QRM Fmea PDF

Annex I: Methods & Tools Annex I: Methods & Tools
ICH Q9 QUALITY RISK MANAGEMENT ICH Q9 QUALITY RISK MANAGEMENT
Purpose of this part

Quality
• To guide through
Risk Management Risk Management Methods and Tools
ICH Q9 • Give an aid by providing key principles on the theory of the

tools
Annex I: Methods & 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.
prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance July 2006, slide 1 prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance July 2006, slide 2

Chapter 5 Initiate
Quality Risk Management Process Introduction
& Annex I Risk Assessment
Risk Identification
• The purpose of this annex is to provide a general overview
of and references for some of the primary tools
Risk Analysis
that might be used in quality risk management
Risk Evaluation
unacceptable
by industry and regulators.
Risk Management tools
Risk Communication
Risk Control • The references are included as an aid to gain more

Risk Reduction knowledge and detail about the particular tool.
Risk Acceptance
• The list of tools is not exhaustive.
Output / Result of the • It is important to note that no one tool or set of tools
Quality Risk Management Process
is applicable to every situation in which a quality risk
Risk Review
Review Events
management procedure is used.
ICH Q9

ICH Q9 QUALITY RISK MANAGEMENT ICH Q9 QUALITY RISK MANAGEMENT CONSIDERATIONS
5. Risk Management Tools 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
Initiate
Risk Assessment
Risk Identification
• Product Risk (safety & efficacy)
Risk Analysis
> e.g. quality attributes:

Risk Evaluation
unacceptable
Ri sk Management tools
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
measured data according to specifications

Output / Result of the
Risk Review
Review Events
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
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE ICH Q9 QUALITY RISK MANAGEMENT
Choose the right tool for the task: An example Annex I.1
Basic
A possible aid general detail
where to use
methods / tools System Risk System Risk Process Risk Product Risk
Risk ranking & filtering

(facility & people) (organisation)
X X X
(safety & efficacy)
Risk Management
Failure mode effect analysis X X
Hazard analysis and critical
control points
X X Facilitation
Process mapping
Flow charts
X
X X Methods
Statistical tools X
Check sheets X X

I.1: Basic risk management facilitation methods I.1: Basic risk management facilitation methods
Flowcharts
• Flowchart
• Check Sheets Start
• Process mapping Activity
• Cause and Effect Diagrams (Ishikawa / fish bone) • Pictorial representations

Activity
of a process
They might be helpful to support risk identification Decision No Action
Yes
• Breaking the process
Result down into its
constituent steps

Check sheets Process mapping
• The indicators may be selected based on unit operations

• Present information • Shows how they are interrelated
in an efficient, clear format
Potential Areas of Use(s) / outcomes
• May be accomplished with • Provides a clear and simple visual representation
a simple listing of items of involved steps
• Facilitates understanding, explaining and systematically
analyzing complex processes and associated risks
• A pre-requisite for the use of some other tools
ICH Q9
Air
Dispensing Cause and Effect Diagrams (Ishikawa / fish bone)
Scale Sieving Fluidized Bed
Dryer
Granulation
Air Environment People Materials
Magnesium
• Process Stearate
Blending
Sieving
mapping
Problem
statement
Equipment Measurement
Tabletting
Packaging System Methods
Coating
F. Erni, Novartis Pharma

Cause and Effect Diagrams (Ishikawa / fish bone) Cause and Effect Diagrams (Ishikawa / fish bone)
• To associate multiple possible causes with a single effect How to perform?
• Constructed to identify and organize possible causes for it • Define and agree a precise problem statement
(put as “head” of fish bone) Think “What could be its
• Primary branch: represents the effect causes?” for each node
• Major branch: corresponds to a major cause • Add it to the “fish bone” diagram
• Minor branch: correspond to more detailed causal factors • For each line pursue back to its root cause
• Consider splitting up overcrowded sections “bones”
• Consider which potential root Environment People Materials
causes and the need for Problem
further investigation on them statement
Equipment Measurement
Methods
System

ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE
Coating Drying Milling Analytical
Cause and Effect Diagrams (Ishikawa / fish bone) Temperature
Spray Rate Redrying
Pan Speed Time Temp

Milling
Gun Distance RH Screen Size Other
Temperature Air Flow Porosity Sampling
Atomizing Air Pressure Shock Cycle Mill Speed Method

Tablet
Drug
Hardness
Operator Precompressing Water Substance
Temp/RH Main Compressing Binder Age
P.S.
Operator Feeder Speed Temp Process Conditions
LOD
Training Press Speed Spray Rate
• Cause and
Punch Penetration HPMC
Depth Spray Pattern
Methoxyl
Plant
Tooling
Feed
Scrape Down
P.S.
Hydroxyl
P.S. Effect
Factors Frame LOD
Compressing
Chopper Speed Other Diagram
Endpoint
Mixer Speed Syloid
Lactose
Raw
for Tablet
Granulation
Coating
Materials Hardness
C. Kingery, The Six Sigma Memory Jogger II Power © Alastair Coupe, Pfizer Inc.
Time
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 • Once failure modes are established,
risk reduction can be used to
Effects Analysis eliminate, reduce or control the potential failures
• FMEA relies on process understanding
(FMEA) • 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

ICH Q9 QUALITY RISK MANAGEMENT ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE
I.2: Failure Mode Effects Analysis (FMEA) I.2: Failure Mode Effects Analysis (FMEA)
How to perform?
1. Establish a team
2. Identify the known and potential failure modes:
Develop lists of known problems and brainstorm other
potentials…
RNP: Risk Priority Number C. Kingery, The Six Sigma Memory Jogger II e.g.
Potential Areas of Use(s)
> Product not meeting specification
• Prioritize risks
• Monitor the effectiveness of risk control activities > Process not meeting yield requirements
• Equipment and facilities > Malfunctioning equipment
• Analyze a manufacturing process > Software problems
to identify high-risk steps or critical parameters ICH Q9 Newly identified failure modes should be added at any time

How to perform? 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 > Scope
> Data from the assessment & control
> Linear: 1, 2, 3, 4 The aim is to come (e.g. No. of identified failure modes)
> Exponential: 1, 2, 4, 8 up with a method > Level of accepted risk without actions i.e. residual risk
> Logarithmic: 1, 10, 100, 1000
of prioritising (e.g. Risk priority Number < 50)
> Recommended actions, responsibilities and due dates
> Self made: 1, 3, 7, 10 (including approval, if appropriate)
Multiplying different scales will differentiate the outcome > Person in charge for follow-up of FMEA
Severity (Consequences of failure) Probability (Likelihood failure will happen)

• 10 Extreme
• Predicted to cause severe impact to quality (Product out of • 8 Regular failures
specifications, no Expert Statement possible) • Expected to happen regularly
• 7 High • 4 Repeated failures

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

Detectability (Ability to find the failure) FMEA: Quantitation of Risk : Severity

10 Dangerously High Failure could lead to death or permanent injury to the customer. Financial:
• 4 Normally not detected >$1,000,000
9 Extremely high Failure could lead to injury to the customer. Failure would create non-compliance
• Failure very likely to be overlooked, hence not detected with registered specifications. Failure likely to lead to recall. Financial: $1,000,000
(no technical solution, no manual control) 8 Very High Failure could lead to adverse reaction for customer. Failure would create
noncompliance with GMP regulations or product registrations. Failure possible to
lead to recall. Financial: $500,000
• 3 Likely not detected 7 High Failure leads to customer percept ion of safety issue. Failure renders individual
• Failure may be overseen unit(s) unusable. Failure causes a high degree of customer dissatisfaction. Recall
for business reasons possible but Authority required recall unlikely. Financial:
(manual control, spot checks) $100,000
6 Moderate Failure causes a high degree of customer dissatisfaction and numerous
• 2 Regularly detected complaints. Failure unlikely to lead to recall. Financial: $50,000
5 Low Failure likely to cause isolated customer complaints. Financial: $10,000
• Failure will normally be detected 4 Very Low Failure relates to non-dosage form issues (like minor packaging problems) and
(manual control, routine work with statistical control) can be easily overcome by the customer. Financial: $5,000
3 Minor Failure could be noticed by the customer but is unlikely to be perceived as
• 1 Always detected significant enough to warrant a complaint.
• Failure can and will be detected in all cases 2 Very Minor Failure not readily apparent to the customer. Financial: <$1,000
(monitoring, technical solution available) 1 None Failure would not be noticeable to the customer. Financial: none
Dr. Gary Harbour, Pfizer

FMEA: Quantitation of Risk : Probability FMEA: Quantitation of Risk: Detection

10 Very High: Failure is More than one occurrence per day or a probability of more than three occurrences in
almost inevitable 10 units (Cpk < 0.33 or <1σ). 10 Absolute The product is not inspected or the defect caused by the failure is not detectable.
Uncertainty
9 One occurrence every three to four days or a probability of three occurrences in 10
units (Cpk ~ 0.33 or ~1 σ). 9 Very Remote Product is sampled, inspected, and released based on Acceptable Quality Level
(AQL) sampling plans.
8 High: Repeated One occurrence per week or a probability of 5 occurrences in 100 units (Cpk ~ 0.67
failures or ~2 σ). 8 Remote Product is accepted based on no defects in a sample.
7 One occurrence every month or one occurrence in 100 units (Cpk ~ 0.83 ~2.5 σ).
7 Very Low Product is 100% manually inspected in the process.
6 Moderate: One occurrence every three months or three occurrences in 1,000 units (Cpk ~ 1.00 or
Occasional Failures ~ 3 σ). 6 Low Product is 100% manually inspected using go/no-go or other mistake-proofing
gauges.
5 One occurrence every six months to one year or one occurrence in 10,000 units (Cpk
~ 1.17 or ~ 3.5 σ). 5 Moderate Some Statistical Process Control (SPC) is used in the process and product is final
inspected off-line.
4 One occurrence per year or six occurrences in 100,000 units (Cpk ~ 1.33 or ~ 4 σ).
4 Moderately High SPC is used and there is immediate reaction to out-of-control conditions.
3 Low: Relatively few One occurrence every one to three years or six occurrences in 10,000,000 units (Cpk
Failures ~ 1.67 or ~5 σ). 3 High An effective SPC program is in place with process capabilities (Cpk) greater than
1.33.
2 One occurrence every three to five years or 2 occurrences in 1,000,000,000 units
(Cpk ~ 2.00 OR ~6 σ). 2 Very High All product is 100% automatically inspected.
1 Remote: Failure is One occurrence in greater than five years or less than two occurrences in 1 Almost Certain The defect is obvious and there is 100% automatic inspection with regular
unlikely 1,000,000,000 units (Cpk > 2.00 OR >6 σ). calibration and preventive maintenance of the inspection equipment.
For batch failures use the time scale for unit failures use the unit scale. Dr. Gary Harbour, Pfizer Dr. Gary Harbour, Pfizer
Severity / Probability / Detection (SPD) I.2: Failure Mode Effects Analysis (FMEA)
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
PhD R.C. Mendson, Menson & Associations, Inc

> Historical data
ICH EWG London, March 2004 Takayoshi Matsumura, Eisai Co.

Drying Process Drying Process
Ranking Severity (S) Probability (P) Detection (D)
10 Death More than once a day Impossible to detect Process Potential Failure Mode Potential Cause S P D RPN
9 ↓ 3 – 4 times a day Remote 1. contamination disheveled gown of operator

Set up insufficient cleaning of equipment
8 Permanent injury Once a week Very slight
2. contamination damage of inlet-air filter
7 ↓ Once a month Slight Start drying degradation of product damage of thermometer
6 Temporary injury Once in three month Low 3. long drying time unstable supply-air volume
5 ↓ Once in half – one year Medium Maintain damage of timer
high Loss On Drying
temperature
4 Reported/ dissatisfied Once a year Moderately high (LOD)
low LOD high dew-point
3 ↓ Once in 1 – 3 years High
non-uniformity of LOD uneven temperature distribution
2 Notice/ no report Once in 3 – 5 years Very High
RPN: Risk Priority Number = S*P*D
1 ↓ Less than once in 5 years Virtually certain
Takayoshi Matsumura, Esai Co Takayoshi Matsumura, Esai Co

Drying Process Drying Process
Process Potential Cause RPN Recommended Action S P D RPN
Process Potential Failure Mode Potential Cause S P D RPN 1. disheveled gown of operator 120 use long gloves and goggles 3 2 8 48
Set up insufficient cleaning of 112 change cleaning procedure 7 2 4 56
1. contamination disheveled gown of operator 3 5 8 120
Set up equipment
insufficient cleaning of 7 2 8 112
equipment 2. damage of inlet-air filter 126 change maintenance period 7 2 6 84
Start drying damage of thermometer 63 change calibration period 7 2 3 42
2. contamination damage of inlet-air filter 7 3 6 126
Start drying degradation of product damage of thermometer 7 3 3 63 3. unstable supply-air volume 40 ― 2 4 5 40
Maintain malfunction of timer 8 ― 2 2 2 8
3. long drying time unstable supply-air volume 2 4 5 40
temperature
Maintain high LOD malfunction of timer 2 2 2 8 high dew-point 27 ― 3 3 3 27
temperature
low LOD high due-point 3 3 3 27 uneven temperature 45 ― 3 5 3 45
distribution
non-uniformity of LOD uneven temperature distribution 3 5 3 45
Take action when RPN is over 100 RPN: Risk Priority Number = S*P*D
Existing controls: IPC of LOD and degradation product after drying process
RPN: Risk Priority Number = S*P*D
Take action when severity is over 5
Takayoshi Matsumura, Eisai Co Remaining critical parameters after taking action; further controls required
Based on Takayoshi Matsumura, Esai Co.
Failure Mode Effects Analysis (FMEA)

I.2: Failure Mode Effects Analysis (FMEA)
Risk Assessment Risk Reduction
Detectability (D)
Detectability (D)
• Analyse a granulation process step
Risk reduction
Probability (P)
Probability (P)
Severity (S)
Severity (S)
Risk factor
Risk factor
[1<2<3<4]
[1<2<3<4]
[1<2<3]
[1<2<3]
(S*P*D)
[1<2<3]
[1<2<3]
(S*P*D)
Event Actions:
Sub-Step Effect Comments
(Failure m ode) Risk reduction strategy
because only a few parameters are adjustable and many automatically interruption
problems can occur by manual operations

not meet specification of by not meeting range;
W et seving Drying Temperature 2 4 1 8 implement 2 temperature measures 1 1 1 1 7
degradation Temperatur monitoring in
batch record
not meet specification of
Granulation Drying water content 2 3 1 6 introduce online NIR 2 1 1 2 4 indirect measurment
degradation
direct measurement; time
Severity (Consequences): introduce IPC analytic 2 2 1 4 2
consuming
humidity measurement in the exausting indirect measurment;
3: high Predicted to cause significant impact to quality (failure to meet specifications) air
2 1 2 4 2
unspecifoc
operator knowledge;
2: moderate Predicted to cause minor impact to quality (failure to meet specifications) not meet specification of
depending on power
Granulation kneeding time 3 3 1 9 reduce personnal fluctuation 3 3 1 9 0 consumption;
dissolution
1: minor Predicted to could have minor impact on quality of the product (quality within specifications) automatisation not possible
at that time
Probability Granulation power consumption

3 2 1 6
try to get to a minumum an optimum of
3 2 1 6 0
depending on kneeding
time depending on material
dissolution kneeding time
4: regular failures Expected to happen frequently not meet specification of
properties
Pre-mixing mixing time 3 2 3 18 IPC measure on content uniformity 3 2 1 6 12 influence on efficacy

3: repeated failures Could happen occasionally content uniformity
Analyse (seeving of granulate sieve to get fine appropriate
Pre-mixing Granulation speed of adding water disolution and 3 3 3 27 3 2 1 6 21
2: occasional failures Expected to happen infrequently desintegration
analysis); use of dosage pumps granulate

1: failure is unlikely Unlikely to happen Pre-mixing Granulation manner of adding water disolution and 3 1 1 3 install spray nozzles 1 1 1 1 2
to get fine appropriate
granulate
desintegration
Detectability all parameters have to be
Adapt internal specification of physical
Granulation Quality of Excipients 3 4 3 36 parameters (e.g. density, metability 1 2 2 4 32 contact supplier
re-evaluated
3: probably not detected May overlook a fault or failture possibly can not be detected (no technical solution up to now) wetability)
Adapt internal specification of physical
all parameters have to be
2: occasionaly not detected Failture may be missed (manual control, routinely work with statistical control) Granulation Quality of API
re-evaluated
3 4 3 36 parameters (e.g. density, metability
wetatility)
1 2 2 4 32 contact supplier
1: detectable Failture can and will be detected (e.g. using statistical tools) Overview Risk before cotrol Max
Average
36
17
Risk after control Max
Average
9
4
32
10
Min 3 Min 1 0
S. Rönninger, Roche S. Rönninger, Roche


I.2 Failure Mode Effects Analysis (FMEA) I.2: Failure Mode Effects Analysis (FMEA)
Risk Assessment
• Prepare a risk profile
Detectability (D)
Probability (P)
Severity (S)
Risk factor
[1<2<3<4]
(S*P*D)
[1<2<3]
[1<2<3]
Event
Sub-Step Effect
(Failure mode)
Severity / Consequences
i negligible
Probability
not meet specification of ii marginal
Granulation Drying water content 2 3 1 6
degradation iii critical
Risk Reduction iv catastrophic
Risk
Detectability (D)
Risk reduction
Probability (P)
protection
Severity (S)
Probability
Risk factor
[1<2<3<4]
(S*P*D)
[1<2<3]
[1<2<3]
Actions:
Risk reduction strategy
Comments
A frequent level
B moderate
C occasional
introduce online NIR 2 1 1 2 4 indirect measurment Consequences
D rare
direct measurement; time
introduce IPC analytic 2 2 1 4 2
consuming
E unlikely
indirect measurment; F very unlikely
humidity measurement in the exaust air 2 1 2 4 2 Picture: © Zurich Insurance Ltd, SwitzerlandS. Rönninger, Roche
unspecific
S. Rönninger, Roche

• Risk Evaluation
• Prepare a risk profile: Probability
> Prepare a risk profile: Consequences
S. Rönninger,
Roche
• Risk Evaluation • Risk Evaluation: Risk Profile
> Prepare a risk profile: Consequences
Hi
gh
ris
k
Lo
w
ris
k
S. Rönninger,
> For high risks, which are not acceptable, risk reduction
Roche measures have to be taken as a high priority S. Rönninger, Roche

How to perform? • QRM for facilities, equipment and utilities
3. Summary (Risk Evaluation) Assess an existing compressed air system
> The effects are rated in terms of their > Old approach: 60 “risks” should have been solved in detail
consequences and the > Initial RM-Approach:
causes are assessed in terms of their probabilities ¾ 4 sessions in total 16 people
a) qualitative or b) quantitative ¾ 153 potential risks discussed
¾ 34 Cases beyond the action limit
> Based on these results a risk profile is completed.
¾ 30 Corrective actions have been performed (- 50%)
> In this profile the risks are compared with the
> Review of RM-Approach after inspection
risk protection level, which determines the accepted ¾ Did you consider this hazard?
probability for defined consequences - yes: show and explain rationale
> Use as an aid to prioritise actions! - yes, but start discussion for a yes/no decision
- no: revisit initial risk assessment

Experiences Experiences
• Limitations
• Ease of applicability > Can be time and resource consuming
> Prospective tool > Mitigation plans must be followed up
> Good tool for operators to use > Not a good tool for analysis of complex systems
> Can be used to identify critical steps for validation > Compound failure effects cannot be analyzed
> More objective than Fault Tree Analysis > Incorporating all possible factors requires a thorough
> Covers minor risks 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
Annex I.3 I.3: Failure Mode, Effects and Criticality Analysis (FMECA)
(IEC 60812)
• Extended to incorporate an investigation
Failure Mode, of the degree of severity of the consequences,
their respective probabilities of occurrence and
Effects and Criticality their detectability
• The product or process specifications should be
Analysis established
• Identify places where additional preventive actions
(FMECA) may be necessary to minimize risks
• Utilized on failures and risks associated with manufacturing
processes ICH Q9

Annex I.4 I.4: Fault Tree Analysis (FTA)

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

process
Analysis • Identifies all potential root causes of an assumed failure or
(FTA) 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

I.4: Fault Tree Analysis (FTA) I.4: Fault Tree Analysis (FTA)
How to perform? • Basic symbols: Basic Flow
Results are represented pictorially
in the form of a tree of fault modes • Fault in a box indicates
FAULT that it is a result of previous faults
At each level in the tree, combinations of fault modes are
described with logical operators (AND, OR, etc.) ICH Q9
• Connects preceding fault
OR with a subsequent fault
that could cause a failure
• Connects two or more faults

AND that must occur simultaneously
to cause the preceding fault
Source: Overview of Risk Management Techniques. Robert C. Menson, PhD (2004).
http://www.sverdrup.com/safety/fta.pdf
• Basic symbols: End Points & Connector • Additional Symbols
• Exclusive OR Gate:
Root cause
• Root cause (= basic fault) Fault occurs
(e.g. part failure, software error, human error) if only one of the input faults occurs
• Priority AND Gate:

• Fault to be further analyzed Fault occurs
with more time or information if needed if all inputs occur in a certain order
• Voting OR Gate:
• Transfer-in and transfer-out events m Fault occurs if “m” or more out of “n”
input faults occurs
Source: Overview of Risk Management Techniques. Robert C. Menson, PhD (2004). Source: Overview of Risk Management Techniques. Robert C. Menson, PhD (2004).

• Investigation of laboratory failures
• Establish the pathway to the root cause of the failure Production outlier Calibration
• While investigating complaints or deviations to fully Out of specification

result or Lab error or systematic or Interfaces
understand their root cause

others random 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

Hard to open
Experiences
or • Better as a retrospective tool
• Visually focused: aid for showing linkages
Production Cap Bottle Stability • Limitations
> Only as good as input
or Bad fit and > Time and resource consuming (needs FMEA as a complement )
> Need skilled leader to focus on what is really important
> Need significant amount of information
Formulation Processing Packaging Solidify Ageing
> Human errors may be difficult to predict
> Many potential fault trees for a system
or
Change closing torque and - Some more useful than others
Supply Too tightly
Defect Closed calibrate periodically - Need to evaluate contribution
Takayoshi Matsumura, Eisai Co
I.2: Failure Mode Effects Analysis (FMEA) Annex I.5

I.4: Fault Tree Analysis (FTA)
FTA FMEA
• Assumes
failure of the
• Assumes
component failure
Hazard Analysis
functionality of a
product
and Critical Control Points
• Identifies the root cause • Identifies functional failure (HACCP)
of functional failure as a result of component
failure
• Top down • Bottom up

I.5: Hazard Analysis and Critical Control Points (HACCP) I.5: Hazard Analysis and Critical Control Points (HACCP)
How to perform?
“A systematic, proactive, 1. Conduct hazard analysis: identify preventive measures for
each step of the process
and preventive method 2. Determine critical control points (CCP’s)
for assuring product quality, 3. Establish target levels and critical limit(s)
reliability, and safety“ 4. Establish system to monitor the CCP’s
5. Establish corrective actions to be taken, if CCP is out of
control
WHO: http://www.who.int/medicines/library/qsm/trs908/trs908-7.pdf 6. Establish verification procedures, that HACCP works
Application of Hazard Analysis and Critical Control Point (HACCP) effectively
methodology to pharmaceuticals, WHO Technical Report Series No 908, 7. Establish documentation of all procedures and keep
Annex 7, WHO, Geneva, 2003 records ICH Q9
ICH Q9 See WHO

Initiate
HACCP Responsibility:
• Site change Risk Assessment = Hazard Analysis giving site
• To identify and manage risks associated with physical, or Identify
preventive measures
Team focused
chemical and biological hazards (including microbiological Technical Determine critical

control points (CCP’s)
contamination) transfer Target levels &

Risk Ma nagement tool: HACCP
critical limit(s)
unacceptable
• Useful when process understanding is sufficiently

Risk Communication
Risk Control: Critical Control Points

Internal consultation
comprehensive to support identification of critical control System to monitor

the CCP’s
points (critical parameters / variables) Corrective actions, Joint

if CCP is out of control
• Facilitates monitoring of critical points in the responsibility

Stakeholder involvement
Output / Results:
manufacturing process process described by HACCP
Risk Review Responsibility:

Verification that
process works effectively receiving site
ICH Q9
• Analyse a tablet process step
System to monitor Possible corrective actions,
because a systematic, proactive, and preventive risk assessment Comments
CCP if CCP is out of control
Keeping records
method helps to adjust parameters of the machine by equipment online

fix parameter to adjust < content uniformity out of range
(autoimmunisation) Batch Record
Automatic maschine without constant operator control in function with the weight of the by equipment online
automatic ejection of tablet
tablet, thickness and hardness (autoimmunisation) Batch Record
Critical Control Point Target Critical
Quality hazard Comments
(CCP) level limits
analytical data in
+/- 10 % IPC on weight rejection (100% mass control)
influence on specification of Batch Record
speed 400'000 <400'000 fix parameter to adjust
appearance
online
compression force automatic ejection of tablet
in function with the weight of the
Batch Record
influence on specification of hardness compression force 15 kN 13-18kN
tablet, thickness and hardness
release limit for stability must be stability studies critical limit: min 50 N stability studies
influence on specification of assay weight variation 200 mg 180-220 mg +/- 10 %

online
optimisation during production IPC of appearance adjust machine parameters
Batch Record

I.5: Hazard Analysis and Critical Control Points (HACCP) Annex I.6
Experiences
• Benefit
> Teamwork in cross functional groups Hazard Operability
> Use very similar principles in Qualification & Validation
> Critical control points (CCPs) are similar to Analysis
critical process parameters
• Limitations of the model (HAZOP)
> 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

I.6: Hazard Operability Analysis (HAZOP) I.6: Hazard Operability Analysis (HAZOP)
(IEC 61882) Concept
• A theory that assumes that risk events are • Focus team discussions
caused by deviations from the design or operating by applying “deviations” to specific nodes
intentions • Deviations are generated
• Identify potential deviations from normal use by applying Guidewords to process parameters
• Examine the process by discussing causes of each
How to perform? deviation
A systematic brainstorming technique > Identify consequences
for identifying hazards using so-called “guide-words” > Evaluate risk and safeguards
applied to relevant parameters: > Make recommendations, if necessary
> No, More, Other Than, None
• Include all parts of the process
ICH Q9 Source: Hazard and Operability Studies in Solid Dosage Manufacture. Nail L. Maxson. (2004).
Guidewords Explanation Remarks
NO、NOT、 The total absence of the No part of the function is active, but also
NONE function nothing else happens
MORE Quantitative increase This applies to quantities & properties such as
flow, temperature, and also for functions such
• Manufacturing processes or
as heating and reacting.
LESS Quantitative decrease
• Equipment and facilities AS WELL AS Qualitative increase All desired functions & operations are achieved.
or Additionally, something else happens. Only a
few functions are achieved, some not.
• Evaluating process safety hazards PARTIALLY Qualitative decrease
REVERSE The logical reverse of the This applies mainly to functions, e.g., reverse
• Primarily as starter of a HACCP desired function 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.
• Operator error (“use error”)
OTHER Total exchange The original function is not performed.
Something totally different happens.
ICH Q9
prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance July 2006, slide 73 prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance Nail L. Maxson. (2004). July 2006, slide 74

Experiences
Deviation Causes Consequences Safeguards Recommend
• Ease of applicability of the model?
High Steam heating z Feed material #1 z Diverse high temp. z Test interlock
temperature in control reaches interlock on on quarterly > Simplifies decision making
blender malfunction decomposition blender basis
temperature
> Allows uniformity of analysis across sites
z Blender vented z Add steam
z Violent reaction with heating control > Process steps guided (“guide words”, if available)
toxic gas generation to monthly PM
• Limitations of the model
z Personnel exposure/
injury > Applies to specific situations only
z Equipment damage > 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).

Annex I.7 I.7: Preliminary Hazard Analysis (PHA)

(ISO14971)
• Analysis based on applying prior experience or knowledge
Preliminary Hazard of a hazard or failure to identify future hazards, hazardous
situations and events that can cause harm
Analysis • In estimating their probability of occurrence for a given
activity, facility, product or system
(PHA) 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
ICH Q9
I.7: Preliminary Hazard Analysis (PHA) I.7: Preliminary Hazard Analysis (PHA)
The steps
Hazards Arising From Product Design
• Risk Matrix Form Hazards Arising From Product Design
Investigation/ Imp
Hazard Sev Freq
Controls (SxF)
> List known Investigation/
Hazard Sev Freq Imp
potential hazards Controls
- Literature SOPs,
- Previous projects Wrong Material Sev Rem I
Crosscheck
- Reportable events
- Complaints Lack of stability Stability studies Min Occ I
• Severity rankings
• Frequency codes and estimates risk codes
• Once established should remain same for similar product
classes

I.7: Preliminary Hazard Analysis (PHA) Annex I.8

• Analyzing existing systems
• Prioritizing hazards Risk ranking
• Evaluate the types of hazards for the general product
type, then the product class and finally the specific
and
product
• Early in the development: little information on design
filtering
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
ICH Q9

I.8: Risk ranking and filtering I.8: Risk ranking and filtering
Compare and prioritize risks
How to perform?
• Requires evaluation of multiple diverse quantitative and • To prioritize manufacturing sites for inspection/audit by
qualitative factors for each risk regulators or industry
• Involves breaking down a basic risk question into as many • Helpful in situations in which the portfolio of risks and the
components as needed to capture factors involved in the underlying consequences to be managed are diverse and
risk difficult to compare using a single tool
• These factors are combined into a single relative risk score
• Useful when management needs to evaluate both
that can then be compared, prioritized and ranked
quantitatively and qualitatively assessed risks within the
same organizational framework ICH Q9
ICH Q9
Evaluation of products and processes with recurring Evaluation of products and processes with recurring quality
quality relevant problems relevant problems
Risk assessment: Risk identification Risk assessment: Risk evaluation

> recurring quality relevant problems within Three columns
based on a
production and/or processes 500 1000 2000
Resources
classical approach 500
Risk assessment: Risk analysis by multiplying factors
Footing on an analysis of 50 50 100 200
> Production problems 1999-2002
> Complaints 2000-2002 Probability 5 5 10 20
> Investigation Reports 2000-2002 1: rare quality events
> Recalls 2000-2002 2: infrequent quality events 1 2 4
> Additional information from manufacturer considered 3. frequent quality events Probability
J. Knöbel, S. Marrer, Roche Based on J. Knöbel, S. Marrer, Roche

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

Analyze production problems Risk evaluation added to production problems
Site Product name Type of recurrent problem/defect Site Product Type of recurrent Proba- Resources Risk (Probability
name problem/defect bility multiplied with
A ABC Broken units Resource)
B ACB Broken tablets A ABC Broken units 4 500 2000
C BAC Melt backs during lyophilization B ACB Broken tablets 2 500 1000
A CAB Foreign particles C BAC Melt backs during 4 50 200
lyophilization
A CAB Foreign particles 2 50 100
J. Knöbel, S. Marrer, Roche J. Knöbel, S. Marrer, Roche


Risk assessment: Risk Control Risk assessment: Risk analysis

Risk control actions added to production problems Analyze process problems
Site Product Type of Corrective Proba- Resources Risk (Probabili
name recurrent actions bility multiplied with
Process Products concerned
problem/defect instituted to Resources) Printing of Variable Data ABC
date
ACB
A ABC Broken units Task force 4 500 2000
headed by BAC
B ACB Broken tablets Investigations in 2 500 1000 CAB
B initiated
C BAC Melt backs Investigating 4 50 200 CBA
during process impro- Blister: blister foil peels off ABC
lyophilization vements
together with ACB
production BAC
A CAB Foreign Project initiated 2 50 100
CAB
particles J. Knöbel, S. Marrer, Roche J. Knöbel, S. Marrer, Roche
Risk assessment: Risk evaluation Risk assessment: Risk Control

Risk evaluation added to process problems Risk control actions added to process problems
Process Products Proba- Resources Risk Process Products Corrective Proba- Resources Risk
concerned bility (Probability concerned actions bility (Probability
multiplied with instituted to multiplied with
Resources) date Resources)
Missing prints of Variable Data ABC 4 500 2000 Missing prints of ABC Project started, 4 500 2000
ACB 4 50 200 Variable Data ACB corrective 4 50 200
BAC measures under 4 50 200
BAC 4 50 200
CAB discussion 4 5 20
CAB 4 5 20
CBA 4 500 2000 CBA 4 500 2000
Blister: blister foil peels off ABC 2 500 2000 Blister: blister ABC Task force 2 500 2000
ACB 2 50 100 foil peels off ACB established 2 50 100
BAC 2 50 100 BAC 2 50 100
CAB 2 50 100J. Knöbel, S. Marrer, Roche CAB 2 50 100J. Knöbel, S. Marrer, Roche

Severity
Evaluation of products and processes with recurring quality Risk Matrix (1)
relevant problems
Medium
Risk
High
Low
Risk Class ONE
Risk communication Ranking
• Providing stakeholders
with the update of the overview of Risk control step
High Risk Class TWO
Probability
Risk Review
Medium
• Regularly the responsible person Risk Class THREE
updates the overview to support line/senior Low
management decisions
J. Knöbel, S. Marrer, Roche Takayoshi Matsumura, Eisai


I.8: Risk ranking and filtering Annex I.9

Detection
Risk Matrix (2)
Medium
Supporting
High
Low
Risk HIGH priority

Filtering
MEDIUM priority
statistical tools
Risk Classification
ONE
TWO
LOW priority
THREE
Takayoshi Matsumura, Eisai

I.9: Supporting statistical tools I.9: Supporting statistical tools
• Control Charts (for example): Control charts (ISO 7870)

> 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 • Shows statistically determined upper and lower control
(see ISO 7873) limits drawn on either side of the process average
> Acceptance Control Charts (see ISO 7966)
• The bounds of the control chart are marked
> Cumulative Sum Charts (ISO 7871)
by upper and lower control limits
> Weighted Moving Average
Aid for: > Calculated by applying statistical formulas to data
• Design of Experiments (DOE) - Effective data
assessment > Data points that fall outside these bounds represent
• Pareto Charts variations due to special causes
- Aid in determining
• Process Capability Analysis the significance of > Can be found and eliminated
the data set(s)
ICH Q9 • Improvements require changes in the process ICH Q9


Control charts Control Chart: Shewhart Control Charts (ISO 8258)
Potential Areas of Use(s) • Use warning limits
• Analysis trend patterns
• Monitoring critical parameters
• Provides information to determine
> Process capability
> Variability
> Control Example
Example
• Some charts are dealing with Potential Areas of Use(s)
warning limits or trend analysis • Statistical control of the process
ICH Q9 ICH Q9


Control Charts with Arithmetic Average and Warning Limits Control Chart: Acceptance Control Charts (ISO 7966)
(ISO 7873) • Chart with a central line
• A control chart with within an acceptable
warning and action limits
process zone
• Ideal the average
should be the
Potential Areas of Use(s) target value
• Enable a base period of quality measure Potential Areas of Use(s)
• Provide a basis for the construction of relationships between a • During regular batch manufacturing can give guidance for
process and product quality determine sample size, action limits and decision criteria
• Producing recommendations for the adjustment of the process • Ongoing improvements under process robustness/six sigma
• Can be applied with process Analytical technology tools program can be initiated
ICH Q9 ICH Q9
Compilation of limits and ranges I.9: Supporting statistical tools

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


Control Charts: Cumulative Sum Charts (ISO 7871) Control Charts: Cumulative Sum Charts (ISO 7871)
• Analyze
process parameters
or analytical results
(e.g. PAT)
• Allow the detection of
slight discrepancies
in a process
before a trend is visible
Assay
using other
control charts Example
ICH Q9


Control Chart: Weighted Moving Average Design of Experiments (DoE)
• A simple, or arithmetic, moving average • Design experiments based on
is calculated by adding the closing results statistical considerations
of the security for a number of time periods
and then dividing this total by • Analyze data and results to determine
the number of time periods > establish key parameters Degradation and fines
Inlet temperature
> process variables

> explore potential interactions
Degradation Fines

Inlet humidity
Inlet humidity
• Analyze process parameters or analytical results (e.g. PAT)

• Allow the detection of slight discrepancies in a process Air flow
before a trend is visible using other control charts ICH Q9 Air flow Air flow

Design of Experiments (DOE) Design of Experiments (DOE) in a submission
Potential Areas of Use(s) • 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 • As an appendix
(Proven Acceptable Ranges > Number and levels of factors under study
• Systematically choosing certain combinations of > The experimental matrix with the values of the responses
variables it is possible to separate their individual for each combination of factors
effects
• Graphical representation
• A special variant: focus on optimizing design
parameters to minimize variation BEFORE optimizing > Coefficient plot of the relative significance of the factors
design to hit mean target values for output parameters under study and interactions between them
ICH Q9 Reflection paper on…PAT: EMEA/INS/277260/2005, March 20, 2006


Design of Experiments (DOE) in a submission Pareto Charts
• Statistical evaluation of the model derived from DoE (e.g. • Created by plotting the
ANOVA table) cumulative frequencies
of the relative frequency data
• Graphical representation of the relationship of the significant in descending order
factors under study with the responses (e.g. response surface • The most essential factors
and contour plots) providing a clear overview of the for the analysis are
conclusions. graphically apparent,
and in an orderly format
• The Design Space (based on real test results and/or on the
model) as defined in ICH Q8 should be described
• Identify those factors that have the greatest cumulative effect on
• Verification of the model derived from DoE a system
• Few important factors in a process: Screen out the less
Reflection paper on…PAT: EMEA/INS/277260/2005, March 20, 2006 significant factors ICH Q9


• Pareto Chart Process Capability Analysis
• Estimate the potential percent of defective product
Cp value cp=0.5 cp=1 cp=3

graphical view of UGW OGW UGW OGW UGW OGW
different cp values
values statistically
13,58 % 0,27 % approx. 0
out of limit
values in the limit
86,42 % 99,73 % > 99,999999 %
process statistically
Result: process statisticaly under control
out of control

Process Capability Analysis Histogram
• A simple, graphical view of accumulated data
Potential Areas of Use(s) > 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
Process
specification
compatibility
• Requirement: Process specific data
• Tool for both regulator and industry Example
ICH Q9 ICH Q9

I.9: Supporting statistical tools Others

Scatter diagrams (x/y-diagram)
• To depict the influence that one variable has on another
• Usually displays points representing
the observed value of one variable
Combination
corresponding to the value of another variable
• How to perform:
of tools
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) Probabilistic Risk Assessment (PRA)

• Integrating various reliability modelling tools How to perform?
such as Fault Tree, Event Tree Block Diagram, FMEA • To identify an undesired top event
to numerically quantify risks e.g. "loss of life" or "loss of mission“
• Determine what quality risk scenarios can occur, what is • Trace out all quality risk that could lead to this events.
the likelihood and the consequences given they occur.
• Conducted through the use of event trees (fault trees)
• Estimates of the parameters used to determine the
• At the lowest level: basic events are assigned probabilities
frequencies and probabilities of the various events
• 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
Examples of combination of tools Examples of combination of tools
Another way to proceed

Another way to proceed
1. Define the scope of QRM
1. Define the scope of an analysis 2. Choose team and team leader
Collect all relevant data surrounding the system
Subject to determine the need for additional information 3. Identify hazards and assess hazard scenarios
4. Build the risk profile to visualize the risks:
2. Describe the desired and controlled conditions of the - set the risk tolerance boundary
process - plot the risks
3. Using a structured approach identify the risk 5. Develop risk reduction actions
by reviewing the direct and indirect causal areas 6. Accept risk reduction actions
4. Using assessment tools (e.g. statistical) assess the hazard 7. Implement risk reduction actions
8. Follow up on success

Zurich Hazard Analysis ICH Q9 Examples of combination of tools

Initiate
Establish a team “Zurich Hazard Analysis” Methodology
Risk Assessment
Step 1 Basic Data Risk Identification A systematic approach managing quality risks
Step 2 Process Conditions
Risk Analysis
Step 3 Hazard Identification • Step 1 Basic Data

Step 4 Hazard Assessment Risk Evaluation
unacceptable > Define the scope carefully
Risk Communication
Step 5 Risk Evaluation Risk Control

> Collect all relevant data about the system
Risk Reduction
Step 6 Risk Reduction > Determine the need for additional data
Measures Risk Acceptance
Step 7 Residual Risk

Output / Result of the • Step 2 Process Conditions
Summary > Describe the desired, quality function of the system
Risk Review
Requirement by a Quality Review Events
Management System © Zurich Insurance Ltd, Switzerland

© by Zurich insurance company

Examples of combination of tools Examples of combination of tools

“Zurich Hazard Analysis” Methodology “Zurich Hazard Analysis” Methodology
• Step 3 Hazard Identification

• Step 5 Risk Evaluation
> Systematic approach by reviewing all critical areas
> The effects are rated in and
> An optimal method doesn’t exist the result completes the risk profile
as it depends on the particular system being analysed
> In this profile the risks are compared
• Step 4 Hazard Assessment with the risk protection level
> The effects are rated in terms of their consequences and
the causes are assessed in terms of their probabilities • Step 6 Risk Reduction Measures Picture: © Zurich Insurance Ltd, Switzerland
> Based on these results a risk profile is created > Measures to be taken for every unacceptable risk to reduce
> In this profile the risks are compared with the the consequences and the probability or both
risk protection level: define the accepted level > Prioritise actions
© Zurich Insurance Ltd, Switzerland Picture: © Zurich Insurance Ltd, Switzerland
Examples of combination of tools

“Zurich Hazard Analysis” Methodology
• Step 7 Residual Risk
> The residual risk is acceptable
if the risk protection level is achieved
> Current scientific knowledge and techniques Conclusion
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
Picture: © Zurich Insurance Ltd, Switzerland

ICH Q9 QUALITY RISK MANAGEMENT CONSIDERATIONS ICH Q9 QUALITY RISK MANAGEMENT
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
• Failure Mode, Effects and Criticality Analysis (FMECA) • Control Charts
> FMEA & links severity, probability & detectability to criticality • Design of Experiments (DOE)
• Fault Tree Analysis (FTA) • Pareto Charts
> Tree of failure modes combinations with logical operators
• Hazard Analysis and Critical Control Points (HACCP) • Probabilistic Risk Assessment (PRA)
> Systematic, proactive, and preventive method on criticality • Process Capability Analysis
• Hazard Operability Analysis (HAZOP)
> Brainstorming technique
• Preliminary Hazard Analysis (PHA) Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
The results from using statistical methods
> Possibilities that the risk event happens Risk Analysis
Risk Evaluation
can not be better than your data
Risk Manage me nt t ools
Risk Comm unication
unacceptable
• Risk ranking and filtering

Risk Control
Risk Reduction
Risk Acceptance
> Compare and prioritize risks with factors for each risk
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
This Annex is intended to identify opportunities
and references for some of the primary tools
for the use of quality risk management principles
by industry and regulators
• Might be used in QRM by industry and competent
(e.g., for both inspections and submissions).
authorities
However, the selection of particular risk management tools is
• This is not an exhaustive list completely dependent upon specific facts and circumstances.
These examples are provided for illustrative purposes and only
• No one tool or set of tools is applicable to every situation suggest potential uses of quality risk management.
in which a QRM procedure is used This Annex is not intended to create any new expectations
beyond the current regulatory requirements.
ICH Q9 Introduction to Annex I
Annex I: Methods & Tools Annex II: Potential Applications
It is not always necessary to use formal risk

management tools in a QRM process,
Quality
however in the right circumstances Risk Management
they can be very powerful
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.
Annex II: Potential Applications Annex II: Potential Applications

Purpose of this part Introduction
• This Annex is intended to identify potential uses

• To guide through of quality risk management principles and tools
Potential Applications for Quality Risk Management by industry and regulators.
• However, the selection of particular risk management tools
is completely dependent upon specific facts and
• Provision of some concrete, circumstances.
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
beyond the current regulatory requirements. ICH Q9

Potential Applications for Quality Risk Management Quality risk management

Quality Risk Management as Part of…
Communication
II.1 Integrated Quality Management facilitates trust
II.2 Regulatory Operations and understanding
II.3 Development
II.4 Facilities, Equipment and Utilities Regulators Industry
II.5 Materials Management operation operation
II.6 Production - Reviews - Submissions
- Inspections - Manufacturing
II.7 Laboratory Control and Stability Studies
II.8 Packaging and Labelling
Quality Risk Management is not a single process Probability and Severity

Start
Process-
step • Given the broad concept of risk
Risk can probability and severity be more narrowly defined?
Decision identification
• Probability has two major meanings
Feedback
procedure > Frequency of “successes” divided by the number of trials
Risk
Sub-Sub- Sub- analysis > Degree of belief
process process
• Severity is even more difficult to qualify as it often has
Start
Start different variable attributes around a quantifiable outcome
Etc. • Examples…
End
End G. Claycamb, FDA, Sept. 2005
End

Which consequence is more severe? 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 What does a “30% chance of rain tomorrow” mean?
next 20 years > 30% of the days like tomorrow will have at least a
Even in a narrow context, trace of rain.
e.g., “microbial contamination”, severity potentially spans:
> 30% of the area will have rain tomorrow.
> Product spoilage…
> 30% of the time tomorrow, it will rain.
> Mild malaise…acute illness…(acute) death
See Gigerenzer, et. al (2005)
> Chronic illness…premature death G. Claycamb, FDA, Sept. 2005 G. Claycamb, FDA, Sept. 2005

Challenges for potential applications 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 Company Shareholder Patient
advantage viability harm harm Quality / GMP
> …
• Answer 2:
Safety & Efficacy
> Look out of a window ICH Q9

S. Rönninger, Sept. 2005
Existing organisation Risk Management Strategy for Excipients
Operations
Development Manufacturing Launch Surveillance
Estimate risk Confirm acceptability Implement protective Implement surveillance

Support vs hazard measures measures
• Characterize • Define specs/quality • Create literature/define • Monitor issues and
materials system practices surveillance criteria assess root causes
Manufacturing Quality Unit Procurement etc • Conduct • Define • Monitor • Re-assess effectiveness of
“hazard exposure process controls process controls process controls
assessment”
Quality Management • Develop risk • Confirm risk • Implement risk mitigation • Re-assess effectiveness of
mitigation strategy mitigation strategy strategy Risk mitigation
Quality Assurance • Define risk control • Select risk control • Implement risk control • Re-assess effectiveness of
measure (s) measure (s) measure (s) Risk control measure(s)
Quality Control
Validation Evaluate results and make appropriate course corrections based on regulations,
customer expectation, company policies and procedures, societal trends and needs
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 > Documentation

> Training and education
Quality Management > Quality defects
> Auditing / Inspection
Industry
> Periodic review
Competent > Change management / change control
Authorities
> Continual improvement

II.1: QRM as Part of integrated Quality Management Existing document structure Law,
regulations,
requirements
• Documentation Existing
internal
documentation Where
to be in
> To review current interpretations and application of system future?
regulatory expectations (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
Records
(e.g. Standard Operating Procedures)
Rules & Procedures Records &

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

ase
k-b ch “risk-based approach” for decision making
Ris proa r
ng
s
al risk
list of MEA table
ap e
nt
ki
id
eci for thin

se me
ns Q 9 • Include consideration of ICH Q9 guideline
Co CH
ba ple
ls
d
residu
I in the “directive on Quality Unit-activities” as a
too
ris Im
requirement
e.g. F
fic
s
k-
ple
us Exam
• During periodic review of regulations, policies,
sp
guidelines and standard operating procedures (SOP) etc.
ing
think about implementing the ICH Q9 principles
• Share examples of specific tools and their use
as a means of sharing best practice

II.1: QRM as Part of integrated Quality Management II.1: QRM as Part of integrated Quality Management
• Training and education • Quality defects

> To determine the appropriateness of initial and/or > To provide the basis for
ongoing training sessions identifying, evaluating, and communicating
- Based on education, experience and working the potential quality impact of a suspected
habits quality defect, complaint, trend, deviation, investigation,
- A periodic assessment of previous training out of specification result, etc.
(effectiveness)
> To identify the training, experience, qualifications > To facilitate risk communications
and physical abilities > To determine appropriate action
> To perform an operation reliably and to address significant product defects,
with no adverse impact on the quality of the product in conjunction with regulatory authorities (e.g., recall)
ICH Q9 ICH Q9

Assess the history of known quality defects Assess the history of known quality defects
• Vision ICH Q9 Site approach
Initiate
> Robust Processes, non-recurrent Q-problems

Identification of opportunities
Risk Assessment for improvement
• Target Risk Identification
Use risk assessment tool
> Continuous improvement to resolve known problems Risk Analysis -risk analysis
-risk evaluation & prioritization
e.g. from CAPA, inspections/audits, non robust Risk Evaluation
unacceptable Select improvement
processes
Risk Communication
opportunities
Risk Control
Dedicated projects
> Preventatively work towards the achievement of a Risk Reduction
- Establish a team
high reliability, productivity, quality of all that we do Risk Acceptance
Problem solving approach
> Manage dedicated projects to support site / departments / Output / Result of the
process / products Risk Review

Risk review :
re-application of
Review Events risk assessment tool
Assess the history of known quality defects Assess the history of known quality defects
• Approach The project approach

> Increase the knowledge of weaknesses for all processes • Teamwork (inter-departmental teams)
at the site and evaluate the related risks possibly using a facilitator
> Tackle individual issues by problem solving methods > Select methodology
e.g. root cause analysis, statistics, tools > Commit resources appropriate to the project, priority and size
• Tool • Problem solving structure

> Risk Assessment tools: select dynamic tool to identify > Problem Finding & Setting
which are the most significant problems in order to > Problem Analysis
allow identification of priorities (e.g. FTA, FMEA, etc.) > Problem solution identification
> SixSigma type Project approach for problem solving > Sharing with management (communication)
teams on each identified priority > Decision making & implementation

II.1: QRM as Part of integrated Quality Management Deviation/ Investigation Report
Deviation / Investigation Report • Risk assessment: Risk analysis

• The event triggers a review of quality risk management > Assessment of effects of the discrepancy
decisions Examples if applicable:
> to control or accept risk related to a process - Product quality
> to ensure these decisions are still valid based on the new
- Drug safety
learning - Registration files / Marketing authorisation
• In detail this could include: - Systems in place
- Availability of goods:
> Initiate Quality Risk Management process:
potentially insufficient stock levels
Product and process information
Initiate Initiate
Quality Risk Management Process Quality Risk Management Process
Risk Assessment Risk Assessment
> Identification of the root cause

Risk Identification Risk Identification
Risk Analysis Risk Analysis
> Define the problem:

Risk Evaluation Risk Evaluation
unacceptable unacceptable
RiskManagement tools

RiskCommunication
Risk Communication
Risk Control Risk Control
Risk Reduction Risk Reduction
Detailed description of the discrepancy

Risk Acceptance Risk Acceptance
Output / Result of the Output / Result of the

Risk Review Risk Review
Review Events Review Events

Deviation/ Investigation Report Deviation/ Investigation Report

• Risk Control: Risk Reduction/ Mitigation
• Risk assessment: Risk evaluation
> Corrective actions to resolve the discrepancy
> Corrective actions to avoid a recurrence in the future
> Consequences for other products / batches
• Risk Control: Risk Acceptance
> Systems failure > Conclusions of measures taken
> Decisions on disposition of the material
> Evaluation of > Define Follow up actions (if applicable)
- Performed > Management summary (if applicable)
- Foreseen actions
Initiate Initiate
> Date and signature

- Measurements

RiskCommunication
RiskCommunication
- responsible manager
- …
- approval of QU
Deviation/ Investigation Report Deviation/ Investigation Report
• Risk Communication • Risk Review
> Frequent interactions (e.g. short daily meeting) > Follow up of action items
> Informal meetings > Summary and evaluation
> Scheduled regular meetings (minutes) e.g. Annual Product Review

Initiate Initiate


RiskCommunication
RiskCommunication


One page: Deviation/ Investigation Report

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 communication:

Risk Assessment
Risk Identification
Risk Analysis
to central coordination unit

Risk Evaluation
unacceptable

RiskCommunication
Risk Control
Risk Reduction
Risk Acceptance

Risk Review
Review Events

Complaint/ Issue Management Complaint/ Issue Management

• Risk assessment: Risk analysis Risk assessment: Risk evaluation
> Assessment of effects of the discrepancy > Consequences for other batches/ products
Examples if applicable: > Systems failure
¾ Lot tracing
> Evaluation of
¾ Product quality
¾ Available data
¾ Patient impact
¾ Performed actions
¾ Registration/ Marketing authorisation
¾ Foreseen actions
¾ Systems in place
¾ Measurements
¾ Availability of stock:
potentially insufficient stock levels..
Initiate
Risk Assessment
¾ … Initiate
Risk Assessment
> Risk communication: to central coordination

> Identification of the root cause


Risk Communication
Risk Communication
unit; involve management, if appropriate

> Risk communication: to expert team

Complaint/ Issue Management Complaint/ Issue Management

• Risk Control: Risk Reduction/ Mitigation • Output/ result: Risk Communication
> Corrective actions to resolve the discrepancy Internal
> Corrective actions to avoid a recurrence in the future > Sites / Affiliates
• Risk Control: Risk Acceptance > Informal meetings
> Conclusions of measures taken (management sign off) > Address in regular meetings
> Decisions on disposition of the material > Training sessions
> Define follow up actions (if applicable) External
> Management summary (if applicable) > Communicate with Competent Authorities
(e.g. Field Alert, incident summary)
Initiate Initiate
> Date and signature of minutes

Risk Evaluation
unacceptable
> “To whom it may concern” – letters Risk Evaluation

unacceptable

RiskCommunication
Risk Communication
> Risk communication: management to decide
> Pharmacies
“next steps”

Complaint/ Issue Management II.1: QRM as Part of integrated Quality Management

• Auditing / Inspection
> To define the frequency and scope of audits
• Risk Review > Taking into account factors such as:
¾ Existing legal requirements
> Follow up of action items ¾ Overall compliance status and history of the company
¾ Robustness of a company’s quality risk management activities
¾ Complexity of the site, manufacturing process,
> Summary and evaluation product and its therapeutic significance
¾ Compliance status and history
e.g. Product Quality Review, Annual Product Review,
¾ Results of previous audits/inspections
follow-up report ¾ Number and significance of quality defects (e.g, recall)
Initiate
Risk Assessment
¾ Results of previous audits/inspections
Major changes of building, equipment, processes, key personnel
Risk Identification
Risk Analysis
Risk Evaluation
¾
unacceptable
Experience with manufacturing of a product

¾
RiskCommunication
Risk Control
Risk Reduction
(e.g. frequency, volume, number of batches)

Risk Acceptance
ICH Q9
Test results of official control laboratories

Risk Review
Review Events
¾

Inspections Risk Communication & Scheduling audits: A framework

Risk Review
Start
cGMP/Compliance
How industry might be able to set up a risk-based evaluation
Inspections scheme to assess the need to audit.
Risk Assessment Risk Control
A similar approach could be used by competent authorities
Risk Identification Risk Acceptance (CA) for scheduling inspections.
(Databases) (Work Planning)
1. Brainstorm
Risk Analysis & RiskReduction
Risk Reduction to create a list of manufacturers / traders to be audited
Risk Evaluation (RiskRanking
(Risk Ranking
(Multi-Factorial Risk andFiltering)
and Filtering) 2. Evaluate all sources of audit reports
Model) from competent authorities, competent companies or third
parties conducted according local and/or other GMP-
Data
Datasources
sourcesinclude
include
Quality standards (e.g. PIC/S, WHO respective VFA, APIC)
QualitySystems
Systems(“Q10”)
(“Q10”) S. Rönninger & EFPIA TG
&&Mfrg
MfrgScience
Science(Q8)
(Q8) D.Horowitz, FDA April 2005 foreign inspections Feb.06
Scheduling audits: A framework Scheduling audits: A framework
3. Evaluate risk factor 4. Weighting on to protection of patient

according to criteria based on managing risk for patients,
which can (easily) be evaluated and maintained:
> Severity: Compliance: effects safety & efficacy

> Severity: Patient interest: effects availability
> Probability: Complexity: Drug(medicinal)product, API etc.
> Detectability: Audit History frequency of audit/inspections
See list on following slides:
- In case of different activities take the highest ranking!
- In case their is nothing known, take the highest ranking!
S. Rönninger & EFPIA TG S. Rönninger & EFPIA TG
foreign inspections foreign inspections
Feb.06 Feb.06


• Compliance (Severity) • Compliance (Severity)
patient risk: addressing safety & efficacy patient risk: addressing availability
S. Rönninger &
EFPIA TG
foreign inspections
Feb.06 S. Rönninger & EFPIA TG foreign inspections Feb.06


• Complexity (Probability) • History
(Detectability)
S. Rönninger & S. Rönninger &

EFPIA TG EFPIA TG
foreign foreign
inspections inspections
Feb.06 Feb.06
Why “96”?
5. Multiply the factors Conclude to schedule an audit when,
6. Sort by overall risk factor
7. Announce audits > Compliance/Severity: Safety & Efficacy = medium (3) or more
on a predetermined figure > Compliance/Severity: Availability = major (4) or more
e.g. 96 > Complexity: Probability = indirect use for
patient (2) or more
> History: Detectability = 3 years ago (4)
or more
S. Rönninger &
EFPIA TG This would result in 3 x 4 x 2 x 4 = 96
foreign
inspections EFPIA TG foreign inspections Feb.06
Feb.06

Scheduling audits II.1: QRM as Part of integrated Quality Management

• Result:
an overview • Periodic review
> Updating
once a year > To select, evaluate and interpret trend
for planning
results within the product quality review
Weighted factors
> To interpret monitoring data
Indication e.g. to support an assessment of the need
for priority for revalidation, changes in sampling etc.
Do not trust in
the values only ICH Q9

II.1: QRM as Part of integrated Quality Management Responsibilities in case of Change Control
Initiate
Industry Quality Risk Management Process
• Change management / change control Risk Assessment
> To manage changes based on Risk Identification

Team focused
knowledge and information Risk Analysis
accumulated in pharmaceutical development and Risk Evaluation
during manufacturing unacceptable

Risk Communication
Risk Control
> To evaluate the impact of the changes Risk Reduction
on the availability of the final product

Risk Acceptance
> To evaluate the impact on product quality of changes


Quality Risk Management Process Regulators
> To determine appropriate actions
preceding the implementation of a change Risk Review
Review Events
ICH Q9
II.1: QRM as Part of integrated Quality Management Continual Improvement

Customer Requirement
• Continual improvement
Regulatory Submission
Supplement/ Variation
Complaint etc.
> To facilitate continual improvement Define
in processes throughout the product lifecycle
Change Control, Pharmaceutical
Annual Review Development
Quality
Risk
Management
Manufacture Design
Technology
Transfer
Customer Satisfaction
ICH Q9 All red arrows are a part of Risk Communication
Takayoshi Matsumura, Eisai Co.

II. 2 Quality risk management as part of… II.2: QRM as Part of regulatory operations
Inspection and assessment activities

Industry
• To assist with resource allocation including e.g.
Regulatory
> Inspection planning
Competent
Authorities > Inspection frequency
operations >
>
Intensity of assessment and inspection
(see "Auditing" section in Annex II.1)
Inspection and assessment activities
• To evaluate the significance of e.g.
> Quality defects
> CAPA following a recall
> Inspectional findings
ICH Q9

Scheduling Inspections II.2: QRM as Part of regulatory operations

• Target: Inspection and assessment activities
Develop criteria, which can (easily) be
• To determine the appropriateness and type
evaluated/maintained by members of
of post-inspection regulatory follow-up
the department responsible for the audit plan….
• To evaluate information submitted by industry
including pharmaceutical development information
See previous section II.1: • To evaluate impact of proposed variations or changes
auditing / inspection • 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)
II. 3 Quality risk management as part of… About development
Critical
Parameters
Development
Industry
that contribute
Competent to variation in customer
Authorities requirements
See also next chapters Parameters that impact
using the intention to be applicable for development customer requirements
II.4: Facilities, Equipment and Utilities
II.5: Materials Management
II.6: Production
II.7: Laboratory Control and Stability Studies
All parameters and dimensions
II.8: Packaging and Labelling 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”
Note: Non detected OoS
Production
• To design a quality product and its manufacturing process could result in a patient risk
> 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)
Validation
> processing options
> process parameters • Consequence: Frequent, major OOS
• Corrective actions eliminate “Special Cause”
ICH Q9 Result: Unstable process Based on A. Hussain, FDA, September 2004

Quality by design : “Special Cause” or “Common Cause” 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 • Reduce “Common Cause” Variability
Result: Stable & Capable A. Hussain, FDA, September 2004 Result: Stable- Yes; Capable? A. Hussain, FDA, September 2004
II.3: QRM as part of development II.3: QRM as part of development

• 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)
> Starting materials • To assess the need for additional studies
> Excipients (e.g., bioequivalence, stability)
relating to scale up and technology transfer
> Packaging materials
• To make use of the “design space” concept

• To establish appropriate specifications, identify critical
(see ICH Q8)
process parameters and establish manufacturing controls
ICH Q9 ICH Q9

P2 of CTD as part of a regulatory submission P2 of CTD as Quality Risk Management process ?

Initiate
Formulation & Process design Risk Assessment
Risk Identification
Risk Analysis
Process understanding
Risk Evaluation
unacceptable
Manufacturing Concept

Risk Communication
Risk Control
Process control Concept Risk Reduction
Risk Acceptance
Product release Concept
Regulatory strategy
Risk Review
In line with Quality Risk Management ? Review the submission Review Events

Target Product Profile
Risk Management approach to focus on critical attributes
Developm.
Development
Drug substance properties; prior knowledge Unit operation
Proposed formulation and manufacturing process Research Dispensing Granulation Drying Blending Tableting
Quality Attributes
Re-
Re-evaluation and confirmation
Dissolution
Re--evaluation and confirmation
Determination of Significant
influence
Formulation understanding Operation
Cause – Effect relationships Disintegration

Process understanding
(Risk Identification with subsequent Risk Analysis) Phase 1 Initial

Hardness
assessment
Risk-based classification Assay
Prior
(Risk Evaluation) Content knowledge
Uniformity
First & Second
Parameters to investigate (e.g. by DOE) Degradation
review cycle
(Risk Reduction 1. proposal; 2. verified)
Stability Formulation
and Process
Appearance understanding
Product and process
FORMULATION characteristics on the PROCESS Identification Third
Re
DESIGN SPACE DESIGN SPACE review cycle

final drug product
Water
Phase 2 BY UNIT OPERATION Control
CONTROL Microbiology
Strategy
Review events Phase 3
STRATEGY
prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance Launch July 2006, slide 203
EFPIA PAT TG, 2006
prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance July 2006, slide 204
EFPIA PAT TG, 2006
low
Risk to patient Process understanding Responsibilities in regulatory operations
Control Strategy Initiate
Unit operation Industry Quality Risk Management Process
Unit operations Blending

Dispensing (Raw Risk Assessment
/ Granulation Drying (Magnesium Tableting Packaging
Material Properties)
Quality attributes Stearate) Risk Identification
Power Not critical to Not critical to
Team focused
Dissolution Particle size API
consumption
Prior knowledge
quality quality
Prior knowledge
water amount and Not critical to Not critical to Risk Analysis
Disintegration Particle size API
feed rate
Prior knowledge
quality quality
Prior knowledge
Quality Attributes
Not critical to Not critical to

Hardness Prior knowledge Prior knowledge Prior knowledge
quality quality
Prior knowledge Risk Evaluation
unacceptable

Risk Communication
Assay Prior knowledge Prior knowledge Prior knowledge Prior knowledge NIR measurement Prior knowledge
Power Not critical to Not critical to Risk Control
Content uniformity Prior knowledge NIR measurement Prior knowledge
consumption quality quality
Risk Reduction B) Inspectorates
Water amount and Not critical to
Degradation Prior knowledge
feed rate quality
Prior knowledge Prior knowledge Prior knowledge
Control water Risk Acceptance
Stability Prior knowledge Prior knowledge
content
Prior knowledge Prior knowledge Prior knowledge
Not critical to Not critical to
Appearance Prior knowledge Prior knowledge Prior knowledge Prior knowledge
quality quality Output / Result of the
Identification NIR of raw material Prior knowledge Prior knowledge Prior knowledge Prior knowledge Prior knowledge
Quality Risk Management Process A) Reviewers
Control water
Water Prior knowledge Prior knowledge
content
Prior knowledge Prior knowledge Prior knowledge Risk Review
Specification of Purified water Review Events

Microbiology starting material used
Prior knowledge Prior knowledge Prior knowledge Prior knowledge
EFPIA PAT TG, 2006
Annex II: Potential Applications Annex II: Development and

Potential Applications Manufacturing
QRM as part of development Conventional approach: Testing after each step to minimize the
provide risk-based knowledge to manufacturer risk prior to the next step
Past Future
Parameters and range We have additional dimensions Raw
Materials
Blending Tabletting Packaging
• Open question:
How to challenge information for submission? Validation
Raw
Answer the questions in ICH Q9 Chapter 4: Materials
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 Quality risk management as part of… II.4: QRM for facilities, equipment and utilities
Design of facility / equipment
Industry To determine appropriate …
• Zones
Facilities
Competent when designing buildings and facilities, e.g.,
Authorities
> flow of material and personnel
& > minimize contamination
> pest control measures
Equipment > prevention of mix-ups
> open versus closed equipment
> clean rooms versus isolator technologies
> dedicated or segregated facilities / equipment ICH Q9
II.4: QRM for facilities, equipment and utilities II.4: QRM for facilities, equipment and utilities
Assessing Facility Needs for the Manufacture of Certain Assessing Facility Needs for the Manufacture of Certain
Medicinal Products Using a Risk Based Approach Medicinal Products Using a Risk Based Approach
• Options for facility dedication / segregation • Options for equipment dedication / segregation
> A physically separate or segregated building > Equipment that is dedicated to a specific product or product
> A separate area which may comprise of one or more rooms range, and identified accordingly
within a multi-purpose facility with its own air-locked > A totally enclosed cabinet (Containment Isolator) that is
personnel/ material accesses and HVAC systems. specifically designed to contain a specific product or
> One or more rooms (Suite) within a multi-purpose facility or product range, and is identified accordingly
dedicated area that is dedicated to a specific product or > An equipment change part (e.g. sieve, filter, etc) that is
product range, and is identified accordingly dedicated to a specific product or product range, and is
identified accordingly
EFPIA. TG dedicated facilities, 2006 EFPIA. TG dedicated facilities, 2006

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


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


Facility Needs: Risk Control Facility Needs: Risk Control
• Examples of Process Risk Controls 1/3 • Examples of Process Risk Controls 2/3


Facility Needs: Risk Control Facility Needs: Risk Control: Operational solutions
• Examples of Process Risk Controls 3/3 • 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
Facility Needs: Risk Acceptance profile Facility Needs: Conclusion
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
• 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
EFPIA. TG
dedicated facilities, 2006 effects at low levels EFPIA. TG dedicated facilities, 2006

QRM for facilities, equipment and utilities Zone concept for API
Zone concept for API: • Risk assessment: Risk identification and analysis
Risk management of Contamination > After the critical point:

Design chemical operations to prevent cross
and Cross-contamination (zone concept) for API contamination by/of the API
• Initiate the Risk Management Process > Before the critical point:
> Defining problem or question Protection has to be considered
- Where will protection be required? > Rationale: Ability of a final purification,
- What kind of protection will be adequate? filtration and/or crystallisation step
> Defining the assessment information Initiate
Risk Assessment
of removing trace levels of Initiate
Risk Assessment
incidental (cross-)contamination
and conclusions


Risk Communication
Risk Communication
- Managing risk based on a

Risk Acceptance

> Notes: Consider industrial hygiene and Risk Acceptance

critical point approach K.-H. Bender, F. Hoffmann-La Roche

Risk Review
Review Events
safety conditions K.-H. Bender, F. Hoffmann-La Roche

Risk Review
Review Events

Zone concept for API Zone concept for API

• Risk assessment: Risk evaluation • Risk assessment: Risk evaluation
> Risk associated with different products
Risk associated with simultaneous operations
- Contamination by particulate matter - plant design
e.g. from equipment, environmental (multi-purpose, dedicated, closed systems)
- requirements for special product categories
- Microbiological contamination (e.g. highly toxic)
e.g. API susceptible to microbiological growth? Risk to product from exposure to work environment
- exposure time, interfaces
- Cross-contamination Initiate
Risk Assessment
(e.g. drums/containers) Initiate
Risk Assessment
e.g. inadequate cleaning and/or material flow,


air-handling, use of closed systems


Risk Communication
Risk Communication

K.-H. Bender, F. Hoffmann-La Roche Review Events


• Risk control • Risk control: Risk reduction
> A decision-making activity focused on controlling risks > Physical and technical solutions
- closed systems
Where will protection be required? - endless bag system
What kind of protection is adequate? - closed sampling
What to do? > Intermittently closed product handling (hybrid solutions)
- Minimize interfaces - glove boxes
- Segregate production facilities - enclosed room or cabin
- Closed systems Initiate
Initiate
> Open product handling

- control people and material movement Risk Analysis Risk Analysis
- air flow controlled sampling


Risk Communication
Risk Communication




• Risk control: Risk reduction • Risk control: Risk Acceptance
- No additional risk control activities are necessary
> Patient impact
- Supported by the decision maker(s).
- Occurrence of harm
- Detection of harm - Includes acceptance of risks
that have not been identified
> Procedural/ structural/ logistical solutions
- gowning procedures > Design appropriate levels of protection
- operational monitoring > Accept the critical point of the process
- optimising material flow Initiate
> Appropriate monitoring may be performed Initiate

- standardized drums/ containers

- …

Risk Communication
Risk Communication




• Risk communication
• The review phase
> Internal:
- “GMP-Master plan” to demonstrate that > Audits / Inspections
the risk management process is used > Regularly assessment of complaints/ deviations
- Capital investment plan can be supported or even on (cross-) contamination topics
changed by the quality risk management process
> External: Initiate

Initiate
- e.g. Site Master File



Risk Communication
Risk Communication


Design of facility / equipment • Design of facility / equipment
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
• Utilities (e.g. Process validation) or cross contamination
> steam, gases, power source, compressed air, heating, (e.g. Cleaning validation)
ventilation and air conditioning (HVAC), water, etc. yes / no
• Preventive maintenance for associated equipment > Severity: Product quality affected? Impact on patient?
> Inventory of necessary spare parts, etc. yes / no
> Detectability: Knowledge of this attribute may affect the
release decision
ICH Q9 B. Dreissig, F. Hoffmann-La Roche

• Design of facility / equipment • 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
¾ determining appropriate clothing and gowning
¾ hygiene concerns
> To protect the environment from hazards

Document consolidation equals risk related to the product being manufactured
reduction via constancy, easy ¾ personnel, potential for cross-contamination
maintenance/training
reduces non compliance risk to patient
B. Dreissig, F. Hoffmann-La Roche

ICH Q9

• Potency Scale – max. daily dose (severity) Cle
• Calibration/preventive maintenance > 10 < 1mg an
> 6 1-10mg in gv
> To set appropriate calibration and maintenance schedules > 4 10-100mg alid
ati
• Qualification of facility/equipment/utilities > 2 100mg-1000mg on
> 1 >1000mg
> To differentiate scope and efforts and decisions • Solubility Scale – in cleaning medium (probability)
based on the intended use > 5 low solubility
¾ multi-versus single-purpose > 4 slightly soluble
> 3 moderately soluble
¾ batch versus continuous production
> 2 soluble
• Cleaning of equipment and environmental control > 1 highly soluble
• Interactions Scale (detectability)
> To determine acceptable (specified) > 9 serious - patients life threatened
cleaning validation limits > 4 moderate patient feels adverse effect
ICH Q9 > 1 low none – patient does not notice P. Gough, D. Begg Ass.
• Computer systems and computer controlled equipment • Computer systems and computer controlled equipment
> To select the design of computer Which risks could be considered?
hardware and software > Patient risk
- Modular
> Compliance risk
- Structured
- Fault tolerance > Application risk
> To determine the extent of validation > Business risk (influenced by other than Q-risks)
- Identification of critical performance parameters > Infrastructure risk
- Selection of the requirements and design
- Code review
- The extent of testing and test methods
- Reliability of electronic records and signatures ICH Q9 W. Schumacher, Roche

• Risks on Comp. systems & comp. controlled equipment • Risks on Comp. systems & comp. controlled equipment
Patient risk Compliance risk
Category Questions Choices Category Questions Choices
A: Death Is the business process subject A: Yes
Will the failure of the system B: Serious harm but not death to predicate rule requirements?
Patient harm Business process
result in C: Minor harm OR
regulation B: No
Is the business process regulated
D: No effect on patient health
by an agency?
Is/are there down stream A: Yes A: Yes, submitted
Secondary processes to the subject system Are the data or records made
Degree of Exposure B: Yes, may be inspected
assurance of safety that could assure safety of the B: No available to regulatory agencies?
C: No
product.
W. Schumacher, Roche W. Schumacher, Roche


Application risk 1/2 Application risk 2/2
Category Questions Choices
Category Questions Choices
A: New technology
A: 0 B: Mature technology but new to
How many technology enablers
B: 1 us
are interfaced to the system? What is our experience with the
C: more than 1 Experience C: Mature technology previously
technology?
A: firmware used by us
B: standard software packages D: Technology approaching
Complexity C: configurable software obsolescence
What is the technology category packages Is the application capable of limiting A: Yes
for the system? Security access at the individual authorized
D: configurable software B: No
user level?
package with custom
additions
E: fully custom software

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


Business risk 3/3 Infrastructure risk
Criticality of records A: Yes A: Local - Proprietary
Is the system the sole source of data On which geographical
contained in the B: Local
for the business process? B: No infrastructure the system will
system C: Regionally
operate?
Does this system supply critical data A: Yes D: Globally
Cross organizational from this
A: New technology
boundaries business process to other business B: No Complexity
processes (outside of this one)? B: Mature technology but new
to us
What is our experience with the
infrastructure? C: Mature technology
previously used by us
D: Technology approaching
obsolescence
Does the system rely on the A: Yes
Security "public internet" in the operation
of the system? B: No


II. 5 Quality risk management as part of… II.5: QRM as part of materials management
• Assessment and evaluation of suppliers and
Industry contract manufacturers
> To provide a comprehensive evaluation
Materials Competent
Authorities
¾ Auditing
¾ Supplier quality agreements
Management • Starting material

> To assess differences and possible quality risks
associated with variability in starting materials
¾ Age
¾ Route of synthesis
ICH Q9
II.5: QRM as part of materials management II.5: QRM as part of materials management
• Use of materials • Storage, logistics and distribution conditions

> Appropriate use material under quarantine > Adequacy of arrangements to ensure maintenance
¾ for further internal processing of appropriate storage and transport conditions
¾ Temperature
> Appropriateness of
¾ Humidity
Reprocessing, reworking, use of returned goods
¾ Container design
> Determine the effect on product quality of discrepancies

in storage or transport conditions
¾ Cold chain management (see other ICH guidelines)
ICH Q9 ICH Q9

II.5: QRM as part of materials management II. 6 Quality risk management as part of…
• Storage, logistics and distribution conditions

> Maintain infrastructure Industry
¾ Capacity to ensure proper shipping conditions
¾ Interim storage Production Competent
Authorities
¾ Handling of hazardous materials and controlled
substances
¾ Customs clearance
> Provide information for ensuring the availability of
pharmaceuticals
¾ Ranking risks to the supply chain (e.g. Anti-Counterfeit)
ICH Q9

II.6: QRM as part of production Integrated Quality Management Validation
• Validation Process Cleaning Support System Computer Method

Validation Validation Validations Validation Validation
> To identify the scope and extent of
verification, qualification and validation activities
¾ Analytical methods Deviation Out of Specification
¾ Processes
¾ Equipment
¾ Cleaning methods Failure Investigation
> To determine the extent for follow-up activities

¾ Sampling CAPA
¾ Monitoring
¾ Re-validation Re-Validation Change Control
> To distinguish between critical and non-critical process
steps to facilitate design of a validation study ICH Q9 Periodic Review
T. Matsumura, Eisai
II.6: QRM as part of production II. 7 Quality risk management as part of…
• In-process sampling & testing
> Evaluate the frequency and extent Industry
of in-process control testing
¾ Justify reduced testing
under conditions of proven control Laboratory control Competent
Authorities
> Evaluate and justify the use of
Process Analytical Technologies (PAT) and
in conjunction with parametric and real time release
• Production planning
stability testing
> To determine appropriate production planning
¾ Dedicated
ICH Q9
¾ Campaign or concurrent production process sequences

II.7: QRM as part of laboratory control and stability testing II. 8 Quality risk management as part of…
• Out of specification results

Industry
> To identify potential root causes and
corrective actions during the investigation
Packaging
Competent
Authorities
• Retest / expiration date setting

> To evaluate adequacy of storage and testing
and
of intermediates, excipients and starting materials
¾ Challenge results of use tests
labeling
¾ Stress tests
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
¾ Ensure product authenticity based on the potential for mix-ups
¾ Label legibility
¾ Involving different product labels
• Selection of container closure system
¾ Including different versions of the same label
> Determine the critical parameters
of the container closure system
ICH Q9 ICH Q9
Quality risk management as part of… Using ICH Q9 will…

• Facilitate
> Communication and transparency
> More informed, scientifically based decision making
Conclusion >
>
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 • Interpreting and adopting the concepts
industry (Development & Manufacture) and of quality risk management into specific areas
regulators (Reviewer & Inspectorate)
• Provides for establishing a defined program > Embed this behavior into quality aspects
for what we already do every day in our jobs of business, technology and regulation
• Supports science-based decision making
> Adopt in existing structures, organizations and Quality
• Optimisation of resources System
• Prevention from overly restrictive and
unnecessary requirements > Balance the documented use of “informal” and “formal”
quality risk management
• Facilitates communication and transparency
Annex II: Potential Applications
Integration of QRM
ICH Q9 QUALITY RISK MANAGEMENT
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

ICH Q9 • Give an aid by providing key principles on the theory of the

Annex I: Methods & Tools Annex I: Methods & Tools

Risk Control • The references are included as an aid to gain more

Annex I: Methods & Tools Annex I: Methods & Tools

5. Risk Management Tools Contributing items to manage quality risks

> e.g. quality attributes:

measured data according to specifications

Risk ranking & filtering

Annex I: Methods & Tools Annex I: Methods & Tools

• Process mapping Activity

• Cause and Effect Diagrams (Ishikawa / fish bone) • Pictorial representations

Annex I: Methods & Tools Annex I: Methods & Tools

• The indicators may be selected based on unit operations

Annex I: Methods & Tools Annex I: Methods & Tools

causes and the need for Problem

further investigation on them statement

Annex I: Methods & Tools Annex I: Methods & Tools

Spray Rate Redrying

Pan Speed Time Temp

Temperature Air Flow Porosity Sampling

Atomizing Air Pressure Shock Cycle Mill Speed Method

Annex I.2 I.2: Failure Mode Effects Analysis (FMEA)

Annex I: Methods & Tools Annex I: Methods & Tools

Annex I: Methods & Tools Annex I: Methods & Tools

Severity (Consequences of failure) Probability (Likelihood failure will happen)

• 7 High • 4 Repeated failures

Annex I: Methods & Tools Annex I: Methods & Tools

Detectability (Ability to find the failure) FMEA: Quantitation of Risk : Severity

Annex I: Methods & Tools Annex I: Methods & Tools

FMEA: Quantitation of Risk : Probability FMEA: Quantitation of Risk: Detection

PhD R.C. Mendson, Menson & Associations, Inc

Annex I: Methods & Tools Annex I: Methods & Tools

9 ↓ 3 – 4 times a day Remote 1. contamination disheveled gown of operator

Annex I: Methods & Tools Annex I: Methods & Tools

Failure Mode Effects Analysis (FMEA)

problems can occur by manual operations

Probability Granulation power consumption

Pre-mixing mixing time 3 2 3 18 IPC measure on content uniformity 3 2 1 6 12 influence on efficacy

not meet specification of

S. Rönninger, Roche S. Rönninger, Roche

Annex I: Methods & Tools Annex I: Methods & Tools

Annex I: Methods & Tools Annex I: Methods & Tools

Annex I: Methods & Tools Annex I: Methods & Tools

Annex I: Methods & Tools Annex I: Methods & Tools

Annex I: Methods & Tools Annex I: Methods & Tools

Annex I.4 I.4: Fault Tree Analysis (FTA)

Fault Tree • Assumes failure of the functionality of a product or

Annex I: Methods & Tools Annex I: Methods & Tools

• Connects two or more faults

• Priority AND Gate:

Annex I: Methods & Tools Annex I: Methods & Tools

• While investigating complaints or deviations to fully Out of specification

understand their root cause

• Ensure that intended improvements will fully resolve the

Annex I: Methods & Tools Annex I: Methods & Tools

I.2: Failure Mode Effects Analysis (FMEA) Annex I.5

Annex I: Methods & Tools Annex I: Methods & Tools

Annex I: Methods & Tools Annex I: Methods & Tools

chemical and biological hazards (including microbiological Technical Determine critical

contamination) transfer Target levels &