Risk Assessment:
Use and Applications
in Pharma and Biotech Manufacturing
Operations
Geoff Pilmoor
Sims Moelich Associates
September 29, 2005
Agenda
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Risk
Risk assessment methods
Use and Trends
Operations
„ Regulatory Compliance
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Risk
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Combination of the probability of occurrence
of harm and severity of that harm (ISO/IEC
Guide 51)
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Initiate
Overall
Approach
Categorize Risk
Assess Risk
Communicate Risk
Accept or Manage
Risk
Monitoring,
Evaluation
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ICH Q9 – Quality Risk
Management Process
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5
Risk
Assessment
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Systematic process of organizing information
to support a risk decision to be made within a
risk management process (ICH Q9)
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Initiators
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Standard Procedure
Discrete event
Change in environment
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Categories
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Patient
Product
Process
Project
Business Continuity
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„
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Strategic
Financial
Reputation
…etc.
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Assess Risk
„
Identification / Listing of Potential Events
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Establish
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„
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Informal approach
Formal process
Severity of Impact of Event
Probability of Event Occurrence
Qualitative versus Quantitative
Consider
„
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Detection of Event can lead to Reduced Severity
Reliability of Detection
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Operational
Risk Tools
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Process mapping
HAZOP (Hazard and Operability Study)
FTA (Fault Tree Analysis)
FMEA (Failure Mode and Effect Analysis)
System impact & component criticality assessment
HACCP (Hazard Analysis and Critical Control
Points)
What if checklist
Scenario analysis
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HAZOP
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Generates a list of critical operations for risk
management
Team based, systematic brainstorming
technique
Assumes risk events are caused by deviations
from design or operating intentions
Considers “Guide words” against relevant
parameters to identify potential deviations
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HAZOP
Start
Explain
overall
design
Select
Section of
System
Explain
design
intent of
Section
Select
operating
condition
Select guide
word
Credible
deviation?
Y
Identify and
document causes,
consequences,
actions
N
N
Last
Section?
N
Y
Last
condition?
N
Y
Last guide
word?
Y
*Example Guide words:
Tabulate
and report
End
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*NO FLOW
*REVERSE FLOW
*MORE FLOW
*LESS FLOW
*MORE LEVEL
*LESS LEVEL
*MORE PRESSURE
*LESS PRESSURE
*MORE TEMPERATURE
*LESS TEMPERATURE
*COMPOSITION CHANGE
*CONTAMINATION
*CORROSION/EROSION
*SERVICE FAILURE
*ABNORMAL OPERATION
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FTA
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Generates a quantitative estimate of likelihood
of each failure mode of a system
Graphical depiction of all causal chains of
failure of a system or sub-system
Assumes failures follow from logical
combinations of causes that occur with known
probability
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Bulb
Fails
No
electricity
Power Plant
Fails
Wind Breaks
Line
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Power Line
Fails
Glass
Broken
Connector
Corroded
FTA
Filament
Broken
Impurities
Vacuum
Leak
Vibrations
Tree Breaks
Line
14
FTA Complexity
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Ranking &
Filtering
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Qualitative rating
Quantitative rating
Look-up table
Generally accepted rules / principles
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Qualitative
Probability
Occurrence
Probability
A) High
• Very likely will occur within a __ month/year
period
B) Medium
• Likely will occur within a __ month/year
period
C) Low
• May occur within a __ month/year period
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Qualitative
Severity
Classification
Interpretation
I) High
• Very significant negative impact (significant
long-term / catastrophic short term)
• Moderate negative impact over short to
medium term
II) Medium
III) Low
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• Minor negative impact over short term
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Qualitative
Classification
Risk Classification
Probability of Event Occurrence
Severity of
Event
High
High
Medium
Low
1
1
2
Medium
1
2
3
Low
2
3
3
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Qualitative
Prioritization
Event Priority
Likelihood of Detection
Risk
Classification
High
Low
Medium
High
1
1
2
Medium
1
2
3
Low
2
3
3
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Bio-process
Example
ess
p
Error
Area
Error
Item
What
happens to
product?
Likelihood
L, M, H
Severity
L, M, H
Risk
Classification
1,2,3
Probability of
Detection
L, M, H
Risk
Priority
L, M, H
Mitigation strategy
ing
SD
ment
Comp
AG
2101
Incorrectly
agitated
H
M
1
M
H
Alarm on agitator
T
2101
Incorrectly
held
L
H
2
H
L
No action
„Severity:
„Probability:
„Detectability:
„H
„H
„H
– Batch loss
„M – Batch Rework
„L - Minor
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– < 1 event per 250 runs
„M – 1 event per 2,500 runs
„L - < 1 event per 2,500 runs
– Each event
„M – 1 in 2 events
„L - ≤ 1 in 3
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Operations Reliability Example
Fluid leak from
Roof
Pipeline service in ceiling
Upper Mfg
Lower Mfg
Weigh
Outer RM Storage
Inner RM Storage
RO
Mechanical Room 1
Mechanical Room 2
Microbiology Lab
QC Lab
2nd Floor Washrooms
Mfg
B
C
Fluid leak from
Roof
Pipeline service in ceiling
Upper Mfg
Lower Mfg
Weigh
Outer RM Storage
Inner RM Storage
RO
Mechanical Room 1
Mechanical Room 2
Microbiology Lab
QC Lab
2nd Floor Washrooms
Mfg
2
4
D
C
D
C
5
4
5
4
Probability of Fluid leak into
Mfg 2
Fill
B
D
C
A
C
Pack
D
<
<
<
<
<
High
Probable
Low
Improbable
Not possible
C
C
B
C
D
D
Risk Index of Fluid leak into
Mfg 2
Fill
2
5
2
1
2
B
C
D
D
D
>
>
>
>
>
Mfg
III
III
IV
III
IV
III
Impact of Fluid leak into
Mfg 2
Fill
III
III
I
II
II
Pack
IV
II
II
II
III
III
III
IV
IV
IV
IV
IV
Pack
5
2
2
1
4
5
5
Catastrophic
Critical
Nuisance
Negligble
Not possible
Fluid leak from
Roof
Pipeline service in ceiling
Upper Mfg
Lower Mfg
Weigh
Outer RM Storage
Inner RM Storage
RO
Mechanical Room 1
Mechanical Room 2
Microbiology Lab
QC Lab
2nd Floor Washrooms
Catastrophic
Occurrence
High Probability
Probable
Low Probability
Improbable
1
1
2
3
Risk Classification
Critical
Nuisance
1
2
1
2
2
4
3
5
Negligible
4
4
5
5
4
5
5
5
5
„Severity:
„Cat
– Major portion of the business will be interrupted for one week or more
„Crit–
Crit– Small portion of business will be interrupted for one week or more,
more, or major
portion of business will be interrupted for up to one week.
„Nuis -Small portion of business interrupted for up to one week
„NegNeg-Small portion of business interrupted for up to one shift
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„Probability:
„H
–1 event per year highly likely
„M – 1 event per 3 years highly likely
„L - 1 event per 3 years may occur
„I – Likely will not occur in 3 years
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Impact / Criticality
Assessment
Non-critical
Critical
Components in Components in
Direct Impact Direct Impact
Systems
Systems
All Components in All Systems
Subject these
items to
Qualification
Non-critical Components in
Indirect Impact Systems
Non-critical Components in No
Impact Systems
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Impact & Criticality
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A system is generally determined to be direct impact if it:
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Produces an ingredient or excipient.
Has surfaces that direct contact with the product
Produces or delivers a gas or liquid that has direct contact with the product
Is used to clean or sanitize direct product contact surfaces of process equipment
Preserves product status (e.g. environmental control such as a freezer)
Produces data which is used to make Quality Operations decisions regarding product status
Is a process control system that may affect product SISPQ, which has no independent verification of
control system performance
A component is generally determined to be critical if it:
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Contacts the product or product components
Is used to demonstrate compliance with a registered process
Presents information that becomes part of a GMP record, is recorded on a GMP document or is
entered into as GMP data into a computer system
Has a direct affect on product quality during normal operation or control
Controls critical process elements that will affect product quality, where there is no independent
verification of control system performance
Provides an alarm for a condition that has a direct affect on product quality
Creates or preserves a critical status of a system
Has a direct affect on product quality if it fails
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API Facility Example
System
No.
System Description
Direct
Impact
In-direct
Impact
No
Impact
HVAC and CONTAINMENT SYSTEMS
AHU1
Manufacturing and storage area
9
FH01
Fume Hood 1
9
FH02
Fume Ho od 2
9
ISO1
Isolator
9
AHU2
Laboratory and offices
9
MECHANICAL and ELECTRICAL UTILITIES
9
N2
Gaseous nitrogen
BST
Building steam
9
CA
Compressed air
9
CH4
Natural gas
9
CWS
Chilled water
9
DCW
Domestic cold water
9
DHW
Domes tic recirculating hot water
9
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Response
to Risk
Significant
Risks
Communicate
to stakeholders
Do what?
Avoid
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Transfer
Mitigate
Accept
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Mitigation
of Risk
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Identify actions to:
Reduce probability of event
„ Reduce severity of event
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Provide early/more reliable detection and initiation of
response to event
Re-assess risk assuming actions, until
acceptable risk level is reached
Implement actions
Monitor and periodically re-assess
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HACCP
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Systematic, proactive (preventative) risk
management process
Facilitates monitoring of critical
manufacturing operations
Most useful when expert product, process
knowledge available
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HACCP
1.
Conduct hazard analysis; Identify preventive measures for each
step of process
2.
Determine critical control points (CCP)
3.
Establish (measurable) critical limits
4.
Establish system to monitor CCPs
5.
Establish corrective action to be taken when monitoring indicates
CCPs are not in control
6.
Establish system to verify HACCP system is working effectively
7.
Establish record-keeping system
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Operational
Trends
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Increasing use and internal acceptance of risk
assessment tools in managing efforts
Reliability
„ Efficiency
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Widespread collection and charting of
operational metrics
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Quantitative information available for risk
assessment, management
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Quality
Compliance
Risk Tools
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Standards / Definitions
Site Risk / Inspection Prioritization
Probabilistic Risk Assessment
Compliance guides
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Standards /
Definitions
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HPFBI Guide 23
Definitions
„ Classification Listings by Observation
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Regulatory
Trends
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Internal use of risk assessment tools in
managing efforts
International standardization, Quality Risk
Management
Increasing acceptance and use of Risk
Assessment in regulation of industry
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Site FDA
Inspection
Priority
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Quantitative approach
Rating above threshold, set based on limited
capacity
FY 2005 pilot project
Site Risk Potential
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Product Risk x Facility Risk x Process Risk
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FDA Site
Selection Model
„Site
Risk Potential
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„Top-Level
Components
„Product
„Process
„
„Categories
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of Risk Factors
„CD1
„CD2
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„Risk
„Facility
„CP2
„CP1
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„CF1
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„CF2
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Factors
„(quantitative
or
qualitative variables)
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FDA Risk
Factors
Product:
Process:
„Intrinsic
„Process
„Sterility
„Rx
or OTC
„Dose Form
Facility:
Control
„Product
type
„Unit Operation
„Contamination
„Recall
History
„Frequency
„Severity
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„History
„GMP
Violation
„Inspection
„Product
volume
Vulnerability
„Product
type
„Unit Operation
„Operation
type
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Future Trends ?
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Risk-Informed regulation of industry will
evolve (versus Risk Assessment)
Risk determinations quantitatively based
(versus qualitative basis)
Regulatory environment will facilitate
increased increased use of risk assessment and
management tools in operations
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Recap
„
Risk and Approach
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Applications and Examples
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Where to get more information
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Questions?
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References: Process Hazards
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CCPS, “Guidelines for Hazard Evaluation Procedures. Second
Edition with Worked Examples”, 1992
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WHO, “Application of Hazard Analysis and Critical Control
Point (HACCP) methodology to pharmaceuticals”
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WHO Technical Report Series, No. 908, 2003
ISO, “Safety of machinery -- Principles of risk assessment”
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ISBN 0-8169-0491-X
ISO 14121:1999
CSA, “Risk Analysis Requirements and Guidelines”
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CAN/CSA-Q634-91
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References: GMP, Regulatory
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HPFBI, “Risk Classification of GMP Observations, 2003
Edition”
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ICH, “Quality Risk Management (draft consensus guideline)”
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Guide-0023
Q9, 2005
FDA, “Risk-based Method for Prioritizing cGMP Inspections
of Pharmaceutical Manufacturing Sites – A Pilot Risk Ranking
Model”, 2004
FDA, “Quality Systems Approach to Pharmaceutical Current
Good Manufacturing Practice Regulations”, 2004
ASME, “Probabilistic Risk Assessment for Nuclear Power
Plant Applications”
„
RA-S-2002
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References: ISPE
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ISPE Baseline® Pharmaceutical and Engineering Guide,
“Volume 5 – Commissioning and Qualification”, First Edition
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Tran, Hasselbalch, Morgan, Claycamp, “Elicitation of Expert
Knowledge about Risks Associated with Pharmaceutical
Manufacturing Processes”
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Pharmaceutical Engineering, Jul/Aug 2005
Phoenix, Andrews, “Adopting a Risk-Based Approach to 21
CFR Part 11 Assessments”
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Pharmaceutical Engineering, Jul/Aug 2005
Coburn, Levinson, Weddel, “A Precedent for Risk-Based
Regulation”
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ISPE, Mar. 2001
Pharmaceutical Engineering, Jul/Aug 2003
GAMP Forum, “Risk Assessment for Use of Automated
Systems Supporting Manufacturing Processes”
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Pharmaceutical Engineering, May/Jun 2003
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Contact the
Speaker
„
Geoff Pilmoor
905.849.1833 x413
Sims Moelich Associates
277 Lakeshore Road E., Oakville, ON
L6J 1H9
Geoff.Pilmoor@SimsMoelich.com
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