This presentation summarizes the use of ASTM Standard E 2500 for Commissioning and Qualifications of Manufacturing Systems.

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2.  This presentation will cover
1. Overview of Quality Risk Management
Process
2. Application of ASTM Standard E 2500 in
Commissioning & Qualification.
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6. 6
 Individual: Risk is a cognitive and emotional
response to expected loss.
 Society: Risk is a societal expression of expected
harm tempered by expected benefits.
 Technical: Risk is usually based on the expected
value of the conditional probability of the event
occurring X the consequence of the event given that
it has occurred.

7.  Risk
◦ Combination of
◦ Probability of occurrence of harm and
◦ Severity of that harm.
 Harm
◦ Damage to Health including the damage that can
occur from the loss of Product Quality or
availability.
 Hazard : Potential Source of Harm

8.  Which consequence is more severe?
◦ 300 lives lost in single, fiery plane crash.
◦ 300 lives lost on roads over a weekend.
◦ 300 lives potentially lost from cancer within the next 20 years
 Which probability is probable?
What does a “30% chance of rain tomorrow” mean?
◦ 30% of the days like tomorrow will have at least a trace of rain.
◦ 30% of the area will have rain tomorrow.
◦ 30% of the time tomorrow, it will rain.

9. Hazard
may
cause harm
Hazard
may not
cause harm
uncertainty
Hazard
is less likely to
cause harm
Manage risks
in relation to
probability
Lack of, or inadequate knowledge

10. Time 
ProcessParameter
Lower Specification Limit (LSL)
Upper Specification Limit (USL)
today
Uncertainty
RISK: For a given severity of risk event, what are the chances
(probability) of exceeding the USL in the next period of time?
Tomorrow ?

11. Time 
ProcessParameter
Lower Specification Limit (LSL)
Upper Specification Limit (USL)
today
Uncertainty
RISK: Control options are scenarios for risk management. Note
that this scenario shows the best estimate is below the USL.
Tomorrow ?

12. Time 
ProcessParameter
Lower Specification Limit (LSL)
Upper Specification Limit (USL)
today
Uncertainty
Take a cut at a moment
in time:
Risk has a distribution.
Tomorrow ?

13.  Risk Identification
What might go wrong?
Risk Assessment
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Risk Review
RiskCommunication
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
Initiate
Quality Risk Management Process
Output / Result of the
Quality Risk Management Process
RiskManagementtools

14.  System Risk (facility & people)
◦ e.g. interfaces, operators risk, environment,
components such as equipment, IT, design elements
 System Risk (organisation)
◦ e.g. Quality systems, controls, measurements,
documentation, regulatory compliance
 Process Risk
◦ e.g. process operations and quality parameters
 Product Risk (safety & efficacy)
◦ e.g. quality attributes:
measured data according to specifications

15.  Risk Identification
What might go wrong?
 Risk Analysis
What is the likelihood (probability) it will go
wrong
 What are the consequences (severity)?
 Risk Evaluation
What is the level of risk? Any mitigating factors?
Risk Assessment
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Risk Review
RiskCommunication
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
Initiate
Quality Risk Management Process
Output / Result of the
Quality Risk Management Process
RiskManagementtools

17.  Risk Identification
What might go wrong?
 Risk Analysis
What is the likelihood (probability) it will go
wrong
 What are the consequences (severity)?
 Risk Evaluation
What is the level of risk? Any mitigating factors?
Risk Assessment
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Risk Review
RiskCommunication
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
Initiate
Quality Risk Management Process
Output / Result of the
Quality Risk Management Process
RiskManagementtools
 Risk Reduction
Mitigation or avoidance of quality risk
Elimination of risks, where appropriate
Risk Control
 Risk Acceptance
Acceptance of Residual Risk

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Start
End
Risk
identification
Risk
analysis
Etc.
Process-
step
Decision
Feedback
procedure
Start
End
Start
End
Sub-
process
Sub-Sub-
process

19. Should risks
be assessed?
Are there clear rules
for decision making?
e.g. regulations
Yes
“no RM“
Risk assessment not required
(No flexibility)
Follow procedures
(e.g. Standard Operating Procedures)
Document results,
decisions and actions
CONSIDERATIONS
1. What might go wrong?
2. What is the likelihood (probability)
it will go wrong?
3. What are the consequences (severity)?No or
justification needed
Can you answer
the risk assessment
questions?
Yes
“informal RM“
Initiate Risk assessment
(risk identification, analysis & evaluation)
Run risk control
(select appropriate measures)
Agree on a team
(small project)
Select a Risk Management tool
(if appropriate e.g. see ICH Q9 Annex I)
No
“formal RM“
Carry out the
quality risk management process
Document the steps
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21.  Supporting statistical tools
◦ Acceptance Control Charts (see ISO 7966)
◦ Control Charts (for example)
 Control Charts with Arithmetic Average and
Warning Limits (see ISO 7873)
 Cumulative Sum Charts; “CuSum” (see ISO 7871)
 Shewhart Control Charts (see ISO 8258)
 Weighted Moving Average
◦ Pareto Charts
◦ Process Capability Analysis
◦ Histograms
◦ Design of Experiments (DOE)
◦ Use others that you are familiar with….
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22.  Risk Assessment is not an “Exact
science”.
 There is no such thing as “Zero” “ Risk”
 What you need to decide is “ What is
acceptable Risk”
 Risk Management is not an “one off”
activity.

23. The evaluation of
the risk to quality
should be based on
scientific knowledge
and ultimately link
to the protection
of the patient
The level of effort,
formality and
documentation
of the quality risk
management process
should be
commensurate with the
level of risk
ICH Q9

24. Systematic process
for the
assessment,
control,
communication and
review
of risks to the
quality of the
drug (medicinal)
product
across the product
lifecycle
ICH Q9

25. Applications in Commissioning & Qualifications
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28.  Centered around Documentation
 Guidance was not Followed as intended
 Criteria not used to gain comprehensive
understating of the Product , Process and
System
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Scope and
Extent of
Qualification
If Everything is
critical then
nothing is

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31.  ASTM E 2500 -07
 A consensus standard based on sound
scientific, engineering and Quality Principles
 Focus on product & process design through
detailed requirements and mitigating risks in
the Design Phase
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32.  Focus on that which affects Product Quality
 Process User Requirements Key to
acceptability
 Risk Assessment and Process Knowledge
used to identify Critical Elements
 Only critical features/ functions are qualified
 Use of Supplier Documents
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33.  Science & Risk based approach to assure that
GMP Equipment & Systems are
◦ Fit for Intended Use
◦ Have been properly Installed
◦ Are Operating Correctly
 Extent of Verification & Level of Detail
◦ Risk to Product Quality
◦ Risk to Patient Safety
◦ Complexity & Novelty of Manufacturing System
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34.  Critical Quality Attribute
◦ Physical ,chemical, biological or
microbiological property that should be
within appropriate limit , range or distribution
to ensure desired product Quality
 Critical Process parameter
◦ A process parameter whose variability has an
impact on a critical quality attribute and
therefore should be monitored or controlled
to ensure process produces desired quality.
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35.  Critical Aspects are
◦ Functions, Features, abilities and
Performance & Quality Characteristics To
Ensure Consistent Product Quality &
Patient Safety
◦ Should be identified & documented based
on scientific product & process
understanding.
◦ Verification should focus on these aspects.
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ASTM E 2500 : System Life Cycle & Validation Approach

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ASTM E 2500 : System Life Cycle & Validation Approach

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ASTM E 2500 : System Life Cycle & Validation Approach

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ASTM E 2500 : Life Cycle Phases

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ASTM E 2500 : System Life Cycle & Validation Approach

41.  Step 1 : Planning and Documentation
 VMP
 Verification Team and Responsibilities
 Document Matrix
 Eligible Vendor Documentation
 Select Risk Assessment Tool
 FMEA can be used to Identify & Evaluate “CRITICAL ASPECTS” of a
Manufacturing System.
 Engineering Change Notification
 Process to document & approve modifications that occur during system
design , startup & Verification
 Applicability to regulatory laws & expectations must be justified

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42.  Step 2 : Identify Subject Matter Expert
 SME’s are responsible for Specifications,
Design & Verification
 Individuals with specific expertise &
responsibility in a particular area
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43.  Step 3 : Requirements Definition
 Process Engineering SME’s develop these
 Identify specific requirements
 Used further for Specifications, Design &
Verification
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44.  Step 4 : Risk Assessment
 SME’s conduct FMEA as a design review
 Identify “CRITICAL ASEPCTS” that affect
systems Installation , Operation and
Performance.
 Identify Control & Verification techniques to
manage risks to an acceptable levels
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45.  Step 5 : Specification & Design
 Leverage Qualified Vendor Expertise ( SME) to identify &
document elements which may affect Critical Quality
Attributes
 Communicate factors that impact product quality to the
system designer
 Strive to mitigate product quality & patient risks through
design
 Functional Specifications provide acceptance criteria for
functional tests specified in the verification plan
 SME’s translate URS into system description & functional
specification
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46.  Step 6 : Verification Plan
 Verify the critical Aspects of the
Manufacturing System
 Design
 Properly installed
 Operate correctly
 Are fit for intended use
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47.  Step 6 : Verification Plan consists of
◦ Inventory Verification List & Verification Test Matrix
 Inventory Verification List
 Identifies all necessary system design &
Verification documentation
 Serves as a Document acquisition checklist
 Contains : URS , FS, HSD , SDS , P & ID’s ,
Electrical & Mechanical Drawings , manuals, a risk
analysis report , Verification Testing Matrix ,
Verification Protocol & Report
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48.  Step 6 : Verification Plan consists of
 Verification Test Matrix
 Identifies Critical Testing based on Risk Levels, Design
Documentation & SME Input
 Identifies Chronological point when testing will be done
◦ Factory , Installation , Start up , Qualification
 NON CRITICAL ASPECTS are documented using the IVL
checklist .
 Do not require SME oversight or QA Personnel.
 CRITICAL ASPECTS require SME scrutiny & documented in
Verification Test Protocol
◦
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49.  Step 6 : Verification Plan consists of
 Verification Test Matrix
 Acceptance criteria are derived from
Functional Requirements in : URS & FS
 VTP lists test to mitigate High Risk aspects
 Tests to demonstrate system functionality,
features, capacity, and output quality.
 Critical Tests are generally executed only
once.
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50.  Step 6 : Verification Plan consists of
 Verification Test Matrix
 VTP contains only the critical testing
necessary to verify that
 A system is properly installed
 It operates correctly
 Fit for its intended use
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51.  Step 6 : Verification Plan consists of
 Verification Test Matrix
 VTP organizes testing as it pertains to
 Installation/ Utility Verification
 Startup/ Operation Verification
 Functional / Performance Verification
 These phases can be used to satisfy Annex
15 requirements.
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52.  Step 6 : Verification Plan consists of
 Verification Test Matrix
 The value of VTP is isolation of CRITICAL
TESTING needed to verify a system.
 CRITICAL TESTING is reviewed by SME & QA
 Other testing and documentation are moved
to IVL checklist.
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53.  Step 7 : Verification Plan Execution
 Verification Test Matrix identifies when testing
document acquisition for the IVL & VTP will
happen
 Testing may be performed as a part of FAT / SAT
protocols or
 Performed according to test functions within a
VTP
 Testing of NON CRITICAL ASPECTS is more simply
verified using IVL
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54.  Step 8 : SYSTEM Verification Report
 Reviews testing conducted during System Design
, Fabrication , Installation , Start Up &
Verification.
 Report is written by an Independent SME
 Independent review of protocol exceptions ,
deviations & punch list
 Summarizes system performance data
 Concludes whether the system is or is not FIT
FOR INTENDED USE
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55.  Step 9 : GMP Release
 Performed by QA
 QA verifies compliance with other other GMP
systems : Training , calibration , maintenance,
operating procedures & change Management.
 Step 10 : GMP operation & Change Management
 Modifications are controlled through Change
Management with focus on CRITICAL ASPECTS &
SYSTEM PERFORMACE
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ASTM E 2500

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Presentation prepared by Drug Regulations – a not for profit
organization. Visit www.drugregulations.org for the latest in
Pharmaceuticals.