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Quality
Risk Management
ICH Q9
Annex I: Methods & Tools
Disclaimer: This presentation includes the authors views on quality risk management theory and practice.
The presentation does not represent official guidance or policy of authorities or industry.
prepared by members of the ICH Q9 EWG slide 1 , May 18, 2006
• To guide through
Risk Management Methods and Tools
Chapter 5 Initiate
Quality Risk Management Process
& Annex I Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
unacceptable
Risk Reduction
Risk Acceptance
Risk Review
Review Events
Introduction
Use the
appropriate tool(s)!
No one tool is
“all inclusive”!
Initiate
Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
unaccept able
Ri skManagement tools
RiskCommunication
Risk Control
Risk Reduction
Risk Acceptance
Risk Review
Review Events
Annex I.1
Basic
Risk Management
Facilitation
Methods
• Pictorial representations
of a process
• Present information
in an efficient, clear format
Magnesium
• Process Stearate
Blending
Sieving
mapping
Tabletting
Packaging
Coating
F. Erni, Novartis Pharma
prepared by members of the ICH Q9 EWG slide 12 , May 18, 2006
Problem
statement
Equipment Measurement
System Methods
Equipment Measurement
System Methods
• Cause and
Punch Penetration HPMC
Depth Spray Pattern
Methoxyl
Plant
Tooling
Feed
Scrape Down
P.S.
Hydroxyl
P.S. Effect
Factors Frame LOD
Compressing
Chopper Speed Other Diagram
Endpoint
Mixer Speed Syloid
Lactose
Raw
for Tablet
Granulation
Coating
Materials Hardness
Power © Alastair Coupe, Pfizer Inc.
Time
prepared by members of the ICH Q9 EWG slide 17 , May 18, 2006
Annex I.2
Failure Mode
Effects Analysis
(FMEA)
How to perform?
Break down large complex processes into manageable steps
ICH Q9
prepared by members of the ICH Q9 EWG slide 19 , May 18, 2006
• 8 Regular failures
• Expected to happen regularly
• 4 Repeated failures
• Expected to happen in a low frequency
• 2 Occasional failures
• Expected to happen infrequently
• 1 Unlikely failures
• Unlikely to happen
8 Very High Failure could lead to adverse reaction for customer. Failure would create
noncompliance with GMP regulations or product registrations. Failure possible to
lead to recall. Financial: $500,000
7 High Failure leads to customer percept ion of safety issue. Failure renders individual
unit(s) unusable. Failure causes a high degree of customer dissatisfaction. Recall
for business reasons possible but Authority required recall unlikely. Financial:
$100,000
6 Moderate Failure causes a high degree of customer dissatisfaction and numerous
complaints. Failure unlikely to lead to recall. Financial: $50,000
5 Low Failure likely to cause isolated customer complaints. Financial: $10,000
4 Very Low Failure relates to non-dosage form issues (like minor packaging problems) and
can be easily overcome by the customer. Financial: $5,000
2 Very Minor Failure not readily apparent to the customer. Financial: <$1,000
6 Moderate: One occurrence every three months or three occurrences in 1,000 units (Cpk ~ 1.00 or
Occasional Failures ~ 3 σ).
5 One occurrence every six months to one year or one occurrence in 10,000 units (Cpk
~ 1.17 or ~ 3.5 σ).
4 One occurrence per year or six occurrences in 100,000 units (Cpk ~ 1.33 or ~ 4 σ).
3 Low: Relatively few One occurrence every one to three years or six occurrences in 10,000,000 units (Cpk
Failures ~ 1.67 or ~5 σ).
2 One occurrence every three to five years or 2 occurrences in 1,000,000,000 units
(Cpk ~ 2.00 OR ~6 σ).
1 Remote: Failure is One occurrence in greater than five years or less than two occurrences in
unlikely 1,000,000,000 units (Cpk > 2.00 OR >6 σ).
For batch failures use the time scale for unit failures use the unit scale. Dr. Gary Harbour, Pfizer
prepared by members of the ICH Q9 EWG slide 28 , May 18, 2006
3 High An effective SPC program is in place with process capabilities (Cpk) greater than
1.33.
2 Very High All product is 100% automatically inspected.
1 Almost Certain The defect is obvious and there is 100% automatic inspection with regular
calibration and preventive maintenance of the inspection equipment.
Existing controls: IPC of LOD and degradation product after drying process
Takayoshi Matsumura, Eisai Co
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S. Rönninger, Roche
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Detectability (D)
Detectability (D)
Risk reduction
Probability (P)
Probability (P)
Severity (S)
Severity (S)
Risk factor
Risk factor
[1<2<3<4]
[1<2<3<4]
(S*P*D)
(S*P*D)
[1<2<3]
[1<2<3]
[1<2<3]
[1<2<3]
Event Actions:
Sub-Step Effect Comments
(Failure mode) Risk reduction strategy
automatically interruption
not meet specification of by not meeting range;
W et seving Drying Temperature 2 4 1 8 implement 2 temperature measures 1 1 1 1 7
degradation Temperatur monitoring in
batch record
not meet specification of
Granulation Drying water content 2 3 1 6 introduce online NIR 2 1 1 2 4 indirect measurment
degradation
direct measurement; time
introduce IPC analytic 2 2 1 4 2
consuming
humidity measurement in the exausting indirect measurment;
2 1 2 4 2
air unspecifoc
operator knowledge;
depending on power
not meet specification of
Granulation kneeding time 3 3 1 9 reduce personnal fluctuation 3 3 1 9 0 consumption;
dissolution
automatisation not possible
at that time
depending on kneeding
not meet specification of try to get to a minumum an optimum of
Granulation power consumption 3 2 1 6 3 2 1 6 0 time depending on material
dissolution kneeding time
properties
not meet specification of
Pre-mixing mixing time 3 2 3 18 IPC measure on content uniformity 3 2 1 6 12 influence on efficacy
content uniformity
not meet specification of
Analyse (seeving of granulate sieve to get fine appropriate
Pre-mixing Granulation speed of adding water disolution and 3 3 3 27 3 2 1 6 21
analysis); use of dosage pumps granulate
desintegration
not meet specification of
to get fine appropriate
Pre-mixing Granulation manner of adding water disolution and 3 1 1 3 install spray nozzles 1 1 1 1 2
granulate
desintegration
Adapt internal specification of physical
all parameters have to be
Granulation Quality of Excipients 3 4 3 36 parameters (e.g. density, metability 1 2 2 4 32 contact supplier
re-evaluated
wetability)
Adapt internal specification of physical
all parameters have to be
Granulation Quality of API 3 4 3 36 parameters (e.g. density, metability 1 2 2 4 32 contact supplier
re-evaluated
wetatility)
Overview Risk before cotrol Max 36 Risk after control Max 9 32
Average 17 Average 4 10
Min 3 Min 1 0
S. Rönninger, Roche
prepared by members of the ICH Q9 EWG slide 37 , May 18, 2006
Risk factor
[1<2<3<4]
(S*P*D)
[1<2<3]
[1<2<3]
Event
Sub-Step Effect
(Failure mode)
Risk Reduction
Detectability (D)
Risk reduction
Probability (P)
Severity (S)
Risk factor
[1<2<3<4]
(S*P*D)
[1<2<3]
[1<2<3]
Actions:
Comments
Risk reduction strategy
Severity / Consequences
i negligible
Probability
ii marginal
iii critical
iv catastrophic
Risk
Probability protection
A frequent level
B moderate
C occasional
Consequences
D rare
E unlikely
F very unlikely
Picture: © Zurich Insurance Ltd, SwitzerlandS. Rönninger, Roche
prepared by members of the ICH Q9 EWG slide 39 , May 18, 2006
S. Rönninger, Roche
prepared by members of the ICH Q9 EWG slide 40 , May 18, 2006
S. Rönninger,
Roche
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S. Rönninger,
Roche
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Hi
g h
ris
k
Lo
w
ris
k
> For high risks, which are not acceptable, risk reduction
measures have to be taken as a high priority S. Rönninger, Roche
prepared by members of the ICH Q9 EWG slide 43 , May 18, 2006
• Ease of applicability
> Prospective tool
> Good tool for operators to use
> Can be used to identify critical steps for validation
> More objective than Fault Tree Analysis
> Covers minor risks
Annex I.3
Failure Mode,
Effects and Criticality
Analysis
(FMECA)
Annex I.4
Fault Tree
Analysis
(FTA)
ICH Q9
prepared by members of the ICH Q9 EWG slide 51 , May 18, 2006
http://www.sverdrup.com/safety/fta.pdf
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Root cause
• Root cause (= basic fault)
(e.g. part failure, software error, human error)
• Voting OR Gate:
m Fault occurs if “m” or more out of “n”
input faults occurs
Source: Overview of Risk Management Techniques. Robert C. Menson, PhD (2004).
prepared by members of the ICH Q9 EWG slide 55 , May 18, 2006
ICH Q9
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Out of specification
result or Lab error or systematic or Interfaces
or
or
Supply Too tightly
Change closing torque and
Defect Closed calibrate periodically
Takayoshi Matsumura, Eisai Co
prepared by members of the ICH Q9 EWG slide 58 , May 18, 2006
Annex I.5
Hazard Analysis
and Critical Control Points
(HACCP)
“A systematic, proactive,
and preventive method
for assuring product quality,
reliability, and safety“
WHO: http://www.who.int/medicines/library/qsm/trs908/trs908-7.pdf
Application of Hazard Analysis and Critical Control Point (HACCP)
methodology to pharmaceuticals, WHO Technical Report Series No 908,
Annex 7, WHO, Geneva, 2003
ICH Q9
prepared by members of the ICH Q9 EWG slide 62 , May 18, 2006
ICH Q9
prepared by members of the ICH Q9 EWG slide 64 , May 18, 2006
System to monitor
the CCP’s
Corrective actions,
if CCP is out of control
Joint
responsibility
Stakeholder involvement
Output / Results:
process described by HACCP
influence on specification of
speed 400'000 <400'000 fix parameter to adjust
appearance
by equipement online
fix parameter to adjust < contentuniformity out of range
(auto correcting) Batch Record
in fuction with the weight of the by equipement online
automatic ejection of tablet
tablet, thikness and hardness (auto correcting) Batch Record
analytical data in
+/- 10 % IPC on weight rejection (100% mass control)
Batch Record
online
compression force automatic ejection of tablet
Batch Record
release limit for stability must be
stability studies critical limit: min 50 N stability studies
braughter
online
optimisation during production IPC of appearance adjust mashine parameters
Batch Record
Annex I.6
Hazard Operability
Analysis
(HAZOP)
How to perform?
A systematic brainstorming technique
for identifying hazards using so-called “guide-words”
applied to relevant parameters:
> No, More, Other Than, None
ICH Q9
prepared by members of the ICH Q9 EWG slide 70 , May 18, 2006
• Manufacturing processes
ICH Q9
prepared by members of the ICH Q9 EWG slide 72 , May 18, 2006
High Steam heating z Feed material #1 z Diverse high temp. z Test interlock
temperature in control reaches interlock on on quarterly
blender malfunction decomposition blender basis
temperature z Blender vented z Add steam
z Violent reaction with heating control
toxic gas generation to monthly PM
z Personnel exposure/
injury
z Equipment damage
Annex I.7
Preliminary Hazard
Analysis
(PHA)
Annex I.8
Risk ranking
and
filtering
How to perform?
• Requires evaluation of multiple diverse quantitative and
qualitative factors for each risk
• Involves breaking down a basic risk question into as many
components as needed to capture factors involved in the
risk
• These factors are combined into a single relative risk score
that can then be compared, prioritized and ranked
ICH Q9
prepared by members of the ICH Q9 EWG slide 82 , May 18, 2006
Resources
classical approach 500
by multiplying factors
50 50 100 200
Probability 5 5 10 20
1: rare quality events
2: infrequent quality events 1 2 4
3. frequent quality events Probability
Based on J. Knöbel, S. Marrer, Roche
prepared by members of the ICH Q9 EWG slide 85 , May 18, 2006
Risk communication
• Providing stakeholders
with the update of the overview of Risk control step
Risk Review
• Regularly the responsible person
updates the overview to support line/senior
management decisions
Medium
Risk
High
Low
Risk Class ONE
Ranking
Medium
Risk Class THREE
Low
High
Low
ONE
TWO
LOW priority
THREE
Annex I.9
Supporting
statistical tools
Example
Potential Areas of Use(s)
• Statistical control of the process
ICH Q9
prepared by members of the ICH Q9 EWG slide 99 , May 18, 2006
S. Rönninger, Roche
prepared by members of the ICH Q9 EWG slide 102 , May 18, 2006
Assay
prepared by members of the ICH Q9 EWG slide 105 , May 18, 2006
Inlet temperature
> process variables
> explore potential interactions
Degradation Fines
Inlet humidity
Inlet humidity
Air flow
Air flow Air flow
prepared by members of the ICH Q9 EWG slide 107 , May 18, 2006
prepared by members of the ICH Q9 EWG slide 112 , May 18, 2006
different cp values
values statistically
13,58 % 0,27 % approx. 0
out of limit
values in the limit
86,42 % 99,73 % > 99,999999 %
process statistically
Result: process statisticaly under control
out of control
prepared by members of the ICH Q9 EWG slide 113 , May 18, 2006
Process
compatibility
Example
ICH Q9
prepared by members of the ICH Q9 EWG slide 115 , May 18, 2006
http://www.sytsma.com/tqmtools/Scat.html
prepared by members of the ICH Q9 EWG slide 116 , May 18, 2006
Others
Combination
of tools
prepared by members of the ICH Q9 EWG slide 117 , May 18, 2006
Combination of Tools
Probabilistic Risk Assessment (PRA)
• Integrating various reliability modelling tools
such as Fault Tree, Event Tree Block Diagram, FMEA
to numerically quantify risks
• Determine what quality risk scenarios can occur, what is
the likelihood and the consequences given they occur.
• Estimates of the parameters used to determine the
frequencies and probabilities of the various events
• It involves the development of models that
delineate the response of systems and operators to
accident initiating events.
http://www.relexsoftware.com/resources/riskassess.asp
prepared by members of the ICH Q9 EWG slide 118 , May 18, 2006
Combination of Tools
Probabilistic Risk Assessment (PRA)
How to perform?
• To identify an undesired top event
e.g. "loss of life" or "loss of mission“
• Trace out all quality risk that could lead to this events.
• Conducted through the use of event trees (fault trees)
• At the lowest level: basic events are assigned probabilities
• Propagated up the logic to reach a probability
prepared by members of the ICH Q9 EWG slide 119 , May 18, 2006
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Risk Reduction
Step 6 Risk Reduction
Measures Risk Acceptance
Management System
© by Zurich insurance company
prepared by members of the ICH Q9 EWG slide 122 , May 18, 2006
Conclusion
prepared by members of the ICH Q9 EWG slide 127 , May 18, 2006
Risk Assessment
Risk Identification
Risk Evaluation
Risk Management t ools
Risk Communication
unacceptable
Risk Acceptance
> Compare and prioritize risks with factors for each risk
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
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