes measure of probability of
batch success rate
Note: Other approaches may be appropriate

How many PV batches?
Step 4:
Translate
Overall 2 Approaches to
Residual Risk Translate Overall
into # of Residual Risk into
PPQ Batches # of PV Batches
Approach 1: Approach 2:
Rationales and Target process
experience confidence &
target process
capability

Approach 1: Rationales and Experience
Residual Number of Rationale

Risk Level Batches
Severe Not Ready Encourage additional development to reduce risk level
(5) for PV
High 10 High # of consecutive successful batches unlikely if
(4) controls are not adequate
Moderate 5 Increased residual risk addressed by preparing 2
(3) additional PV batches to provide further
demonstration of process consistency
Low 3 Knowledge & Control Strategy regarded as sufficient.
(2) 3 PPQ batches has historically been appropriate for
demonstrating process consistency for many low-risk
processes
Minimal 1-2 Minimal residual risk with less than 3 PPQ batches
(1) required, e.g. for verifying specific controls associated
with a well-understood change to a process

Approach 2: Target process confidence
& target process capability
• Process Capability (CpK) is used as a measure of

the capability of the process to consistently meet
the quality requirements
• Assumption: CpK ≥1 as a starting point for

assessing the capability of a process undergoing
validation

• Used as a measure for level of confidence

needed in the CpK and thereby as a degree of
assurance
• High level of confidence in the CpK can be built

only with time and experience (during Stage 3)
• Residual Risk Level used to define the

confidence needed at completion of Stage 2.

Residual Target Comments
Risk Level Confidence
Severe (5) N/A Major gaps in knowledge & understanding.
Additional effort on product/process/control strategy
High (4) 97% development may be necessary. High confidence
level needed to provide high degree of assurance.
Moderate 95% Target confidence levels designed to provide

(3) reasonable assurance of process capability. Higher
Low (2) 90% confidence levels would be achieved during Stage 3.
Minimal (1) N/A High “confidence” based on existing understanding

and capability of control strategy. Does not require
additional assurance during PV beyond
demonstration that commercial systems and
procedures are appropriate.

Residual Risk Min # of Target Acceptance Criteria
Level batches Confidence
for CpK 1.0 Readily Pass Marginally Pass Fail
Calculated Calculated CpK Calculated CpK
CpK
Severe (5) Not Ready N/A

for PPQ
High (4) 11 97%
≥ 1.0
Moderate 8 95%
≥ 1.6 and < 1.0
(3)
< 1.6
Low (2) 5 90%
Minimal (1) 1-3 N/A
• Based on a Target CpK of 1.0 and an actual CpK of 1.6.

• May include clinical manufacture, demonstration, or other at-scale lots.
Assumes process will be under statistical control & data will show
normal distribution.

PPQ Outcome Pass / Fail Other Impact on Initial CPV
Considerations Sampling Approach*
Readily Pass Pass N/A Supports Stage 3 routine
calculated CpK sampling
Marginally Pass Pass All input/output Consider enhanced
calculated CpK parameters within monitoring for CQA’s not
range meeting “Readily Pass”
Fail calculated Investigate -Parameter values Consider enhanced
CpK -Intra-lot CpK monitoring; May include
-Probability of some testing beyond
detection PPQ.
-Process
improvement
options
*PPQ outcome is one consideration in establishing CPV Plan

This session
Using Risk to determine no of batches
Risk vs criticality

FMEA - recap
• Study the Failure Mode and Effect Analysis
• It involves reviewing as many

components, assemblies, and
subsystems as possible to identify
failure modes, and their causes and
effects.

Ishikawa – Cause and Effect Diagram

Quality Risk Management (QRM)
FMEA does not help identify sources of

variation
• This session will take a step back and look at the
basics
• We will ponder some topics:
• Is the “Criticality Assessment” a “Variability
Assessment” when discussing CQAs/CPPs for
Qualification & Validation activities?
• Do we throw out our innate understanding of the
hazard because we are “FMEA” driven?

ICH Q9 Quality Risk Management (&
Annex 20 of PIC/S PE 009-8)
• ICH Q9 explains the “What” of QRM [10 pages]
• Annex I of ICH Q9 provides concepts and ideas on the
“How to”-formal and informal [4 pages]
• Annex II of ICH Q9 details the potential “Where” of
QRM [5 pages]
• A “roadmap” is presented to us within the document,
but do we follow it for Qualification & Validation
activities?
• For example, do we make use of QRM tools other than
FMEA (or FMECA) effectively?

• Risk is defined as the Begin the QRM Process
combination of the Risk Assessment
probability of occurrence Risk Identification
of harm and the severity Risk Analysis

of that harm
• Harm: Damage to health, Risk Evaluation
including the damage that
Risk Communication
can occur from loss of
Risk Control
QRM
Risk Reduction
product quality or
Tools
availability. Risk Acceptance
• Severity: A measure of Output of the QRM Process
the possible consequences

of a hazard. Risk Review
Review Events

Wet Floor Broken Leg
(Hazard: The potential (Harm: Damage to health, including
source of harm) the damage that can occur from loss
of product quality or availability)
Severity: A measure of the possible

consequences of a hazard.
Risk is defined as the combination of the probability of occurrence of harm

and the severity of that harm

Deductive vs Inductive Reasoning
Deductive Inductive (forward logic)
?
Intoxicated?
Destroyed my car.
How did this happen? What will happen if I
drive?
FTA FMEA
STA PHA
C&E Analysis

Inductive Reasoning
Risk
Outcome Identification
Hypothesis Risk Analysis
Risk
Evaluation
Observation
Risk
Reduction
“Top-down"
“Think up”
Risk
Failures! Confirmation
Acceptance
More Proactive?

Deductive Reasoning
Risk
Acceptance Theory
Risk
Reduction
Tentative
Hypothesis
Risk
Evaluation
Risk Analysis Pattern
“Bottom-up"
“Narrow down”
Risk Failure!
Observation
Identification More Reactive?

Inductive vs Deductive QRM
QRM Tool Inductive Deductive “Complexity”
FMEA Yes No Medium

FMECA Yes No Medium
FTA No Yes High
HACCP Yes Yes Low
HAZOP Yes No Medium
PHA Yes No Low
Risk Ranking and Yes Yes Low
Filtering
Supporting Statistical Yes Yes Low
Tools

Appendix I: Risk Management Methods
& Tools
• General overview-references some primary tools
“It is important to note that no one tool or set of tools is

applicable to every situation in which a QRM procedure
is used”
FMEA FMECA FTA HACCP
Risk Ranking Supporting

HAZOP PHA
& Filtering Stats Tools

& Tools
QRM Tools Input Process Output
FMEA Relies on product Once potential failure Summarises modes of
& process modes are established, risk failure, factors causing
understanding. reduction can be used to these failures and the
Manageable eliminate, contain, reduce likely effects of these
process steps. or control the potential failures.
failures.
FMECA Relies on product Once potential failure The output of an FMECA
& process modes are established, risk is a relative risk “score”
understanding. reduction can be used to for each failure mode,
Manageable eliminate, contain, reduce which is used to rank the
process steps. or control the potential modes on a relative risk
failures. basis.
FTA System (or sub- Evaluates system (or sub- The output of an FTA
system) failures system) failures one at a includes a visual
time but can combine representation of failure
multiple causes of failure modes.
by identifying causal
chains.

Failure Mode Effects Analysis (FMEA)
Occurrence
Occurrence
Detection
Detection
Severity
Severity
Item or Potential Potential Potential Current Recommended Responsibility Action
RPN
RPN
process Failure Effect(s) Cause(s) Controls Action & Target Date Taken
Step Mode of Failure
FMECA: Extended to incorporate an investigation of the

degree of severity of the consequences, their respective
probabilities of occurrence and their detectability

& Tools
HACCP Product and It is a structured approach Risk management
process that applies technical & information that
understanding. scientific principles to facilitates monitoring of
analyze, evaluate, prevent, critical points not only in
and control the risk or the manufacturing
adverse consequence(s) of process but also in other
hazard(s) life cycle phases.
HAZOP All processes & It is a systematic As is the case with
safety hazards. brainstorming technique HACCP, the output of a
for identifying hazards HAZOP analysis is a list of
using so-called “guide- critical operations for risk
words”. management.
PHA Product, process 1) Identification, 2) Typically, hazards
and facility design Evaluation 3) Ranking, and identified in the PHA are
information 4) Remediation further assessed with
other risk management
tools such as those in this
section.

Preliminary Hazard Analysis (PHA)
• Early in the development: little information on design

details or operating procedures will often be a
precursor to further studies
• For product, process and facility design
• Further assessed with other risk management tools
Hazards Arising from Product Design
Hazard Investigation/ Severity Frequency Impact

Controls (S) (F) (SxF)

& Tools
Risk Risk ranking and Forms a single relative risk Risk ranking methods are
Ranking filtering can be score that can then be particularly helpful in
and used to prioritize used for ranking risks. situations in which the
Filtering manufacturing “Filters,” in the form of portfolio of risks and the
sites for weighting factors or cut- underlying consequences
inspection/audit by offs for risk scores, can be to be managed are
regulators or used to scale or fit the risk diverse and difficult to
industry. ranking to management or compare using a single
policy objectives. tool.
Supporting Statistical data They can enable effective Control Charts, Design of
Statistical data assessment, aid in Experiments (DOE),
Tools determining the Histograms, Pareto
significance of the data Charts, Process Capability
set(s), and facilitate more Analysis
reliable decision making.

Appendix II: Potential Applications for
QRM
In II.1: Integrated Quality Management
• To interpret monitoring data (e.g., to support an
assessment of the appropriateness of revalidation or
changes in sampling).
• To determine appropriate actions preceding the
implementation of a change, e.g., additional testing,
(re)qualification, (re)validation or communication
with regulators.

QRM
In II.4: Facilities, Systems & Equipment
• To determine the scope and extent of qualification of
facilities, buildings, and production equipment and/or
laboratory instruments (including proper calibration
methods).
• To determine acceptable (specified) cleaning
validation limits.

QRM
In II.4: Facilities, Systems & Equipment
To select the design of computer hardware and
software (e.g., modular, structured, fault tolerance);
To determine the extent of validation, e.g.,
• identification of critical performance parameters;
selection of the requirements and design;
• code review;
• the extent of testing and test methods;
• reliability of electronic records and signatures.

QRM
II.6 Production
• To identify the scope and extent of verification,
qualification and validation activities (e.g., analytical
methods, processes, equipment and cleaning
methods;
• To determine the extent for follow-up activities (e.g.,
sampling, monitoring and re-validation);
• To distinguish between critical and non-critical
process steps to facilitate design of a validation
study.

Uses in Qualification & Validation
QRM Tools Uses in Q&V
Tools
FMEA All Q&V Stages-prioritize potential risks and monitor the effectiveness
of risk control activities.
FMECA All Stages-Prioritize potential risks and monitor the effectiveness of
risk control activities. Understand the impact of detectability
FTA Establish the pathway to the root cause of the failure during Q&V. Is
useful both for risk assessment and in developing monitoring
programs as an output of Q&V.
HACCP Used to identify and manage risks associated with physical, chemical
and biological hazards (including microbiological contamination).
HAZOP This facilitates regular monitoring of critical points in the
manufacturing process. Used early in the design stage. Q&V input.
PHA Used early in the development of a project when there is little
information on design details or operating procedures; thus, it will
often be a precursor to further studies. Useful “first cut” for Q&V.
Risk Ranking Risk ranking is useful when management needs to evaluate both
and Filtering quantitatively-assessed and qualitatively-assessed risks within the
same organizational framework.
Stats Tools They can enable effective data assessment throughout Q&V activities

QRM vs Impact Assessment Example
“Top Down” End
Product carryover exceeds

Critical Quality Attributes
acceptance criteria
Critical Process Cleaning Agent

Parameters Concentration
System CIP System
Subsystem Chemical Addition
Component Chemical Feed Pump
End
“Bottom Up”
From ISPE GPG Applied Risk Management for C&Q
QRM vs Impact Assessment
Characteristics Impact Assessment Formal Risk

(Baseline® Guide 5) Assessment
“Top Down” or “Bottom Up” “Bottom Up” “Top Down”
Ability to identify specific process risks Low High
Ability to identify specific Critical Low High
Aspects
Ability to prioritise Qualification efforts Medium High
Cost in time and resources Medium High
Need for SMEs experienced in the tool Low High
to be used
Acceptability to regulators Medium High
Usefulness as “lifecycle” document in Low High
future
From ISPE GPG Applied Risk Management for C&Q

“Criticality” in Annex 15
• “It is a requirement of GMP that manufacturers

identify what validation work is needed to prove
control of the critical aspects of their particular
operations.”
• “The protocol should specify critical steps and
acceptance criteria.”
• “Evidence should be available to support and verify
the operating parameters and limits for the critical
variables of the operating equipment.”
• “Risk analysis: Method to assess and characterise
the critical parameters in the functionality of an
equipment or process.”

Going from QTPP to CQA
• We assume that during product

development the clinicians and
toxicologists have established that
these parameters are high risk to
the patient.
• So we are looking at reducing the
variability of these attributes.

Connecting a CQA to a CPP
• The manufacturer during product

development and based on prior
product and process knowledge
establishes that these process
parameters have a high impact on
variability.
• “Validation” looks at ways to provide
confidence that the variability is
controlled.
Ishikawa – Cause and Effect Diagram

The PharmOut “STIC-man”!
Summary Table from Ishikawa Criticality

Activity 3: QRM
Please assign a
Speaker/Scribe at
each table
Please complete the Blue Sheets as a

group and return them to us
If there are any

questions,
please ask!

Thank you for your time.
Questions?
Trevor Schoerie
Lead Consultant
trevor.schoerie@pharmout.net
www.pharmout.net

Validation RISK Criticality

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Session 3

Validation, Risk and

“GAMP 5 – Risk Based ……”

• In process validation we want to

Slide 2 © PharmOut 2014

Slide 3 © PharmOut 2014

Using Risk to determine no of batches

Slide 4 © PharmOut 2014

Slide 7 © PharmOut 2014

Comprehensive Prior Knowledge may support fewer PV batches

Prior Knowledge Process Design PV

Limited Prior Knowledge may require more PV batches

Slide 8 © PharmOut 2014

This depends on the risk and the following elements:

Based on science, experience and

Slide 9 © PharmOut 2014

Slide 12 © PharmOut 2014

Identification of CQA and impact of CQA

Slide 13 © PharmOut 2014

Product Relative Risk Ranking

Slide 14 © PharmOut 2014

Process Relative Risk Ranking

Table continued on the next slide

Slide 15 © PharmOut 2014

Process Relative Risk Ranking

Slide 16 © PharmOut 2014

Slide 17 © PharmOut 2014

Experience with • How consistently the process has performed

Monitoring capability • How the process is monitored and variability is

Slide 18 © PharmOut 2014

Control Source of Relative Risk Ranking

Slide 19 © PharmOut 2014

Control Source of Relative Risk Ranking

Slide 20 © PharmOut 2014

Control Source of Relative Risk Ranking

Slide 21 © PharmOut 2014

Slide 22 © PharmOut 2014

The residual risk level reflects the confidence in

Slide 23 © PharmOut 2014

Slide 24 © PharmOut 2014

1. Based on rationales and experience

Note: Other approaches may be appropriate

Slide 25 © PharmOut 2014

Slide 26 © PharmOut 2014

Residual Number of Rationale

Slide 27 © PharmOut 2014

• Process Capability (CpK) is used as a measure of

• Assumption: CpK ≥1 as a starting point for

Slide 28 © PharmOut 2014

• Used as a measure for level of confidence

• High level of confidence in the CpK can be built

• Residual Risk Level used to define the

Slide 29 © PharmOut 2014

Moderate 95% Target confidence levels designed to provide

Minimal (1) N/A High “confidence” based on existing understanding

Slide 30 © PharmOut 2014

Severe (5) Not Ready N/A

• Based on a Target CpK of 1.0 and an actual CpK of 1.6.

Slide 31 © PharmOut 2014

*PPQ outcome is one consideration in establishing CPV Plan

Slide 32 © PharmOut 2014

Using Risk to determine no of batches

Slide 33 © PharmOut 2014