Tools - Applications PDF

Annex I: Methods & Tools
ICH Q9 QUALITY RISK MANAGEMENT
Purpose of this part
Quality
Risk Management
ICH Q9
To guide through
Risk Management Methods and Tools
Give an aid by providing key principles on the theory of the
tools
Give some examples and methods of use
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.
July 2006, slide 1
prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance
Chapter 5
& Annex I
Introduction
Initiate
Quality Risk Management Process
Risk Assessment
The purpose of this annex is to provide a general overview

of and references for some of the primary tools
that might be used in quality risk management
by industry and regulators.
Risk Identification
Risk Analysis
Risk Evaluation
Risk Control
Risk Reduction
Risk Acceptance
Risk Management tools
unacceptable
Risk Communication
July 2006, slide 2
The references are included as an aid to gain more

knowledge and detail about the particular tool.
The list of tools is not exhaustive.
It is important to note that no one tool or set of tools
is applicable to every situation in which a quality risk
management procedure is used.
Output / Result of the

Risk Review
Review Events
ICH Q9
July 2006, slide 3
July 2006, slide 4
5. Risk Management Tools
CONSIDERATIONS
Contributing items to manage quality risks

System Risk (facility & people)
> e.g. interfaces, operators risk, environment,
components such as equipment, IT, design elements
Use the
appropriate tool(s)!
System Risk (organisation)

> e.g. Quality systems, controls, measurements, documentation,
regulatory compliance
No one tool is
all inclusive!
Process Risk
> e.g. process operations and quality parameters
Product Risk (safety & efficacy)
Initiate
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Communication
Risk Reduction
Risk Acceptance
Ri sk Management tools
unacceptable
Risk Control

Risk Review
Review Events
July 2006, slide 5
> e.g. quality attributes:

measured data according to specifications
July 2006, slide 6
Disclaimer: The ICH Q9 briefing pack is offered as a supplementary explanation of the material in ICH Q9. It was prepared by some members of
the ICH Q9 EWG for example only. It has not gone through any ICH formal process. It does not represent an official policy/guidance.
ICH Q9 Briefing pack II, July 2006, page 1
EXAMPLE
Choose the right tool for the task: An example
A possible aid
where to use
methods / tools
general
Basic
Risk Management
Facilitation
Methods
detail
System Risk System Risk Process Risk Product Risk

(facility & people) (organisation)
Risk ranking & filtering

Failure mode effect analysis
Hazard analysis and critical
control points
Process mapping
Flow charts
Statistical tools
Check sheets
Annex I.1
X
X
X
(safety & efficacy)
X
X
X
X
X
X
X
X
July 2006, slide 7
July 2006, slide 8
I.1: Basic risk management facilitation methods

Flowcharts
Flowchart
Check Sheets
Start
Process mapping
Activity
Cause and Effect Diagrams (Ishikawa / fish bone)
Pictorial representations
of a process
Activity
They might be helpful to support risk identification
Decision
No
Action
Breaking the process

down into its
constituent steps
Yes
Result
July 2006, slide 9
July 2006, slide 10
Check sheets
Process mapping
The indicators may be selected based on unit operations
Present information
in an efficient, clear format
Shows how they are interrelated
May be accomplished with

a simple listing of items
Provides a clear and simple visual representation

of involved steps
Potential Areas of Use(s) / outcomes
Facilitates understanding, explaining and systematically

analyzing complex processes and associated risks
A pre-requisite for the use of some other tools
ICH Q9
July 2006, slide 11
July 2006, slide 12
EXAMPLE

Air
Dispensing
Granulation
Magnesium
Stearate
Process
mapping
Fluidized Bed
Dryer
Sieving
Scale
Environment
Air
People
Materials
Blending
Sieving
Problem
statement
Tabletting
Packaging
Coating
Measurement
System
Equipment
Methods
F. Erni, Novartis Pharma

July 2006, slide 13
July 2006, slide 14
To associate multiple possible causes with a single effect

Constructed to identify and organize possible causes for it
How to perform?
Define and agree a precise problem statement
(put as head of fish bone) Think What could be its
causes? for each node
Add it to the fish bone diagram
For each line pursue back to its root cause
Consider splitting up overcrowded sections bones
Consider which potential root
causes and the need for
further investigation on them
Primary branch: represents the effect

Major branch:
corresponds to a major cause
Minor branch:
correspond to more detailed causal factors
Environment
Equipment
July 2006, slide 15
Materials
Measurement
System
Problem
statement
Methods
July 2006, slide 16
EXAMPLE
EXAMPLE

Coating
Spray Rate
Drying
Temperature
RH
Temperature
Operator
Training
Mill Speed
Precompressing
Temp
Press Speed
Spray Rate
P.S.
Scrape Down
HPMC
Methoxyl
Hydroxyl
P.S.
LOD
Chopper Speed
Other
Mixer Speed
Syloid
Lactose
Endpoint
July 2006, slide 17
P.S.
Process Conditions
LOD
Spray Pattern
Tooling
Feed
Frame
Power
Time
Coating
Granulation
Tablet
Hardness
Age
Binder
Feeder Speed
Method
Drug
Substance
Water
Main Compressing
Compressing
C. Kingery, The Six Sigma Memory Jogger II
Other
Sampling
Porosity
Shock Cycle
Punch Penetration
Depth
Plant
Factors
Screen Size
Air Flow
Atomizing Air Pressure
Temp/RH
Analytical
Temp
Time
Milling
Gun Distance
Operator
Milling
Redrying
Pan Speed
People
Raw
Materials
Cause and
Effect
Diagram
for Tablet
Hardness
Alastair Coupe, Pfizer Inc.

July 2006, slide 18
Annex I.2
I.2: Failure Mode Effects Analysis (FMEA)

(see IEC 60812)
Evaluation of potential failure modes for processes

The likely effect on outcomes and/or product performance
Failure Mode
Effects Analysis
(FMEA)
Once failure modes are established,

risk reduction can be used to
eliminate, reduce or control the potential failures
FMEA relies on process understanding
Summarize the important modes of failure, factors causing
these failures and the likely effects of these failures
How to perform?
Break down large complex processes into manageable steps
ICH Q9
July 2006, slide 19
July 2006, slide 20
EXAMPLE
How to perform?
1. Establish a team
2. Identify the known and potential failure modes:
RNP: Risk Priority Number C. Kingery, The Six Sigma Memory Jogger II
Potential Areas of Use(s)

Prioritize risks
Monitor the effectiveness of risk control activities
Equipment and facilities
Analyze a manufacturing process
to identify high-risk steps or critical parameters
> Product not meeting specification

> Process not meeting yield requirements
> Malfunctioning equipment
> Software problems
ICH Q9
July 2006, slide 21
Develop lists of known problems and brainstorm other

potentials
e.g.
Newly identified failure modes should be added at any time

EXAMPLE
How to perform?
3. Characterise the severity, probability and detectability
4. Define actions
An equal number of levels is sometimes helpful
5. Revisit the ranking
> Some preference to 3, 4, 5, 6 or 10 levels
6. Define residual risk
> But: an even number of levels avoids the mid point
7. Perform a short summary
Use different scales

1, 2, 3, 4
> Exponential:
1, 2, 4, 8
> Logarithmic:
1, 10, 100, 1000
> Self made:
1, 3, 7, 10
The aim is to come

up with a method
of prioritising
> Scope
> Data from the assessment & control
(e.g. No. of identified failure modes)
> Level of accepted risk without actions i.e. residual risk

(e.g. Risk priority Number < 50)
> Recommended actions, responsibilities and due dates

(including approval, if appropriate)
> Person in charge for follow-up of FMEA
Multiplying different scales will differentiate the outcome

EXAMPLE
How to perform?
> Linear:
July 2006, slide 22
July 2006, slide 23
July 2006, slide 24
EXAMPLE
Severity (Consequences of failure)

10 Extreme
Expected to happen regularly
7 High
Predicted to cause significant impact on quality (Failure to meet
specifications, no Stability data, Expert Statement possible)
4 Repeated failures
Expected to happen in a low frequency
2 Occasional failures
3 Moderate
Expected to happen infrequently
Predicted to cause minor impact on quality (Failure to meet

specifications, Stability data available)
1 Unlikely failures
1 Low
Unlikely to happen
Predicted to have no/minor impact on quality of the product

(Quality within specifications)
July 2006, slide 25

EXAMPLE
Normally not detected

Failure very likely to be overlooked, hence not detected
(no technical solution, no manual control)
Likely not detected

Failure may be overseen
(manual control, spot checks)
Regularly detected
Failure will normally be detected
(manual control, routine work with statistical control)
EXAMPLE
FMEA: Quantitation of Risk : Severity
Detectability (Ability to find the failure)
July 2006, slide 26
EXAMPLE
8 Regular failures
Predicted to cause severe impact to quality (Product out of

specifications, no Expert Statement possible)
Probability (Likelihood failure will happen)
Always detected
Failure can and will be detected in all cases
(monitoring, technical solution available)
10
Dangerously High
Extremely high
Failure could lead to death or permanent injury to the customer. Financial:

>$1,000,000
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
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
Moderate
Failure causes a high degree of customer dissatisfaction and numerous

complaints. Failure unlikely to lead to recall. Financial: $50,000
Low
Failure likely to cause isolated customer complaints. Financial: $10,000
Very Low
Minor
Very Minor
None
Failure could lead to injury to the customer. Failure would create non-compliance
with registered specifications. Failure likely to lead to recall. Financial: $1,000,000
Failure relates to non-dosage form issues (like minor packaging problems) and
can be easily overcome by the customer. Financial: $5,000
Failure could be noticed by the customer but is unlikely to be perceived as
significant enough to warrant a complaint.
Failure not readily apparent to the customer. Financial: <$1,000
Failure would not be noticeable to the customer. Financial: none
Dr. Gary Harbour, Pfizer
July 2006, slide 27
EXAMPLE
FMEA: Quantitation of Risk : Probability

10
Very High: Failure is

almost inevitable
More than one occurrence per day or a probability of more than three occurrences in
10 units (Cpk < 0.33 or <1).
10
Absolute
Uncertainty
Very Remote
One occurrence per week or a probability of 5 occurrences in 100 units (Cpk ~ 0.67
or ~2 ).
Remote
Very Low
One occurrence every three months or three occurrences in 1,000 units (Cpk ~ 1.00 or
~ 3 ).
Low
One occurrence every six months to one year or one occurrence in 10,000 units (Cpk
~ 1.17 or ~ 3.5 ).
Moderate
One occurrence per year or six occurrences in 100,000 units (Cpk ~ 1.33 or ~ 4 ).
Moderately High
One occurrence every one to three years or six occurrences in 10,000,000 units (Cpk
~ 1.67 or ~5 ).
High
One occurrence every three to five years or 2 occurrences in 1,000,000,000 units

(Cpk ~ 2.00 OR ~6 ).
Very High
One occurrence in greater than five years or less than two occurrences in
1,000,000,000 units (Cpk > 2.00 OR >6 ).
Almost Certain
High: Repeated
failures
7
6
One occurrence every month or one occurrence in 100 units (Cpk ~ 0.83 ~2.5 ).
Moderate:
Occasional Failures
Low: Relatively few

Failures
2
1
Remote: Failure is
unlikely
For batch failures use the time scale for unit failures use the unit scale.
EXAMPLE
FMEA: Quantitation of Risk: Detection
One occurrence every three to four days or a probability of three occurrences in 10

units (Cpk ~ 0.33 or ~1 ).
July 2006, slide 28
The product is not inspected or the defect caused by the failure is not detectable.
Product is sampled, inspected, and released based on Acceptable Quality Level
(AQL) sampling plans.
Product is accepted based on no defects in a sample.
Product is 100% manually inspected in the process.
Product is 100% manually inspected using go/no-go or other mistake-proofing
gauges.
Some Statistical Process Control (SPC) is used in the process and product is final
inspected off-line.
SPC is used and there is immediate reaction to out-of-control conditions.
An effective SPC program is in place with process capabilities (Cpk) greater than
1.33.
All product is 100% automatically inspected.
The defect is obvious and there is 100% automatic inspection with regular
calibration and preventive maintenance of the inspection equipment.

July 2006, slide 29
July 2006, slide 30
EXAMPLE
Severity / Probability / Detection (SPD)
EXAMPLE

Drying Process
Severity (S)
> Link to end product functional failure
> Medical Department involvement
Probability (P)
> Use historical data
> Similar processes products
Detection
> Method validation studies
> Historical data
PhD R.C. Mendson, Menson & Associations, Inc

ICH EWG London, March 2004
Takayoshi Matsumura, Eisai Co.
July 2006, slide 31
EXAMPLE
Severity (S)
EXAMPLE

Drying Process

Drying Process
Ranking
July 2006, slide 32
Detection (D)
Probability (P)
10
Death
More than once a day
Impossible to detect
3 4 times a day
Remote
Permanent injury
Once a week
Very slight
Once a month
Slight
Temporary injury
Once in three month
Low
Once in half one year
Medium
Reported/ dissatisfied Once a year
Once in 1 3 years
High
Notice/ no report
Once in 3 5 years
Very High
Less than once in 5 years
Virtually certain
Process
Potential Failure Mode
Potential Cause
1.
Set up
contamination
2.
Start drying
contamination
damage of inlet-air filter
degradation of product
damage of thermometer
RPN
unstable supply-air volume

damage of timer
(LOD)
Moderately high
low LOD
high dew-point
non-uniformity of LOD
uneven temperature distribution
RPN: Risk Priority Number = S*P*D

Takayoshi Matsumura, Esai Co
Takayoshi Matsumura, Esai Co

July 2006, slide 33
July 2006, slide 34
EXAMPLE

Drying Process
Potential Failure Mode
Potential Cause
RPN
disheveled gown of operator
120
insufficient cleaning of
equipment
112
126
1.
Set up
contamination
2.
Start drying
contamination
degradation of product
63
3.
Maintain
temperature
long drying time
40
high LOD
malfunction of timer
low LOD
high due-point
27
non-uniformity of LOD
uneven temperature distribution
45
Existing controls: IPC of LOD and degradation product after drying process
Takayoshi Matsumura, Eisai Co
EXAMPLE

Drying Process
Process
Process
insufficient cleaning of equipment
long drying time

3.
Maintain
high Loss On Drying
temperature
July 2006, slide 35
1.
Set up
2.
Start drying
3.
Maintain
temperature
Potential Cause
RPN
Recommended Action
120
use long gloves and goggles
S P D RPN
3 2 8
48
insufficient cleaning of
equipment
112
change cleaning procedure
7 2 4
56
126
change maintenance period
7 2 6
84
63
change calibration period
7 2 3
42
40
40
2 4 5
malfunction of timer
2 2 2
high dew-point
27
3 3 3
27
uneven temperature
distribution
45
3 5 3
45
Take action when RPN is over 100

Take action when severity is over 5
Remaining critical parameters after taking action; further controls required
Based on Takayoshi Matsumura, Esai Co.
July 2006, slide 36
Predicted to cause significant impact to quality (failure to meet specifications)

Predicted to cause minor impact to quality (failure to meet specifications)
Predicted to could have minor impact on quality of the product (quality within specifications)
Expected to happen frequently
Could happen occasionally
Expected to happen infrequently
Unlikely to happen
May overlook a fault or failture possibly can not be detected (no technical solution up to now)
Failture may be missed (manual control, routinely work with statistical control)
Failture can and will be detected (e.g. using statistical tools)
S. Rnninger, Roche
July 2006, slide 37

EXAMPLE
I.2 Failure Mode Effects Analysis (FMEA)

Detectability (D)
[1<2<3]
Risk factor
(S*P*D)
water content
not meet specification of

degradation
Severity (S)
[1<2<3]
Effect
Risk factor
(S*P*D)
Risk reduction
Severity (S)
[1<2<3]
implement 2 temperature measures
Granulation Drying
water content

degradation
introduce online NIR
indirect measurment
introduce IPC analytic
humidity measurement in the exausting

air
Granulation
kneeding time

dissolution
Granulation
power consumption

dissolution
Pre-mixing
mixing time
Pre-mixing Granulation
speed of adding water

content uniformity
disolution and
desintegration
reduce personnal fluctuation
try to get to a minumum an optimum of

kneeding time
direct measurement; time

consuming
indirect measurment;
unspecifoc
operator knowledge;
depending on power
consumption;
automatisation not possible
at that time
depending on kneeding
time depending on material
properties
18
IPC measure on content uniformity
12
influence on efficacy
27
Analyse (seeving of granulate sieve

analysis); use of dosage pumps
21
to get fine appropriate

granulate
install spray nozzles
Adapt internal specification of physical

parameters (e.g. density, metability
wetability)
32
contact supplier
32
contact supplier
9
4
1
32
10
0
Pre-mixing Granulation
manner of adding water

disolution and
desintegration
Granulation
Quality of Excipients
all parameters have to be

re-evaluated
36
Granulation
Quality of API
all parameters have to be

re-evaluated
36
Overview
Comments
Risk before cotrol
Max
Average
Min
36
17
3
Adapt internal specification of physical

parameters (e.g. density, metability
wetatility)
Risk after control
Max
Average
Min
to get fine appropriate

granulate
S. Rnninger, Roche
July 2006, slide 38
EXAMPLE
Severity / Consequences
i
ii
iii
iv
Severity (S)
[1<2<3]
Probability (P)
[1<2<3<4]
Detectability (D)
[1<2<3]
Risk factor
(S*P*D)
Risk reduction
Risk Reduction
introduce online NIR
introduce IPC analytic
humidity measurement in the exaust air
Comments
indirect measurment
direct measurement; time
consuming
indirect measurment;
unspecific
S. Rnninger, Roche
July 2006, slide 39

negligible
marginal
critical
catastrophic
Probability
A
frequent
B
moderate
C
occasional
D
rare
E
F
Risk
protection
level
Consequences
unlikely
very unlikely
Picture: Zurich Insurance Ltd, SwitzerlandS. Rnninger, Roche
July 2006, slide 40

EXAMPLE
EXAMPLE
Risk Evaluation
Prepare a risk profile: Probability
> Prepare a risk profile: Consequences
S. Rnninger,
Roche
S. Rnninger, Roche
Probability (P)
[1<2<3<4]
Temperature
automatically interruption
by not meeting range;
Temperatur monitoring in
batch record
Actions:
Risk reduction strategy
Prepare a risk profile
Probability (P)
[1<2<3<4]
Event
(Failure mode)
Actions:
Risk reduction strategy
W et seving Drying

degradation
Risk Assessment
Granulation Drying
Effect
Sub-Step
Risk Reduction
Event
(Failure m ode)
Sub-Step
Probability
Severity (Consequences):
3: high
2: moderate
1: minor
Probability
4: regular failures
3: repeated failures
2: occasional failures
1: failure is unlikely
Detectability
3: probably not detected
2: occasionaly not detected
1: detectable
Risk Assessment
Detectability (D)
[1<2<3]
because only a few parameters are adjustable and many

problems can occur by manual operations
EXAMPLE
Risk factor
(S*P*D)
Analyse a granulation process step
Severity (S)
[1<2<3]
Probability (P)
[1<2<3<4]
EXAMPLE
Detectability (D)
[1<2<3]
Failure Mode Effects Analysis (FMEA)
July 2006, slide 41
July 2006, slide 42
EXAMPLE
EXAMPLE
Risk Evaluation
Risk Evaluation: Risk Profile
> Prepare a risk profile: Consequences
Hi
gh
Lo
w
S. Rnninger,
Roche
July 2006, slide 43

EXAMPLE
> For high risks, which are not acceptable, risk reduction
measures have to be taken as a high priority
S. Rnninger, Roche
EXAMPLE
QRM for facilities, equipment and utilities
Assess an existing compressed air system
3. Summary (Risk Evaluation)
> Old approach: 60 risks should have been solved in detail
> The effects are rated in terms of their

consequences and the
causes are assessed in terms of their probabilities
a) qualitative or b) quantitative
> Initial RM-Approach:
4 sessions in total 16 people

153 potential risks discussed
34 Cases beyond the action limit
30 Corrective actions have been performed (- 50%)
> Based on these results a risk profile is completed.

> In this profile the risks are compared with the
risk protection level, which determines the accepted
probability for defined consequences
> Review of RM-Approach after inspection

Did you consider this hazard?
- yes:
- yes, but
- no:
> Use as an aid to prioritise actions!

S. Rnninger, Roche
July 2006, slide 45
show and explain rationale

start discussion for a yes/no decision
revisit initial risk assessment
July 2006, slide 46

EXAMPLE
Experiences
Experiences
EXAMPLE
Limitations
Ease of applicability
>
>
>
>
>
Can be time and resource consuming

Mitigation plans must be followed up
Not a good tool for analysis of complex systems
Compound failure effects cannot be analyzed
Incorporating all possible factors requires a thorough
knowledge of characteristics and performance of the
different components of the system
> Successful completion requires
expertise, experience and good team skills
> Dealing with data redundancies can be difficult
Based on Takayoshi Matsumura, Esai Co
> 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
July 2006, slide 44
How to perform?
ris
k
ris
k
July 2006, slide 47
July 2006, slide 48
Annex I.3
I.3: Failure Mode, Effects and Criticality Analysis (FMECA)

(IEC 60812)
Extended to incorporate an investigation

of the degree of severity of the consequences,
their respective probabilities of occurrence and
their detectability
Failure Mode,
Effects and Criticality
Analysis
(FMECA)
The product or process specifications should be

established
Identify places where additional preventive actions
may be necessary to minimize risks
Utilized on failures and risks associated with manufacturing
ICH Q9
processes
July 2006, slide 49
July 2006, slide 50
Annex I.4
I.4: Fault Tree Analysis (FTA)

(IEC 61025)
Fault Tree
Analysis
(FTA)
Assumes failure of the functionality of a product or

process
Identifies all potential root causes of an assumed failure or
problem that it is thought to be important to prevent
Evaluates system (or sub-system) failures one at a time
Can combine multiple causes by identifying causal chains
ICH Q9
July 2006, slide 51
July 2006, slide 52
EXAMPLE

How to perform?
Basic symbols: Basic Flow
Results are represented pictorially

in the form of a tree of fault modes
At each level in the tree, combinations of fault modes are
described with logical operators (AND, OR, etc.)
ICH Q9
http://www.sverdrup.com/safety/fta.pdf
July 2006, slide 53
FAULT
Fault in a box indicates

that it is a result of previous faults
OR
Connects preceding fault

with a subsequent fault
that could cause a failure
AND
Connects two or more faults

that must occur simultaneously
to cause the preceding fault
Source: Overview of Risk Management Techniques. Robert C. Menson, PhD (2004).
July 2006, slide 54
EXAMPLE
EXAMPLE
Basic symbols: End Points & Connector
Additional Symbols
Root cause
Exclusive OR Gate:
Fault occurs
if only one of the input faults occurs
Root cause (= basic fault)

(e.g. part failure, software error, human error)
Priority AND Gate:

Fault occurs
if all inputs occur in a certain order
Fault to be further analyzed

with more time or information if needed
Transfer-in and transfer-out events
Voting OR Gate:
Fault occurs if m or more out of n
input faults occurs

July 2006, slide 55

July 2006, slide 56
EXAMPLE
Investigation of laboratory failures

Establish the pathway to the root cause of the failure
outlier
Production
While investigating complaints or deviations to fully

understand their root cause
Out of specification
result
or
Lab error
or
others
systematic
random
Calibration
or
Interfaces
other
Ensure that intended improvements will fully resolve the

issue and not lead to other issues
Evaluating how multiple factors affect a given issue
ICH Q9
July 2006, slide 57
July 2006, slide 58
EXAMPLE
Hard to open
Experiences
Better as a retrospective tool
or
Visually focused: aid for showing linkages

Cap
Production
or
Formulation
Bottle
Packaging
Solidify
or
Supply
Defect
Too tightly
Closed
>
>
>
>
>
>
and
Bad fit
Processing
Limitations
Stability
Ageing
Change closing torque and

calibrate periodically
Only as good as input

Time and resource consuming (needs FMEA as a complement )
Need skilled leader to focus on what is really important
Need significant amount of information
Human errors may be difficult to predict
Many potential fault trees for a system
- Some more useful than others
- Need to evaluate contribution
Takayoshi Matsumura, Eisai Co
July 2006, slide 59
July 2006, slide 60
EXAMPLE

FMEA
FTA
Assumes
failure of the
functionality of a
product
Assumes
component failure
Identifies the root cause Identifies functional failure

as a result of component
of functional failure
failure
Top down
Annex I.5
Hazard Analysis
and Critical Control Points
(HACCP)
Bottom up
July 2006, slide 61
July 2006, slide 62
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
July 2006, slide 63
EXAMPLE

Initiate
HACCP
Facilitates monitoring of critical points in the

manufacturing process
ICH Q9
July 2006, slide 65
Team focused
Responsibility:
giving site
Hazard Analysis
Identify
preventive measures
Determine critical
control points (CCPs)
Target levels &
critical limit(s)
Risk Communication
Useful when process understanding is sufficiently

comprehensive to support identification of critical control
points (critical parameters / variables)
Risk Assessment
Risk Control: Critical Control Points

System to monitor
the CCPs
Corrective actions,
if CCP is out of control
unacceptable
Risk Ma nagement tool: HACCP
To identify and manage risks associated with physical,

chemical and biological hazards (including microbiological
contamination)
Site change
or
Technical
transfer
Internal consultation
See WHO
July 2006, slide 64
Stakeholder involvement
How to perform?
1. Conduct hazard analysis: identify preventive measures for
each step of the process
2. Determine critical control points (CCPs)
3. Establish target levels and critical limit(s)
4. Establish system to monitor the CCPs
5. Establish corrective actions to be taken, if CCP is out of
control
6. Establish verification procedures, that HACCP works
effectively
7. Establish documentation of all procedures and keep
ICH Q9
records
Joint
responsibility
Output / Results:
process described by HACCP
Risk Review
Verification that
process works effectively
Responsibility:
receiving site
July 2006, slide 66
EXAMPLE
Analyse a tablet process step

because a systematic, proactive, and preventive risk assessment
method helps to adjust parameters of the machine
Automatic maschine without constant operator control
Quality hazard
influence on specification of
appearance
Critical Control Point

(CCP)
speed
Target
level
Critical
limits
400'000
<400'000
fix parameter to adjust
15 kN
13-18kN
in function with the weight of the

tablet, thickness and hardness
200 mg
180-220 mg
EXAMPLE

System to monitor Possible corrective actions,
CCP
if CCP is out of control
Comments
by equipment
(autoimmunisation)
online
Batch Record
in function with the weight of the by equipment

tablet, thickness and hardness
(autoimmunisation)
automatic ejection of tablet
online
Batch Record
+/- 10 %
rejection (100% mass control)
analytical data in
Batch Record
automatic ejection of tablet
online
Batch Record
Comments
IPC on weight
compression force
influence on specification of hardness compression force
influence on specification of assay
weight variation
Keeping records
< content uniformity out of range
fix parameter to adjust
release limit for stability must be
stability studies
critical limit: min 50 N
stability studies
adjust machine parameters
online
Batch Record
+/- 10 %
optimisation during production
July 2006, slide 67
IPC of appearance
July 2006, slide 68
Annex I.6
Experiences
Benefit
Hazard Operability
Analysis
(HAZOP)
> Teamwork in cross functional groups

> Use very similar principles in Qualification & Validation
> Critical control points (CCPs) are similar to
critical process parameters
Limitations of the model

> Has to be combined with another tool (e.g. FMEA, statistical tools)
> Not good for complex processes
> Assumes you know the processes
> Most CCPs should be addressed for risk control activities
> May need to use other models for quantifying risk
July 2006, slide 69
I.6: Hazard Operability Analysis (HAZOP)
(IEC 61882)
Concept
A theory that assumes that risk events are

caused by deviations from the design or operating
intentions
Focus team discussions

by applying deviations to specific nodes
Identify potential deviations from normal use
Deviations are generated

by applying Guidewords to process parameters
How to perform?
A systematic brainstorming technique
for identifying hazards using so-called guide-words
applied to relevant parameters:
Examine the process by discussing causes of each

deviation
> Identify consequences
> Evaluate risk and safeguards
> Make recommendations, if necessary
> No, More, Other Than, None
Include all parts of the process

ICH Q9
July 2006, slide 70
July 2006, slide 71
Source: Hazard and Operability Studies in Solid Dosage Manufacture. Nail L. Maxson. (2004).
July 2006, slide 72

Guidewords

Manufacturing processes
Explanation
The total absence of the
function
No part of the function is active, but also

nothing else happens
MORE
Quantitative increase
This applies to quantities & properties such as

flow, temperature, and also for functions such
as heating and reacting.
or
Equipment and facilities
LESS
Quantitative decrease
AS WELL AS
Qualitative increase
or
Evaluating process safety hazards

Primarily as starter of a HACCP
Qualitative decrease
REVERSE
The logical reverse of the

desired function
This applies mainly to functions, e.g., reverse

flow or reversible chemical reaction. It can also
be applied to materials, e.g., poison instead of
antidote, or D- instead of L- optical isomer.
OTHER
Total exchange
The original function is not performed.

Something totally different happens.
ICH Q9
July 2006, slide 73

EXAMPLE
High
temperature in
blender
Causes
Steam heating
control
malfunction
Consequences
z Feed material #1
reaches
decomposition
temperature
Nail L. Maxson. (2004).
July 2006, slide 74
Deviation
All desired functions & operations are achieved.

Additionally, something else happens. Only a
few functions are achieved, some not.
PARTIALLY
Operator error (use error)
Remarks
NONOT
NONE
Safeguards
Recommend
z Diverse high temp.

interlock on
blender
z Test interlock
on quarterly
basis
z Blender vented
z Add steam
heating control
to monthly PM
z Violent reaction with

toxic gas generation
z Personnel exposure/
injury
Experiences
Ease of applicability of the model?
> Simplifies decision making
> Allows uniformity of analysis across sites
> Process steps guided (guide words, if available)
Limitations of the model

>
>
>
>
>
z Equipment damage
Applies to specific situations only

May need to use other models for quantifying risk
Not a structured approach
Not designed for quantifiable risk assessment
Complex output
Nail L. Maxson. (2004).

July 2006, slide 75
July 2006, slide 76
Annex I.7
I.7: Preliminary Hazard Analysis (PHA)

(ISO14971)
Analysis based on applying prior experience or knowledge

of a hazard or failure to identify future hazards, hazardous
situations and events that can cause harm
Preliminary Hazard
Analysis
(PHA)
In estimating their probability of occurrence for a given

activity, facility, product or system
How to perform?
Identification of the possibilities that the risk event happens
Qualitative evaluation of the extent of possible
injury or damage to health that could result
Identification of possible remedial measures
July 2006, slide 77
ICH Q9
July 2006, slide 78
EXAMPLE

The steps
Risk Matrix Form
> List known
potential hazards
- Literature
- Previous projects
- Reportable events
- Complaints
Hazards Arising From Product Design

Hazard
Investigation/
Controls
EXAMPLE
Sev
Freq
Imp
(SxF)
Hazards Arising From Product Design

Investigation/
Controls
SOPs,
Crosscheck
Hazard
Wrong Material
Lack of stability Stability studies
Sev
Freq
Imp
Sev
Rem
Min
Occ
Severity rankings
Frequency codes and estimates risk codes
Once established should remain same for similar product
classes
July 2006, slide 79
July 2006, slide 80
Annex I.8

Analyzing existing systems
Prioritizing hazards
Evaluate the types of hazards for the general product
type, then the product class and finally the specific
product
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
Risk ranking
and
filtering
ICH Q9
July 2006, slide 81
July 2006, slide 82
I.8: Risk ranking and filtering
Compare and prioritize risks

How to perform?
Requires evaluation of multiple diverse quantitative and
qualitative factors for each risk
To prioritize manufacturing sites for inspection/audit by

regulators or industry
Involves breaking down a basic risk question into as many

components as needed to capture factors involved in the
risk
Helpful in situations in which the portfolio of risks and the

underlying consequences to be managed are diverse and
difficult to compare using a single tool
These factors are combined into a single relative risk score

that can then be compared, prioritized and ranked
ICH Q9
July 2006, slide 83
Useful when management needs to evaluate both

quantitatively and qualitatively assessed risks within the
same organizational framework
ICH Q9
July 2006, slide 84
EXAMPLE
EXAMPLE

Evaluation of products and processes with recurring quality
relevant problems
Risk assessment: Risk identification
Risk assessment: Risk evaluation

Three columns
based on a
classical approach
by multiplying factors
> recurring quality relevant problems within

production and/or processes
Risk assessment: Risk analysis

Footing on an analysis of
> Production problems 1999-2002
> Complaints 2000-2002
> Investigation Reports 2000-2002
> Recalls 2000-2002
> Additional information from manufacturer considered
Probability
1: rare quality events
2: infrequent quality events
3. frequent quality events
Resources
Evaluation of products and processes with recurring

quality relevant problems
500
500
1000
2000
50
50
100
200
10
20
Probability
Based on J. Knbel, S. Marrer, Roche
J. Knbel, S. Marrer, Roche

July 2006, slide 85
July 2006, slide 86
EXAMPLE
EXAMPLE

relevant problems

relevant problems
Analyze production problems
Risk evaluation added to production problems
Site
Product name
Type of recurrent problem/defect
Site
ABC
ACB
BAC
CAB
Broken units
Broken tablets
Melt backs during lyophilization
Foreign particles
Product
name
Type of recurrent
problem/defect
Probability
Resources
A
B
C
A
A
B
C
ABC
ACB
BAC
4
2
4
500
500
50
CAB
Broken units
Broken tablets
Melt backs during
lyophilization
Foreign particles
50

July 2006, slide 87
Risk (Probability
multiplied with
Resource)
2000
1000
200
100
July 2006, slide 88
EXAMPLE
EXAMPLE

relevant problems

relevant problems
Risk assessment: Risk Control
Risk control actions added to production problems

Site
Product
name
Type of
recurrent
problem/defect
ABC
Broken units
ACB
Broken tablets
BAC
Melt backs
during
lyophilization
CAB
Foreign
particles
Corrective
actions
instituted to
date
Task force
headed by
Investigations in
B initiated
Investigating
process improvements
together with
production
Project initiated
Probability
Resources
500
2000
500
1000
50
200
Analyze process problems
Risk (Probabili
multiplied with
Resources)
Process
Printing of Variable Data
Products concerned
ABC
ACB
BAC
CAB
CBA
Blister: blister foil peels off
ABC
ACB
BAC
50
100
CAB
July 2006, slide 89

July 2006, slide 90
EXAMPLE
EXAMPLE

relevant problems

relevant problems
Risk assessment: Risk Control
Risk evaluation added to process problems

Process
Products
concerned
Missing prints of Variable Data
ABC
ACB
BAC
CAB
CBA
ABC
ACB
BAC
CAB
Resources
4
4
4
4
4
2
2
2
2
500
50
50
5
500
500
50
50
50
Risk
(Probability
multiplied with
Resources)
2000
200
200
20
2000
2000
100
100
100J. Knbel, S. Marrer, Roche
July 2006, slide 91
Process
Products
concerned
Missing prints of
Variable Data
ABC
ACB
BAC
CAB
CBA
ABC
ACB
BAC
CAB
Blister: blister
foil peels off
Corrective
actions
instituted to
date
Project started,
corrective
measures under
discussion
Task force
established
Probability
Resources
4
4
4
4
4
2
2
2
2
500
50
50
5
500
500
50
50
50
Risk
(Probability
multiplied with
Resources)
2000
200
200
20
2000
2000
100
100
100J. Knbel, S. Marrer, Roche
July 2006, slide 92
EXAMPLE
EXAMPLE

relevant problems
Risk Matrix (1)
Providing stakeholders
with the update of the overview of Risk control step
Low
Risk
Ranking
Risk communication
Medium
Severity
Probability
Regularly the responsible person

updates the overview to support line/senior
management decisions
Risk Class ONE
Risk Class TWO
High
Risk Review
High
Blister: blister foil peels off
Risk control actions added to process problems
Probability
Medium
Risk Class THREE
Low

July 2006, slide 93

EXAMPLE
Annex I.9
High
Low
Medium
Detection
Risk Matrix (2)
Risk Classification
July 2006, slide 94
Risk
Filtering
Takayoshi Matsumura, Eisai

HIGH priority
MEDIUM priority
Supporting
statistical tools
ONE
TWO
LOW priority
THREE
Takayoshi Matsumura, Eisai

July 2006, slide 95
July 2006, slide 96
I.9: Supporting statistical tools

Control charts (ISO 7870)
Control Charts (for example):

> Shewhart Control Charts (see ISO 8258)
Indicates the range of variability that is built into a system
> Control Charts with Arithmetic Average and Warning Limits

(see ISO 7873)
Shows statistically determined upper and lower control

limits drawn on either side of the process average
> Acceptance Control Charts (see ISO 7966)
The bounds of the control chart are marked

by upper and lower control limits
> Cumulative Sum Charts (ISO 7871)

> Weighted Moving Average
Design of Experiments (DOE)

Pareto Charts
Process Capability Analysis
ICH Q9
Aid for:
- Effective data
assessment
- Aid in determining
the significance of
the data set(s)
July 2006, slide 97
> Calculated by applying statistical formulas to data

> Data points that fall outside these bounds represent
variations due to special causes
> Can be found and eliminated
Improvements require changes in the process
ICH Q9
July 2006, slide 98

Control Chart: Shewhart Control Charts (ISO 8258)
Control charts
Use warning limits
Analysis trend patterns
Monitoring critical parameters

Provides information to determine
> Process capability
> Variability
> Control
Some charts are dealing with
warning limits or trend analysis
Example
Example

Statistical control of the process
ICH Q9
July 2006, slide 99
ICH Q9
Control Charts with Arithmetic Average and Warning Limits

(ISO 7873)
Control Chart: Acceptance Control Charts (ISO 7966)

Chart with a central line
within an acceptable
process zone
A control chart with

warning and action limits
Ideal the average

should be the
target value
Enable a base period of quality measure
Provide a basis for the construction of relationships between a

process and product quality
During regular batch manufacturing can give guidance for

determine sample size, action limits and decision criteria
Producing recommendations for the adjustment of the process

Can be applied with process Analytical technology tools
July 2006, slide 100
ICH Q9
Ongoing improvements under process robustness/six sigma

program can be initiated
ICH Q9
EXAMPLE
Compilation of limits and ranges
Control Charts: Cumulative Sum Charts (ISO 7871)

Sum of deviations from the mean or predefined value and
plot against time or number of occurrences (e.g. V-mask)
Determines if a monitored process is changing

They will detect shifts of .5 sigma to 2 sigma in about half
the time of Shewhart charts with the same sample size
S. Rnninger, Roche
EXAMPLE
Allow the detection of

slight discrepancies
in a process
before a trend is visible
using other
control charts
Assay
Analyze
process parameters
or analytical results
(e.g. PAT)
Example
ICH Q9
Control Chart: Weighted Moving Average
Design of Experiments (DoE)
A simple, or arithmetic, moving average

is calculated by adding the closing results
of the security for a number of time periods
and then dividing this total by
the number of time periods
Design experiments based on

statistical considerations
Analyze data and results to determine
> establish key parameters
Degradation and fines
> process variables

> explore potential interactions
ICH Q9
Fines
Inlet humidity
Analyze process parameters or analytical results (e.g. PAT)
Inlet humidity
Degradation

Allow the detection of slight discrepancies in a process
before a trend is visible using other control charts
Inlet temperature
Air flow
Air flow
Air flow
EXAMPLE
Design of Experiments (DOE) in a submission
Type of experimental design used e.g. full/ fractional factorial
Research and development area
Justification of the selection of factors and responses
Retrospective evaluation of established parameters

(Proven Acceptable Ranges
As an appendix
> Number and levels of factors under study
Systematically choosing certain combinations of

variables it is possible to separate their individual
effects
> The experimental matrix with the values of the responses

for each combination of factors
A special variant: focus on optimizing design

parameters to minimize variation BEFORE optimizing
design to hit mean target values for output parameters
Graphical representation
> Coefficient plot of the relative significance of the factors
under study and interactions between them
ICH Q9
Reflection paper onPAT: EMEA/INS/277260/2005, March 20, 2006
EXAMPLE
Design of Experiments (DOE) in a submission
Pareto Charts
Statistical evaluation of the model derived from DoE (e.g.

ANOVA table)
Created by plotting the

cumulative frequencies
of the relative frequency data
in descending order
Graphical representation of the relationship of the significant

factors under study with the responses (e.g. response surface
and contour plots) providing a clear overview of the
conclusions.
The Design Space (based on real test results and/or on the
model) as defined in ICH Q8 should be described
Verification of the model derived from DoE
Reflection paper onPAT: EMEA/INS/277260/2005, March 20, 2006

The most essential factors

for the analysis are
graphically apparent,
and in an orderly format

Identify those factors that have the greatest cumulative effect on
a system
Few important factors in a process: Screen out the less
significant factors
ICH Q9

EXAMPLE

Pareto Chart
Estimate the potential percent of defective product

Cp value
graphical view of
different cp values
values statistically
out of limit
values in the limit
Result:
cp=0.5
cp=1
UGW
OGW
UGW
cp=3
OGW
UGW
OGW
13,58 %
0,27 %
approx. 0
86,42 %
99,73 %
> 99,999999 %
process statistically
out of control
process statisticaly under control
Histogram
A simple, graphical view of accumulated data
> including its dispersion and central tendency

Provide the easiest way to evaluate the distribution of data
Monitor / measure process variability

Analyze data retrospectively
> Annual Product Review
Determine the relationship between process variability and

specification
Process
compatibility
Requirement: Process specific data

Tool for both regulator and industry
Example
ICH Q9
ICH Q9
Others
Scatter diagrams (x/y-diagram)

To depict the influence that one variable has on another
Combination
of tools
Usually displays points representing

the observed value of one variable
corresponding to the value of another variable
How to perform:
plot two parameters x and y in a two dimensional way
ICH Q9
http://www.sytsma.com/tqmtools/Scat.html
Combination of Tools
Combination of Tools
Probabilistic Risk Assessment (PRA)
How to perform?

Integrating various reliability modelling tools
such as Fault Tree, Event Tree Block Diagram, FMEA
to numerically quantify risks
To identify an undesired top event

e.g. "loss of life" or "loss of mission
Determine what quality risk scenarios can occur, what is

the likelihood and the consequences given they occur.
Trace out all quality risk that could lead to this events.
Estimates of the parameters used to determine the

frequencies and probabilities of the various events
At the lowest level: basic events are assigned probabilities
Conducted through the use of event trees (fault trees)

Propagated up the logic to reach a probability
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
EXAMPLE
Examples of combination of tools
EXAMPLE

Another way to proceed
Another way to proceed
1. Define the scope of QRM
1. Define the scope of an analysis

Collect all relevant data surrounding the system
Subject to determine the need for additional information
2. Choose team and team leader

3. Identify hazards and assess hazard scenarios
4. Build the risk profile to visualize the risks:
- set the risk tolerance boundary
- plot the risks
2. Describe the desired and controlled conditions of the

process
3. Using a structured approach identify the risk
by reviewing the direct and indirect causal areas
5. Develop risk reduction actions
4. Using assessment tools (e.g. statistical) assess the hazard
7. Implement risk reduction actions
6. Accept risk reduction actions

8. Follow up on success
EXAMPLE
ICH Q9
Zurich Hazard Analysis
A systematic approach managing quality risks
Risk Identification
Risk Analysis
Step 3 Hazard Identification

Step 4 Hazard Assessment
Step 1 Basic Data
Risk Evaluation
Risk Communication
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Step 6 Risk Reduction

Measures
Step 7 Residual Risk
Summary
> Collect all relevant data about the system

> Determine the need for additional data
> Describe the desired, quality function of the system
Risk Review
Review Events
Zurich Insurance Ltd, Switzerland
by Zurich insurance company

EXAMPLE
EXAMPLE
Zurich Hazard Analysis Methodology
Step 3 Hazard Identification
Step 5 Risk Evaluation
> Systematic approach by reviewing all critical areas

> An optimal method doesnt exist
as it depends on the particular system being analysed
Step 4 Hazard Assessment
> The effects are rated in terms of their consequences and
the causes are assessed in terms of their probabilities
> Based on these results a risk profile is created
> The effects are rated in and

the result completes the risk profile
> In this profile the risks are compared
with the risk protection level
Step 6 Risk Reduction Measures
Picture: Zurich Insurance Ltd, Switzerland
> Measures to be taken for every unacceptable risk to reduce

the consequences and the probability or both
> In this profile the risks are compared with the

risk protection level: define the accepted level
Zurich Insurance Ltd, Switzerland
> Define the scope carefully
Step 2 Process Conditions

Requirement by a Quality
Management System
EXAMPLE
Risk Assessment
Step 1 Basic Data

Step 2 Process Conditions
Initiate
Establish a team
Step 5 Risk Evaluation
> Prioritise actions


EXAMPLE

Step 7 Residual Risk
> The residual risk is acceptable
if the risk protection level is achieved
> Current scientific knowledge and techniques
must be considered in coming to this decision
as well as the authorities
Communicate results (Risk Communication)
> Summarise the relevant risks
> Low risks may be neglected
Maintain Risk Management (Risk Review)
> Updated regularly especially in any change
Conclusion



CONSIDERATIONS
Simple explanations of some tools
Overview: Some risk management tools
Failure Mode Effects Analysis (FMEA)
Supporting statistical tools
> Break down large complex processes into manageable steps
Control Charts
Failure Mode, Effects and Criticality Analysis (FMECA)
> FMEA & links severity, probability & detectability to criticality
Fault Tree Analysis (FTA)
Pareto Charts
> Tree of failure modes combinations with logical operators
Hazard Analysis and Critical Control Points (HACCP)
> Systematic, proactive, and preventive method on criticality
Hazard Operability Analysis (HAZOP)

> Brainstorming technique
Preliminary Hazard Analysis (PHA)
> Compare and prioritize risks with factors for each risk
Risk Identification
Risk Analysis
Risk Comm unication
Risk ranking and filtering
Initiate Quality
Risk Management Process
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Risk Manage me nt t ools
> Possibilities that the risk event happens
The results from using statistical methods

can not be better than your data
Output / Result of the Quality

Risk Management Process
Risk Review
Review Events
Conclusion on Methods and Tools
Conclusion: ICH Q9 makes suggestions

for improvements of Quality
Provides a general overview of

and references for some of the primary tools
This Annex is intended to identify opportunities

for the use of quality risk management principles
by industry and regulators
(e.g., for both inspections and submissions).
Might be used in QRM by industry and competent

authorities
However, the selection of particular risk management tools is

completely dependent upon specific facts and circumstances.
This is not an exhaustive list

No one tool or set of tools is applicable to every situation
in which a QRM procedure is used
These examples are provided for illustrative purposes and only

suggest potential uses of quality risk management.
This Annex is not intended to create any new expectations
beyond the current regulatory requirements.
ICH Q9 Introduction to Annex I
Annex II: Potential Applications
It is not always necessary to use formal risk

management tools in a QRM process,
however in the right circumstances
they can be very powerful
Quality
Risk Management
ICH Q9
Annex II:
Potential Applications
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.
Purpose of this part
Introduction
To guide through
Potential Applications for Quality Risk Management
This Annex is intended to identify potential uses

of quality risk management principles and tools
by industry and regulators.
However, the selection of particular risk management tools
is completely dependent upon specific facts and
circumstances.
Provision of some concrete,

non exhaustive examples
These examples are provided for illustrative purposes

and only suggest potential uses of quality risk
management.
This Annex is not intended to create any new expectations
ICH Q9
beyond the current regulatory requirements.
Potential Applications for Quality Risk Management
Integrated Quality Management
II.2
Regulatory Operations
II.3
Development
II.4
Facilities, Equipment and Utilities
II.5
Materials Management
II.6
Production
II.7
Laboratory Control and Stability Studies
II.8
Packaging and Labelling
CONSIDERATIONS
Quality risk management
Communication
Quality Risk Management as Part of

II.1
facilitates trust
and understanding
Regulators
operation
Industry
operation
- Reviews
- Inspections
- Submissions
- Manufacturing
Quality Risk Management is not a single process

Processstep
Start
Given the broad concept of risk

can probability and severity be more narrowly defined?
Risk
identification
Decision
Probability has two major meanings
Feedback
procedure
Sub-Subprocess
> Frequency of successes divided by the number of trials

Risk
analysis
Subprocess
Start
> Degree of belief

Severity is even more difficult to qualify as it often has
different variable attributes around a quantifiable outcome
Start
Examples
Etc.
End
EXAMPLE
Probability and Severity
End
G. Claycamb, FDA, Sept. 2005
End
EXAMPLE
Which consequence is more severe?
EXAMPLE
Simple Probability Statements?
300 lives lost in single, fiery plane crash
A common understanding of probability is elusive!
300 lives lost on country roads over a weekend
For example:
300 lives potentially lost from cancer within the

next 20 years
What does a 30% chance of rain tomorrow mean?
Even in a narrow context,

e.g., microbial contamination, severity potentially spans:
> Product spoilage
> 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.
> Mild malaiseacute illness(acute) death

> Chronic illnesspremature death
See Gigerenzer, et. al (2005)


EXAMPLE
Challenges for potential applications
EXAMPLE
Managing risks in a company
Problem:
What is the risk of a rain shower now?
Answer 1:
Company
> Set up a new department with 5 employees

> Develop a computer program for this risk (weather forecast)
Strategic risks
Operational risks
Financial risks
Compliance risks
> 10 external meetings, 2 conferences, 5 publications,

Environmental
> Verify with experimental data
Regulatory filing
> Revisit your program on an annual basis
Competitor
advantage
>
Company
viability
Shareholder
harm
Patient
harm
Quality / GMP
Safety & Efficacy
Answer 2:
ICH Q9
> Look out of a window

S. Rnninger, Sept. 2005
EXAMPLE
Existing organisation
EXAMPLE
Risk Management Strategy for Excipients

Development
Operations
Estimate risk
vs hazard
Support
Manufacturing
Launch
Confirm acceptability
Implement protective
measures
Surveillance
Implement surveillance
measures
Characterize
materials
Define specs/quality
system practices
Create literature/define
surveillance criteria
Monitor issues and

assess root causes
Conduct
hazard exposure
assessment
Define
process controls
Monitor
process controls
Re-assess effectiveness of
process controls
Quality Management
Develop risk
mitigation strategy
Confirm risk
mitigation strategy
Implement risk mitigation

strategy
Risk mitigation
Quality Assurance
Define risk control

measure (s)
Select risk control

measure (s)
Implement risk control

measure (s)
Manufacturing
Quality Unit
Procurement
etc
Risk control measure(s)
Quality Control
Evaluate results and make appropriate course corrections based on regulations,

customer expectation, company policies and procedures, societal trends and needs
Validation
QRM
Patricia Rafidison, Dow Corning Life Sciences; IPEC Europe, June 2005
II. 1 Quality risk management as part of
Quality risk management as part of

II.1: Integrated quality management
Integrated
Quality Management
> Documentation
> Training and education
> Quality defects
Industry
Competent
Authorities
> Auditing / Inspection

> Periodic review
> Change management / change control
> Continual improvement
II.1: QRM as Part of integrated Quality Management
Existing document structure
Documentation
> To review current interpretations and application of
regulatory expectations
Existing
internal
documentation
system
Law,
regulations,
requirements
Where
to be in
future?
(Mission, Policy)
What to do?
(e.g. Directives)
> To determine the desirability of and/or develop

the content for SOPs, guidelines, etc.
How to do?
(e.g. Guidelines)
Detailed instructions
(e.g. Standard Operating Procedures)
ICH Q9
Rules & Procedures

(internal regulations)
Records
Records &
Reports
Include ICH Q9
Application of documentation system
EXAMPLE
A topic for any quality management system might be a

risk-based approach for decision making
ris Im
kba ple
us Exam
se me
ing
ple
d
nt
sp
s
eci for thin
ki
fic
ng
too
ls
e.g. F
list of MEA table
residu
al risk
s
d
ase
k-b ch
Ris proa r
e
ap
id
ns Q 9
Co CH
I
Include consideration of ICH Q9 guideline

in the directive on Quality Unit-activities as a
requirement
During periodic review of regulations, policies,
guidelines and standard operating procedures (SOP) etc.
think about implementing the ICH Q9 principles
Share examples of specific tools and their use
as a means of sharing best practice
Training and education
Quality defects
> To determine the appropriateness of initial and/or

ongoing training sessions
- Based on education, experience and working
habits
- A periodic assessment of previous training
(effectiveness)
> To provide the basis for

identifying, evaluating, and communicating
the potential quality impact of a suspected
quality defect, complaint, trend, deviation, investigation,
out of specification result, etc.
> To facilitate risk communications
> To identify the training, experience, qualifications

and physical abilities
> To perform an operation reliably and
with no adverse impact on the quality of the product
> To determine appropriate action

to address significant product defects,
in conjunction with regulatory authorities (e.g., recall)
ICH Q9
ICH Q9
EXAMPLE
Assess the history of known quality defects
EXAMPLE

ICH Q9
Vision
Site approach
Initiate
> Robust Processes, non-recurrent Q-problems
Identification of opportunities
for improvement
Risk Assessment
Target
Risk Identification
> Manage dedicated projects to support site / departments /

process / products
unacceptable
Risk Communication
> Preventatively work towards the achievement of a

high reliability, productivity, quality of all that we do
Use risk assessment tool

-risk analysis
-risk evaluation & prioritization
Risk Analysis
Risk Evaluation
Risk Control
Risk Reduction
Risk Acceptance
> Continuous improvement to resolve known problems

e.g. from CAPA, inspections/audits, non robust
processes

Risk Review
Review Events
Select improvement
opportunities
Dedicated projects
- Establish a team
Problem solving approach
Risk review :
re-application of
risk assessment tool
EXAMPLE
EXAMPLE
The project approach
Approach
Teamwork (inter-departmental teams)

possibly using a facilitator
> Increase the knowledge of weaknesses for all processes

at the site and evaluate the related risks
> Select methodology
> Tackle individual issues by problem solving methods

e.g. root cause analysis, statistics, tools
> Commit resources appropriate to the project, priority and size
Problem solving structure
Tool
> Risk Assessment tools: select dynamic tool to identify
which are the most significant problems in order to
allow identification of priorities (e.g. FTA, FMEA, etc.)
> Problem Finding & Setting
> SixSigma type Project approach for problem solving

teams on each identified priority
> Sharing with management (communication)
> Problem Analysis

> Problem solution identification
> Decision making & implementation
EXAMPLE
EXAMPLE
Deviation/ Investigation Report

Deviation / Investigation Report
> Assessment of effects of the discrepancy

Examples if applicable:
- Product quality
- Drug safety
- Registration files / Marketing authorisation
- Systems in place
- Availability of goods:
potentially insufficient stock levels
The event triggers a review of quality risk management

decisions
> to control or accept risk related to a process
> to ensure these decisions are still valid based on the new
learning
In detail this could include:

> Initiate Quality Risk Management process:
Product and process information
Initiate
Initiate
Risk Assessment
Risk Assessment
Risk Analysis
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
> Identification of the root cause
Risk Identification
Risk Analysis
Risk Evaluation

Risk Reduction
Risk Acceptance

Risk Review
Risk Review
Review Events
Review Events
unacceptable
Risk Control
unacceptable
RiskManagement tools
> Define the problem:

Detailed description of the discrepancy
Risk Evaluation
RiskCommunication
Risk Identification
EXAMPLE
EXAMPLE
Risk Control: Risk Reduction/ Mitigation
> Corrective actions to resolve the discrepancy

> Corrective actions to avoid a recurrence in the future
> Consequences for other products / batches
Risk Control: Risk Acceptance

> Conclusions of measures taken
> Systems failure
> Decisions on disposition of the material

> Define Follow up actions (if applicable)
> Management summary (if applicable)
Risk Assessment
Risk Identification
Risk Analysis
Risk Control
Risk Reduction
Risk Acceptance
unacceptable

Risk Review
Review Events
> Date and signature

- responsible manager
- approval of QU
Initiate
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Control
Risk Reduction
Risk Acceptance
unacceptable
RiskCommunication
Risk Evaluation
RiskCommunication
Initiate
> Evaluation of
- Performed
- Foreseen actions
- Measurements
-

Risk Review
Review Events
EXAMPLE
EXAMPLE
Risk Communication
Risk Review
> Frequent interactions (e.g. short daily meeting)
> Follow up of action items
> Informal meetings
> Summary and evaluation

e.g. Annual Product Review
> Scheduled regular meetings (minutes)

Initiate
Initiate
Risk Assessment
Risk Assessment
Risk Identification
Risk Identification
Risk Analysis
Risk Analysis
Risk Reduction
Risk Acceptance
Risk Evaluation
RiskCommunication
Risk Control

Risk Reduction
Risk Acceptance

Risk Review
Risk Review
Review Events
Review Events
unacceptable
Risk Control
unacceptable
RiskCommunication
Risk Evaluation
EXAMPLE
One page: Deviation/ Investigation Report
EXAMPLE
Complaint/ Issue Management
Initiate Quality Risk Management process

> Information on the complaint/ issue
> Product information
Risk identification: Define the problem

> Detailed description of the complaint/ issue
> Risk to patient? Recall needed?
Initiate
Risk Assessment
Risk Identification
Risk Analysis
RiskCommunication
Risk Evaluation
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
> Risk communication:

to central coordination unit

Risk Review
Review Events
EXAMPLE
> Consequences for other batches/ products

> Systems failure
Lot tracing
Product quality
Patient impact
Registration/ Marketing authorisation
Systems in place
Availability of stock:
potentially insufficient stock levels..
> Evaluation of
Initiate
Risk Assessment
Risk Reduction
Initiate
Risk Assessment
Risk Identification
Risk Acceptance

> Risk communication: to central coordination

unit; involve management, if appropriate
Risk Review
Risk Control
Risk Reduction
Risk Acceptance
unacceptable

Risk Review
Review Events
Risk Analysis
Risk Evaluation
Risk Communication
Risk Control
unacceptable
Risk Communication
Risk Evaluation
> Risk communication: to expert team
Available data
Performed actions
Foreseen actions
Measurements
Risk Identification
Risk Analysis
EXAMPLE
> Assessment of effects of the discrepancy

Examples if applicable:
> Identification of the root cause
Review Events
EXAMPLE
Risk Control: Risk Reduction/ Mitigation
Output/ result: Risk Communication
> Corrective actions to resolve the discrepancy

> Corrective actions to avoid a recurrence in the future
Risk Control: Risk Acceptance

> Conclusions of measures taken (management sign off)
> Decisions on disposition of the material
> Define follow up actions (if applicable)
> Management summary (if applicable)
Initiate
Risk Assessment
> Date and signature of minutes
Risk Identification
Risk Analysis
Risk Control
Risk Reduction
Risk Acceptance

Risk Review
Initiate
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Reduction
Risk Acceptance

Risk Review
Review Events
Review Events
unacceptable
Risk Control
unacceptable
> Risk communication: management to decide

next steps
RiskCommunication
Risk Evaluation
Internal
> Sites / Affiliates
> Informal meetings
> Address in regular meetings
> Training sessions
External
> Communicate with Competent Authorities
(e.g. Field Alert, incident summary)
> To whom it may concern letters
> Pharmacies
EXAMPLE
Risk Communication
EXAMPLE

Auditing / Inspection
> To define the frequency and scope of audits
Risk Review
> Taking into account factors such as:
> Follow up of action items

> Summary and evaluation
e.g. Product Quality Review, Annual Product Review,
follow-up report
Initiate
Risk Assessment
Risk Identification
Risk Analysis
Risk Reduction
Risk Acceptance
unacceptable
RiskCommunication
Risk Evaluation
Risk Control

Risk Review
Review Events

EXAMPLE
Risk Assessment
Risk Control
Risk Identification
Risk Acceptance
(Databases)
(Work Planning)
Risk Analysis &

Risk Evaluation
RiskReduction
Reduction
Risk
Data
Datasources
sourcesinclude
include
Quality
QualitySystems
Systems(Q10)
(Q10)
&&Mfrg
MfrgScience
Science(Q8)
(Q8)
EXAMPLE
How industry might be able to set up a risk-based evaluation

scheme to assess the need to audit.
cGMP/Compliance
Inspections
(Multi-Factorial Risk
Model)
Scheduling audits: A framework
Risk Communication &

Risk Review
Start
Inspections
Existing legal requirements

Overall compliance status and history of the company
Robustness of a companys quality risk management activities
Complexity of the site, manufacturing process,
product and its therapeutic significance
Compliance status and history
Results of previous audits/inspections
Number and significance of quality defects (e.g, recall)
Results of previous audits/inspections
Major changes of building, equipment, processes, key personnel
Experience with manufacturing of a product
(e.g. frequency, volume, number of batches)
ICH Q9
Test results of official control laboratories
(RiskRanking
Ranking
(Risk
andFiltering)
Filtering)
and
A similar approach could be used by competent authorities

(CA) for scheduling inspections.
1. Brainstorm
to create a list of manufacturers / traders to be audited
2. Evaluate all sources of audit reports
from competent authorities, competent companies or third
parties conducted according local and/or other GMPstandards (e.g. PIC/S, WHO respective VFA, APIC)
S. Rnninger & EFPIA TG
foreign inspections Feb.06
D.Horowitz, FDA April 2005

EXAMPLE

3. Evaluate risk factor
according to criteria based on managing risk for patients,
which can (easily) be evaluated and maintained:
> Severity:
Compliance:
> Severity:
Patient interest: effects availability
> Probability:
Complexity:
> Detectability: Audit History
EXAMPLE

4. Weighting on to protection of patient
effects safety & efficacy

Drug(medicinal)product, API etc.
frequency of audit/inspections

foreign inspections
Feb.06

See list on following slides:

- In case of different activities take the highest ranking!
- In case their is nothing known, take the highest ranking!
Compliance (Severity)
patient risk: addressing safety & efficacy
Compliance (Severity)
patient risk: addressing availability
S. Rnninger &
EFPIA TG
foreign inspections
Feb.06

EXAMPLE
S. Rnninger & EFPIA TG foreign inspections Feb.06


EXAMPLE
Complexity (Probability)
History
(Detectability)
S. Rnninger &
EFPIA TG
foreign
inspections
Feb.06

EXAMPLE

foreign inspections
Feb.06
EXAMPLE
S. Rnninger &
EFPIA TG
foreign
inspections
Feb.06
EXAMPLE
EXAMPLE
5. Multiply the factors
Why 96?
Conclude to schedule an audit when,
6. Sort by overall risk factor

7. Announce audits
on a predetermined figure
e.g. 96
S. Rnninger &
EFPIA TG
foreign
inspections
Feb.06
>
Compliance/Severity: Safety & Efficacy
= medium (3) or more
>
Compliance/Severity: Availability
= major (4) or more
>
Complexity: Probability
= indirect use for

patient (2) or more
>
History: Detectability
= 3 years ago (4)

or more
This would result in 3 x 4 x 2 x 4 = 96

EFPIA TG foreign inspections Feb.06
EXAMPLE
Scheduling audits
Result:
an overview
Periodic review
> Updating
once a year
for planning
> To select, evaluate and interpret trend

results within the product quality review
Weighted factors
> To interpret monitoring data

e.g. to support an assessment of the need
for revalidation, changes in sampling etc.
Indication
for priority
Do not trust in
the values only
ICH Q9
EXAMPLE
Responsibilities in case of Change Control
Initiate
Industry
Change management / change control
Risk Assessment
Team focused
> To manage changes based on

knowledge and information
accumulated in pharmaceutical development and
during manufacturing
Risk Identification
Risk Analysis
Risk Evaluation
> To determine appropriate actions

preceding the implementation of a change
ICH Q9
Risk Communication
> To evaluate the impact on product quality of changes
Risk Control
Risk Reduction
Risk Acceptance

unacceptable
> To evaluate the impact of the changes

on the availability of the final product
Regulators
Risk Review
Review Events
Supplement/ Variation
> To facilitate continual improvement

in processes throughout the product lifecycle
Quality
Risk
Management
Pharmaceutical
Development
Manufacture
Technology
Transfer
Customer Satisfaction
Design
All red arrows are a part of Risk Communication
ICH Q9
Complaint etc.
Define
Change Control,
Annual Review
Regulatory Submission
Customer Requirement
Continual improvement
EXAMPLE
Continual Improvement
Takayoshi Matsumura, Eisai Co.
II.2: QRM as Part of regulatory operations

Inspection and assessment activities
Industry
Regulatory
operations
Competent
Authorities
To assist with resource allocation including e.g.

>
>
>
>
Inspection planning
Inspection frequency
Intensity of assessment and inspection
(see "Auditing" section in Annex II.1)
To evaluate the significance of e.g.

> Quality defects
> CAPA following a recall
> Inspectional findings

ICH Q9

EXAMPLE
Scheduling Inspections
II.2: QRM as Part of regulatory operations
Target:
Develop criteria, which can (easily) be
evaluated/maintained by members of
the department responsible for the audit plan.

To determine the appropriateness and type
of post-inspection regulatory follow-up
To evaluate information submitted by industry
including pharmaceutical development information
See previous section II.1:

auditing / inspection
To evaluate impact of proposed variations or changes

To identify risks which should be communicated
> between inspectors and assessors
To facilitate better understanding

> how risks can be or are controlled
ICH Q9
(e.g., parametric release, Process Analytical Technology (PAT)
About development
Development
CONSIDERATIONS
Critical
Parameters
that contribute
to variation in customer
requirements
Industry
Competent
Authorities
See also next chapters

using the intention to be applicable for development
Parameters that impact

customer requirements
II.4: Facilities, Equipment and Utilities

II.5: Materials Management
II.6: Production
II.7: Laboratory Control and Stability Studies
II.8: Packaging and Labelling
All parameters and dimensions

that define a product
Note: Process understanding and criticality may be applied only to new products
T. Matsumura, Eisai Co.

II.3: QRM as part of development
Quality by design: Special Cause or Common Cause
EXAMPLE
To design a quality product and its manufacturing process
Note: Non detected OoS

could result in a patient risk
Production
> to consistently deliver the intended performance

of the product (see ICH Q8)
To enhance knowledge of product performance

over a wide range of
> material attributes
(e.g. particle size distribution, moisture content, flow properties)
> processing options
Validation
Consequence: Frequent, major OOS
Corrective actions eliminate Special Cause
> process parameters
Result: Unstable process
ICH Q9
Based on A. Hussain, FDA, September 2004

EXAMPLE
Quality by design : Special Cause or Common Cause
EXAMPLE
Quality by design : Special Cause or Common Cause
Production
Production
Validation
Validation
Reduce Common Cause Variability
Consequence: Minor, occasional OoS
Consequence: On the continuous improvement path
Result: Stable & Capable

Reduce Common Cause Variability
A. Hussain, FDA, September 2004

Result: Stable- Yes; Capable?

A. Hussain, FDA, September 2004

To assess the critical attributes of
To decrease variability of quality attributes:
> Raw materials
> reduce product and material defects
> Solvents
> reduce manufacturing defects
> Active Pharmaceutical Ingredient (API)
To assess the need for additional studies

(e.g., bioequivalence, stability)
relating to scale up and technology transfer
> Starting materials

> Excipients
> Packaging materials
To make use of the design space concept

(see ICH Q8)
To establish appropriate specifications, identify critical

process parameters and establish manufacturing controls
ICH Q9
ICH Q9
EXAMPLE
P2 of CTD as part of a regulatory submission
EXAMPLE
P2 of CTD as Quality Risk Management process ?

Initiate
Formulation & Process design
Risk Assessment
Risk Identification
Risk Analysis
Process understanding
Risk Evaluation
Risk Communication
Process control Concept

Product release Concept
Risk Review
In line with Quality Risk Management ?
Review the submission
Risk Management approach to focus on critical attributes
Formulation understanding Operation

Re-evaluation and confirmation
Re-
(Risk Identification with subsequent Risk Analysis)
Research
Phase 1
Risk-based classification
(Risk Evaluation)
Parameters to investigate (e.g. by DOE)

(Risk Reduction 1. proposal; 2. verified)
Phase 2
Product and process

characteristics on the
final drug product
CONTROL
STRATEGY
PROCESS
DESIGN SPACE
BY UNIT OPERATION
Review events
Launch
Phase 3
EFPIA PAT TG, 2006
Quality Attributes
Proposed formulation and manufacturing process

Determination of
Cause Effect relationships
EXAMPLE
Unit operation
Drug substance properties; prior knowledge
FORMULATION
DESIGN SPACE

EXAMPLE
Target Product Profile
Re--evaluation and confirmation
Re
Developm.
Development
Review Events

Risk Reduction
Risk Acceptance

Regulatory strategy
Risk Control
unacceptable
Manufacturing Concept
Dispensing
Granulation
Drying
Dissolution
Blending
Tableting
Significant
influence
Disintegration
Initial
assessment
Hardness
Assay
Prior
knowledge
Content
Uniformity
First & Second

review cycle
Degradation
Formulation
and Process
understanding
Stability
Appearance
Third
review cycle
Identification
Water
Control
Strategy
Microbiology
EFPIA PAT TG, 2006
EXAMPLE
low
Control Strategy
Particle size API
Hardness
Prior knowledge
Prior knowledge
Prior knowledge
Assay
Prior knowledge
Prior knowledge
Prior knowledge
Content uniformity
Prior knowledge
Degradation
Prior knowledge
Power
consumption
Water amount and
feed rate
Stability
Prior knowledge
Prior knowledge
Appearance
Prior knowledge
Prior knowledge
Not critical to
quality
Not critical to
quality
Control water
content
Not critical to
quality
Identification
NIR of raw material Prior knowledge
Water
Prior knowledge
Microbiology
Specification of
starting material
Power
Prior knowledge
consumption
water amount and
Prior knowledge
feed rate
Blending
(Magnesium
Stearate)
Not critical to
quality
Not critical to
quality
Not critical to
quality
Not critical to
quality
Not critical to
quality
Not critical to
quality
Prior knowledge
Prior knowledge
Risk Identification
Risk Analysis
Prior knowledge
Risk Evaluation
unacceptable
NIR measurement
Prior knowledge
NIR measurement
Prior knowledge
Prior knowledge
Prior knowledge
Prior knowledge
Prior knowledge
Prior knowledge
Prior knowledge
Prior knowledge
Not critical to
quality
Prior knowledge
Prior knowledge
Prior knowledge
Prior knowledge
Prior knowledge
Control water
content
Prior knowledge
Prior knowledge
Prior knowledge
Purified water
used
Prior knowledge
Prior knowledge
Prior knowledge
Risk Assessment
Packaging
Not critical to
quality
Prior knowledge
Prior knowledge
Initiate
Industry
Tableting
Team focused
Particle size API
Disintegration
Drying
Risk Communication
Dissolution
Granulation
Prior knowledge
EFPIA PAT TG, 2006

EXAMPLE
QRM as part of development

provide risk-based knowledge to manufacturer
Dispensing (Raw
Material Properties)
EXAMPLE
Responsibilities in regulatory operations
Risk Control
Risk Reduction
Risk Acceptance
Quality Attributes
Unit operation
Unit operations
/
Quality attributes
Risk to patient

B) Inspectorates
A) Reviewers
Risk Review
Review Events
Annex II: Development

Potential Applications
and
Manufacturing
EXAMPLE
Conventional approach: Testing after each step to minimize the

risk prior to the next step
Past
Future
Parameters and range
We have additional dimensions
Open question:
How to challenge information for submission?
Raw
Materials
Blending
Tabletting
Packaging
Validation
Raw
Materials
Answer the questions in ICH Q9 Chapter 4:
Blending
Tabletting
Packaging
> What might go wrong?

> What is the likelihood (probability)
it will go wrong?
PAT: Continuous or more frequent testing and control during each

step to minimize/control the risk prior to the next step
> What are the consequences (severity)?

PAT: Process Analytical Technology Takayoshi Matsumura, Eisai
II.4: QRM for facilities, equipment and utilities

Design of facility / equipment
Industry
Facilities
&
Equipment
Competent
Authorities
To determine appropriate
Zones
when designing buildings and facilities, e.g.,
> flow of material and personnel
> minimize contamination
> pest control measures
> prevention of mix-ups
> open versus closed equipment
> clean rooms versus isolator technologies
> dedicated or segregated facilities / equipment
ICH Q9
EXAMPLE
EXAMPLE
Assessing Facility Needs for the Manufacture of Certain

Medicinal Products Using a Risk Based Approach
Assessing Facility Needs for the Manufacture of Certain

Medicinal Products Using a Risk Based Approach
Options for facility dedication / segregation
Options for equipment dedication / segregation
> A physically separate or segregated building

> A separate area which may comprise of one or more rooms
within a multi-purpose facility with its own air-locked
personnel/ material accesses and HVAC systems.
> One or more rooms (Suite) within a multi-purpose facility or
dedicated area that is dedicated to a specific product or
product range, and is identified accordingly
> Equipment that is dedicated to a specific product or product

range, and identified accordingly
> A totally enclosed cabinet (Containment Isolator) that is
specifically designed to contain a specific product or
product range, and is identified accordingly
> An equipment change part (e.g. sieve, filter, etc) that is
dedicated to a specific product or product range, and is
identified accordingly
EFPIA. TG dedicated facilities, 2006


EXAMPLE
EXAMPLE
Facility Needs: Risk Assessment of Severity of Harm
Facility Needs: Risk Assessment of the process 1/2


EXAMPLE
EXAMPLE
Facility Needs: Risk Assessment of the process 2/2
Facility Needs a Process Risk Control
Consider the need improve the situation by one or more

of the following options:
>Improve the formulation
>Minimise the release of material at source using
the most appropriate equipment and technology.
>Contain any residual material or product by means
of facility, air handling, and other techniques.
>Assure adequate cleaning and/or inactivation.
>Instigate a specific monitoring program

EXAMPLE
EXAMPLE
Facility Needs: Risk Control
Examples of Process Risk Controls 1/2

EXAMPLE
EXAMPLE

EXAMPLE
EXAMPLE
Facility Needs: Risk Control: Operational solutions
A number of different technical solutions are possible:

> Product Campaign in multi-product facility
with campaign/extended cleaning
> Appropriately Dedicated Equipment
> Containment in multi-product area
> Closed Processes
> Dedicated suite (airlock, dedicated HVAC)
> Dedicated area
> Dedicated building

EXAMPLE
EXAMPLE

Facility Needs: Conclusion
Facility Needs: Risk Acceptance profile
This approach takes into account the risk based criteria:

the potential safety risk to patients from cross contamination,
different scales and/or stages of production
the physical form of the product at each stage of products and
factors which may affect ease of removal or deactivation
the appropriate technical means to minimise and demonstrate
effective ongoing control of the identified objective risk to
patient safety
EFPIA. TG
dedicated facilities, 2006
the controls and supporting evidence necessary to support the

alternative use of facilities and equipment previously used for
materials identified with high potential for adverse medical
effects at low levels
EXAMPLE
EXAMPLE
QRM for facilities, equipment and utilities
Zone concept for API
Zone concept for API:
Risk assessment: Risk identification and analysis
Risk management of Contamination

and Cross-contamination (zone concept) for API
> After the critical point:

Design chemical operations to prevent cross
contamination by/of the API
Initiate the Risk Management Process
> Before the critical point:

Protection has to be considered
> Defining problem or question

- Where will protection be required?
- What kind of protection will be adequate?
Initiate
Risk Assessment
Risk Identification
Risk Analysis
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
> Notes:

Risk Review
Review Events
Ability of a final purification,

filtration and/or crystallisation step
of removing trace levels of
incidental (cross-)contamination
Consider industrial hygiene and
safety conditions K.-H. Bender, F. Hoffmann-La Roche
Risk Analysis
Risk Evaluation
unacceptable
Risk Reduction
Risk Acceptance

Risk Review
Review Events
EXAMPLE
EXAMPLE
> Risk associated with different products
Risk associated with simultaneous operations

- plant design
(multi-purpose, dedicated, closed systems)
- requirements for special product categories
(e.g. highly toxic)
- Contamination by particulate matter

e.g. from equipment, environmental
- Microbiological contamination
Risk to product from exposure to work environment

- exposure time, interfaces
(e.g. drums/containers)
e.g. API susceptible to microbiological growth?
- Cross-contamination
Initiate
Risk Assessment
Risk Identification
Risk Reduction
Risk Acceptance
Risk Evaluation
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance

Risk Review
K.-H. Bender, F. Hoffmann-La Roche
Review Events
unacceptable
Risk Control
Risk Communication
Risk Analysis
unacceptable

Initiate
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
e.g. inadequate cleaning and/or material flow,

air-handling, use of closed systems
Risk Identification
Risk Control
Initiate
Risk Assessment
Risk Communication
Risk Evaluation
> Defining the assessment information

and conclusions
- Managing risk based on a
critical point approach
> Rationale:
Risk Communication
Risk Review
Review Events
EXAMPLE
EXAMPLE
Risk control
Risk control: Risk reduction
> A decision-making activity focused on controlling risks
> Physical and technical solutions

- closed systems
- endless bag system
- closed sampling
Where will protection be required?

What kind of protection is adequate?
> Intermittently closed product handling (hybrid solutions)

- glove boxes
- enclosed room or cabin
Risk Identification
Risk Analysis
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
> Open product handling

- air flow controlled sampling
Initiate
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation

Risk Review
Review Events
Review Events
EXAMPLE
EXAMPLE
Risk control: Risk reduction
Risk control: Risk Acceptance

- No additional risk control activities are necessary
- Supported by the decision maker(s).
- Includes acceptance of risks
that have not been identified
> Patient impact

- Occurrence of harm
- Detection of harm
> Design appropriate levels of protection

> Accept the critical point of the process
> Appropriate monitoring may be performed
Initiate
Risk Assessment
Risk Identification
Initiate
Risk Assessment
Risk Identification
Risk Analysis
Risk Analysis
Risk Control
Risk Reduction
Risk Acceptance
Risk Evaluation
Risk Communication
unacceptable

Risk Reduction
Risk Acceptance

Risk Review
Risk Review
Review Events
unacceptable
Risk Control
Risk Communication
Risk Evaluation
> Procedural/ structural/ logistical solutions

- gowning procedures
- operational monitoring
- optimising material flow
- standardized drums/ containers
-
Review Events
EXAMPLE
EXAMPLE
Risk communication
The review phase
> Internal:
- GMP-Master plan to demonstrate that
the risk management process is used
- Capital investment plan can be supported or even
changed by the quality risk management process
> External:
- e.g. Site Master File
> Audits / Inspections

> Regularly assessment of complaints/ deviations
on (cross-) contamination topics
Initiate
Initiate
Risk Assessment
Risk Assessment
Risk Identification
Risk Identification
Risk Analysis
Risk Analysis
Risk Reduction
Risk Acceptance
Risk Evaluation
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance

Risk Review
Review Events
unacceptable
Risk Control
unacceptable
Risk Communication
Risk Evaluation

Risk Reduction
Risk Acceptance

Risk Review

unacceptable
Risk Control
Risk Communication
Risk Evaluation
Risk Communication
Initiate
Risk Assessment
What to do?
- Minimize interfaces
- Segregate production facilities
- Closed systems
- control people and material movement
Risk Review
Review Events
EXAMPLE

To determine appropriate
Risk criteria for Facility qualification (DQ/IQ/OQ/PQ)
Product contact materials for equipment and containers
> Probability: Equipment has contact with product

full surface (vessel) / partial (gasket) / no contact
> Selection of stainless steel grade, gaskets, lubricants, etc.
> Severity: possible source for contamination

(e.g. Process validation) or cross contamination
(e.g. Cleaning validation)
yes / no
Utilities
> steam, gases, power source, compressed air, heating,
ventilation and air conditioning (HVAC), water, etc.
Preventive maintenance for associated equipment
> Severity: Product quality affected? Impact on patient?

yes / no
> Inventory of necessary spare parts, etc.
> Detectability: Knowledge of this attribute may affect the

release decision
ICH Q9
B. Dreissig, F. Hoffmann-La Roche

EXAMPLE
Hygiene aspects in facilities
Master Qualification Plan of a new facility:

Document reduction initiative
> To protect the product from environmental hazards

including chemical, microbiological, physical hazards
determining appropriate clothing and gowning
hygiene concerns
> To protect the environment from hazards

related to the product being manufactured
Document consolidation equals risk

reduction via constancy, easy
maintenance/training
reduces non compliance risk to patient
personnel, potential for cross-contamination

ICH Q9
B. Dreissig, F. Hoffmann-La Roche


Potency Scale max. daily dose (severity)
Calibration/preventive maintenance
> To set appropriate calibration and maintenance schedules
Qualification of facility/equipment/utilities
> To differentiate scope and efforts and decisions
based on the intended use
> 10
> 6
> 4
> 2
> 1
< 1mg
1-10mg
10-100mg
100mg-1000mg
>1000mg
Cle
an
in
gv
alid
ati
on
Solubility Scale in cleaning medium (probability)

>
>
>
>
>
multi-versus single-purpose
batch versus continuous production
Cleaning of equipment and environmental control
5
4
3
2
1
low solubility
slightly soluble
moderately soluble
soluble
highly soluble
Interactions Scale (detectability)
> To determine acceptable (specified)

cleaning validation limits
ICH Q9
EXAMPLE
>
>
>
9
4
1
serious moderate
low
patients life threatened

patient feels adverse effect
none patient does not notice
P. Gough, D. Begg Ass.

Computer systems and computer controlled equipment

> To select the design of computer
hardware and software
- Modular
- Structured
- Fault tolerance
> Patient risk

> Compliance risk
> Application risk
> Business risk (influenced by other than Q-risks)
> Infrastructure risk
ICH Q9

EXAMPLE
Patient harm
Choices
A: Death
B: Serious harm but not death
C: Minor harm
D: No effect on patient health
A: Yes
Is/are there down stream

Secondary
processes to the subject system
assurance of safety that could assure safety of the
B: No
product.

Category
Questions
Choices
Is the business process subject A: Yes
to predicate rule requirements?
OR
B: No
Is the business process regulated
by an agency?
A: Yes, submitted
Are the data or records made
Degree of Exposure
B: Yes, may be inspected
available to regulatory agencies?
C: No
Business process
regulation
W. Schumacher, Roche
EXAMPLE
Risks on Comp. systems & comp. controlled equipment

Application risk 1/2
Questions
Choices
A: 0
B: 1
C: more than 1
A: firmware
B: standard software packages
C: configurable software
What is the technology category
packages
for the system?
D: configurable software
package with custom
additions
E: fully custom software
How many technology enablers
are interfaced to the system?

Application risk 2/2
Category
Experience
Security
Questions
Choices
A: New technology
B: Mature technology but new to
us
What is our experience with the
C: Mature technology previously
technology?
used by us
D: Technology approaching
obsolescence
Is the application capable of limiting A: Yes
access at the individual authorized
B: No
user level?

EXAMPLE
Complexity
EXAMPLE

Compliance risk
Category

Patient risk
Will the failure of the system

result in
Questions
Computer systems and computer controlled equipment

Which risks could be considered?
> To determine the extent of validation

- 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
Category
EXAMPLE
EXAMPLE

Business risk 1/3
Category
Position in Value
Chain
Number of users
(Usage)
EXAMPLE

Business risk 2/3
Category
Choices
A: < yearly
B: monthly
C: daily
A: One site
Location of system
Select where the System is
B: Within a region
(Usage)
implemented
C: Throughout the global
organization
A: There is no alternative system
or manual procedure
B: YES, with a backup system or
an alternative system
Criticality of business Can the business continue to operate
system
if the system fails
C: YES, with manual processes - a
major resource impact
D: YES, with manual processes - a
minimum resource impact
Questions
Choices
A: Discovery Research
B: GLP Research
C: Development GMP
D: Development GCP
E: API Manuf.
Identify where in the value chain the
F: Form. Manuf. & Pack
system is used
G: Marketing / Dem. Manag.
H: Prod. Plann. & Log.
I: Supp. Proc. HR
K: Supp. Proc. Informatics
L: Supp Proc Finance
A: 1
Estimate the number of users of the B: 2 to 20
system
C: 21 to 100
D: more than 100
Frequency of Usage
(Usage)
Questions
Estimate how frequently the system
users operate or interface with the
system

EXAMPLE
Cross organizational
boundaries
Does this system supply critical data A: Yes

from this
business process to other business B: No
processes (outside of this one)?
EXAMPLE

Business risk 3/3
Questions
Choices
A: Yes
Is the system the sole source of data
for the business process?
B: No
Category
Criticality of records
contained in the
system

Infrastructure risk
Category
Questions
On which geographical
infrastructure the system will
operate?
Complexity
What is our experience with the
infrastructure?
Security
Choices
A: Local - Proprietary
B: Local
C: Regionally
D: Globally
A: New technology
B: Mature technology but new
to us
C: Mature technology
previously used by us
D: Technology approaching
obsolescence
A: Yes
Does the system rely on the

"public internet" in the operation
B: No
of the system?
II.5: QRM as part of materials management

Industry
Materials
Management
Assessment and evaluation of suppliers and

contract manufacturers
> To provide a comprehensive evaluation
Competent
Authorities
Auditing
Supplier quality agreements
Starting material
> To assess differences and possible quality risks
associated with variability in starting materials
Age
Route of synthesis
ICH Q9
Use of materials
Storage, logistics and distribution conditions
> Appropriate use material under quarantine
> Adequacy of arrangements to ensure maintenance

of appropriate storage and transport conditions
for further internal processing
Temperature
Humidity
Container design
> Appropriateness of
Reprocessing, reworking, use of returned goods
> Determine the effect on product quality of discrepancies

in storage or transport conditions
Cold chain management (see other ICH guidelines)
ICH Q9
ICH Q9
Storage, logistics and distribution conditions

> Maintain infrastructure
Industry
Capacity to ensure proper shipping conditions

Interim storage
Handling of hazardous materials and controlled
Production
Competent
Authorities
substances
Customs clearance
> Provide information for ensuring the availability of

pharmaceuticals
Ranking risks to the supply chain (e.g. Anti-Counterfeit)
ICH Q9
EXAMPLE
Integrated Quality Management
II.6: QRM as part of production

Validation
Process
Validation
> To identify the scope and extent of

verification, qualification and validation activities
Cleaning
Validation
Validation
Support System
Validations
Computer
Validation
Deviation
Analytical methods
Processes
Equipment
Cleaning methods
Method
Validation
Out of Specification
Failure Investigation
> To determine the extent for follow-up activities

CAPA
Sampling
Monitoring
Re-validation
Change Control
Re-Validation
> To distinguish between critical and non-critical process

ICH Q9
steps to facilitate design of a validation study
Periodic Review
T. Matsumura, Eisai
II.6: QRM as part of production
In-process sampling & testing

> Evaluate the frequency and extent
of in-process control testing
Industry
Laboratory control
and
stability testing
Justify reduced testing
under conditions of proven control
> Evaluate and justify the use of

Process Analytical Technologies (PAT)
in conjunction with parametric and real time release
Production planning
Competent
Authorities
> To determine appropriate production planning

Dedicated
ICH Q9
Campaign or concurrent production process sequences
II.7: QRM as part of laboratory control and stability testing
II. 8
Out of specification results
Industry
> To identify potential root causes and

corrective actions during the investigation
Packaging
and
labeling
Retest / expiration date setting

> To evaluate adequacy of storage and testing
of intermediates, excipients and starting materials
Challenge results of use tests
Stress tests
Competent
Authorities
ICH Q9
QRM as part of packaging and labelling
QRM as part of packaging and labelling
Design of packages
Label controls
> Design the secondary package for the protection of

primary packaged product
> Design label control procedures

based on the potential for mix-ups
Ensure product authenticity

Label legibility
Involving different product labels
Selection of container closure system

Including different versions of the same label
> Determine the critical parameters

of the container closure system
ICH Q9
ICH Q9
Using ICH Q9 will

Facilitate
>
>
>
>
>
Conclusion
Communication and transparency

More informed, scientifically based decision making
Patient focused actions on quality risks
Realistic and appropriate solutions
Use of existing solutions (Share best practice/prior knowledge)
Manage critical to quality aspects

> Through systems, organisations, processes & products
> Maintain responsibility & accountability for QRM
Focus activity towards patient protection

It should never be used as a hobby horse / preconceived idea
Opportunity for the Industry & Competent Authorities
Challenges for Industry & Competent Authorities
Using the same guideline apply QRM to

industry (Development & Manufacture) and
regulators (Reviewer & Inspectorate)
Interpreting and adopting the concepts

of quality risk management into specific areas
Provides for establishing a defined program

for what we already do every day in our jobs
> Embed this behavior into quality aspects

of business, technology and regulation
Supports science-based decision making
> Adopt in existing structures, organizations and Quality

System
Optimisation of resources
Prevention from overly restrictive and
unnecessary requirements
> Balance the documented use of informal and formal

quality risk management
Facilitates communication and transparency

Integration of QRM
into existing systems
and regulatory processes
will require a
development of trust over time

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Annex I: Methods & Tools

Annex I: Methods & Tools

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

Purpose of this part

Annex I: Methods & Tools

Give some examples and methods of use

Annex I: Methods & Tools

Annex I: Methods & Tools

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

The purpose of this annex is to provide a general overview

Risk Management tools

July 2006, slide 2

The references are included as an aid to gain more

Output / Result of the

Annex I: Methods & Tools

July 2006, slide 4

Annex I: Methods & Tools

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

5. Risk Management Tools

Contributing items to manage quality risks

System Risk (organisation)

Product Risk (safety & efficacy)

Output / Result of the

July 2006, slide 5

> e.g. quality attributes:

July 2006, slide 6

ICH Q9 Briefing pack II, July 2006, page 1

Annex I: Methods & Tools

Annex I: Methods & Tools

ICH Q9 QUALITY RISK MANAGEMENT

Choose the right tool for the task: An example

System Risk System Risk Process Risk Product Risk

Risk ranking & filtering

ICH Q9 QUALITY RISK MANAGEMENT

(safety & efficacy)

July 2006, slide 7

Annex I: Methods & Tools

July 2006, slide 8

Annex I: Methods & Tools

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

I.1: Basic risk management facilitation methods

I.1: Basic risk management facilitation methods

Cause and Effect Diagrams (Ishikawa / fish bone)

They might be helpful to support risk identification

Breaking the process

July 2006, slide 9

Annex I: Methods & Tools

July 2006, slide 10

Annex I: Methods & Tools

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

I.1: Basic risk management facilitation methods

I.1: Basic risk management facilitation methods

Shows how they are interrelated

May be accomplished with

Provides a clear and simple visual representation

Potential Areas of Use(s) / outcomes

Facilitates understanding, explaining and systematically

July 2006, slide 11