QRM

Quality
Risk Management
WHO & ICH Q9
21 August 2019 Quality Risk Management Prepared by Fuad Hassan Amer 1

ICH Q-Documents
 Q1 Stability
 Q2 Analytical Validation
 Q3 Impurities
 Q4 Pharmacopoeias
 Q5 Quality of Biotechnological Products
 Q6 Specifications
 Q7 Good Manufacturing Practice
 Q8 Pharmaceutical Development
Different:
 Q9 Quality Risk Management - not a recipe
 Q10 Pharmaceutical Quality Systems - not a “SOP”
just a guidance
Quality Risk Management
21 August 2019 2
Prepared by Fuad Hassan Amer
ICH Q9 Link back to patient risk
Opportunities to impact
risk using quality risk
Design management
Process
Materials Manufacturing
Facilities
Distribution
Patient

21 August 2019 3
Risk Management across the
Product lifecycle for drug (medicinal) products
Research
Preclinical
Phase
Clinical
Phases End of
life cycle
Launch
Manufacturing
& Distribution
GLP Safety
GCP Efficacy
GMP Quality
GDP ICH Q9
21 August 2019 4
CONSIDERATIONS
Managing the risk of drug (medicinal)

product use
Medication or Device
Known Side Effects Product Defects
Error
Avoidable Unavoidable
ICH Q9
Efficacy Quality
Safety Preventable
Adverse
Events
Unexpected Injury or
Consequences Death
Public Health
Source: basic model adapted from FDA (1999). Managing the Risks from Medical Product Use.

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The new paradigm
“risk-based”
concepts and
principles

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Incremental steps
Pharmaceutical Development (Q8)
Changed Past: Data transfer / Variable output
Paradigm Present: Knowledge transfer / Science
based / Consistent output
Quality Risk Management (Q9)

Past: Used, however poorly defined
Present: Opportunity to use structured
process thinking
Pharmaceutical Quality Systems (Q10)

Past: GMP checklist
Future: Quality Systems across product
Q9
life cycle
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How Q9 interacts with Q8 and Q10
Risk from Manufacturing site
High
Q10 Pharm. Quality Systems
t
en
me
ov
pr
im
l
ua
Using Q9
in
nt
co
Quality Risk
Management
principles
Low Q8 Pharmaceutical Development
Low High
Product / Process Risk
Base: J. Ramsbotham, Solvay Pharm. NL / EFPIA
21 August 2019 8
ICH Q9 Link back to patient risk
Opportunities to impact
risk using quality risk
Design management Q9
Process
Materials Manufacturing
Facilities
Distribution
Patient
Q8 Q10
Quality Risk Management G.- Claycamp, FDA, June 2006
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CONSIDERATIONS
A Vision of the future becomes fact

Old Approach New Approach Remarks
Quality decisions divorced Quality decisions and filing Design Space concept
from science and risk committments based on introduced to integrate
Broad Concept evaluation. Process Understanding process knowledge with
Adherence to filing and Risk Management. regulatory evaluation.
commitments. Quality by Design.
Post-factum sampling and Management of variability Quality by design definition
quality testing. Process control focused on applied. Measure critical
Quality Process Validation. critical attributes. process parameters to control
Continuous Quality output product quality.
Verification.
Systems designed to inhibit Changes managed within Regulators and industry place
changes & minimize business company's quality system. higher reliance / trust /
Systems risks. Discourages Real time batch release understanding on systems.
improvement & innovation. feasible. Multidisciplinary evaluation
and decision making.
Compliance focus. Regulatory scrutiny adjusted Requires mechanisms to
Changes require prior to level of Process communicate Process
Regulatory approval. Understanding. Continuous Understanding data
improvement allowed ("inspectable rather than
within Design Space. reviewable") .
Quality Risk Management Based on EFPIA, PAT Topic Group, 2005
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ICH Q9
What does it mean?

What is it worth?
Where does it lead?

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CONSIDERATIONS
Managing risk is a behavior
“The investigation of risks

is at once
a scientific activity and
an expression of culture”
Kasperson, Renn, Slovic et al. (1988)

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CONSIDERATIONS
Risk Management as a discipline

provides multiple benefits
 Understand and influence the factors (hazards)
which impact regulators and industry business
 Create awareness and a culture
> Supports an effective pro-active behaviour
> Open factual dialogue
> Make decisions traceable and consistent
 Provide assurance
> Risks are adequately managed
> Compliance to external and internal requirements
 Recognise risks at a desired level
> Zero risk not possible
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CONSIDERATIONS
Different meaning of risk

 Individual
> Risk is a cognitive and emotional response to expected loss
 Technicians
> Risk is usually based on the expected value of the
conditional probability of the event occurring multiplied by
the consequences of the event given that it has occurred
 ICH Q9
> Combination of the probability of occurrence of harm and
the severity of that harm
Quality Risk Management Based on G. Claycamp, FDA, September 2005

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The “risk-based approach”
Parameters
probability
for
evaluating risks
severity
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CONSIDERATIONS
Parameters for “calculating” risks

A picture of the life cycle
= Risk Priority Number

Probability x Detectability x Severity
Refers to
Refers to
Refers to
past today future time
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CONSIDERATIONS
(Dis)Advantage calculated numbers & data
 Numbers
> Does the “Risk Priority Number” tell the truth?
 Keep a robust data set for further evaluation!
> Is the data set comparable?
> Are the data plain and concise?
> What about trending and use of statistics
including extrapolation?
> What amount of data is enough?
e.g. start with the existing data set

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CONSIDERATIONS
Risk and Uncertainty Tomorrow ?

Process Parameter 
Upper Specification Limit (USL) Uncertainty
Lower Specification Limit (LSL)
Time  today
RISK: For a given severity of risk event, what are the chances
(probability) of exceeding the USL in the next period of time?
Quality Risk Management G. Claycamp, FDA, Sept. 2005
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CONSIDERATIONS
Risk and Uncertainty

Different Risk Management Control?
Tomorrow ?
Upper Specification Limit (USL)
Uncertainty
Time  today
RISK: Control options are scenarios for risk management. Note

that this scenario shows the best estimate is below the USL.
21 August 2019 19
CONSIDERATIONS
Risk and Uncertainty

Is the Risk of Exceeding USL = Zero?
Tomorrow ?
Upper Specification Limit (USL)
Uncertainty
Time  Take a cut today

at a
moment in time:
Risk has a distribution.
21 August 2019 20
Definitions
Quality Degree to which a set
of inherent properties
of a product, system or process
fulfills requirements
Risk combination of the
probability of occurrence of harm and
the severity of that harm
Management
Systematic process for the assessment,
control, communication and review
QRM of risks to the quality of the
drug (medicinal) product
across the product lifecycle
Quality Risk Management ICH Q9
21 August 2019 21
CONSIDERATIONS
Has QRM already been implemented?
Yes, however we need to firm-up and

set the priorities in relation to risks
 We need to know…
> How good is our QRM compliance and decision making?
> To what extent QRM has to be implemented or formalised?
 An then focus efforts and communicate in order to…

> Avoid duplication of effort and to align initiatives
> Develop scope by using different viewpoints
e.g. from management, internal and external customers
21 August 2019 22
Risk Management
Not a new concept
 ISO/IEC Guide 73: 2002 - Risk Management -
Vocabulary - Guidelines for use in Standards
 ISO/IEC Guide 51:1999 - Safety Aspects -
Guideline for their inclusion in standards
 WHO Technical Report Series No 908, 2003 Annex 7 Application
of Hazard Analysis and Critical Control Point (HACCP)
methodology to pharmaceuticals
 GAMP Good Practice Guide ISPE, 2005
A risk-based approach to compliant electronic records and
signatures
 ISO 14971:2000 - Application of Risk Management
to Medical Devices
21 August 2019 23
ISO 14971 (medical devices) & ICH Q9
Initiate
Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
unacceptable
Risk Management tools

Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the

Quality Risk Management Process
Risk Review
Review Events

21 August 2019 24
Quality Risk Management is NOT
 Hiding risks
 Writing half the truth (e.g. in an investigation report)
 A means of removing industry’s obligation to comply

with regulatory requirements

21 August 2019 25
Manage quality risks!
What if
disaster happens?
Consequences
Prior use of QRM may

lower the consequences
Nowadays
QRM
Using QRM
Quality management as function of time

Based on Prof. M. Haller, University St. Gallen, Switzerland
21 August 2019 26
Implementing ICH Q9 means
The weakest chain will no longer be a problem

21 August 2019 27
Integrate QRM during product life cycle
Gain experience
Analyse root cause: (Risk of) Failure ?
Continuous Manufacture
improvement for market
Quality Risk
Management
Improve it (QRM) Do, what you say
Update Approval
documentation
Say, what you do

21 August 2019 28
Conclusions for ICH Q9
 Over all: Positive Contribution to patient protection

> Further develops Quality Risk Management awareness,
that is already part of industry and regulatory culture
 Ongoing change in behaviour

> Identifying risks can be positive
> A long list of identified risks that are assessed and
controlled provides high quality capability
 Awareness of quality risks
> “Risk-based approach”
> A potential of risks remains - No “Zero” risk!
21 August 2019 29
Opportunities & Benefits
 Encourages transparency
> Create baseline for more science-based decisions
 Facilitates communication
> Matrix team approach
> An aid to convince the stakeholders with trust
 Encourages a preventive approach
> Proactive control of risks and uncertainty
> Benefit of knowledge transfer by team approach
 Changes behavior
> Better understanding of risk-based decisions
> Acceptance of residual risks
21 August 2019 30
PRINCIPLES OF QUALITY RISK MANAGEMENT
 The evaluation of the risk to quality

> scientific knowledge
> ultimately link to the protection of the patient
 According to the level of risk commensurate
> level of effort
> level of formality
> level of documentation

21 August 2019 31
Responsibilities
 interdisciplinary teams
 Decision makers should
> coordinating quality risk management across various
functions and departments of their organization; and
> Assure that a quality risk management process is defined,

deployed and reviewed and that adequate resources are
available

21 August 2019 32
Initiating a Quality Risk Management Process
Specify a timeline,
deliverables and
Identify a leader appropriate level
and necessary of decision
resources making
Assemble
background
Define the information
problem and/or
risk question

21 August 2019 33
The personnel should be able to:
(a) conduct a risk analysis;
(b) identify and analyse potential risks;
(c) identify, evaluate risks and determine which ones
should be controlled and which ones can be
accepted;
(d) recommend and implement adequate risk control
measures;
(e) devise procedures for risk review, monitoring and
verification.

21 August 2019 34
The objectives and scope of the
QRM activities should be:
CLEARLY DEFINED

21 August 2019 35
Knowledge of the product and
process
FLOW DIAGRAM

21 August 2019 36
Risk Assessment
1. What might go wrong?
2. What is the likelihood
(probability) it will go
wrong?
3. What are the
consequences (severity)?
21 August 2019 37
Risk Assessment
DECISION-TREE

21 August 2019 38
Consider The Potential Risks In
Relation To The Following
– Materials and ingredients;
– Physical characteristics and composition of the product;
– Processing procedures;
– Microbial limits, where applicable;
– Premises;
– Equipment;
– Packaging;
– Sanitation and hygiene;
– Personnel – human error;
– Utilities;
– Supply chain.
21 August 2019 39
Risk Control
1. Is the risk above an acceptable

level?
2. What can be done to reduce or

eliminate risks?
3. What is the appropriate balance

among benefits, risks and
resources?
4. Are new risks introduced as a

result of the identified risks being
controlled? Quality Risk Management
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21 August 2019 41
21 August 2019 42
Risk Control

level?

eliminate risks?

resources?

controlled? Quality Risk Management
21 August 2019 43
21 August 2019 44
Risk Control

level?

eliminate risks?

resources?

controlled?
21 August 2019 45
Risk Control
Corrective Actions:
WHEN?
WHO?
RECORD

21 August 2019 46
Risk Communication
Sharing of information
about risk and risk
management between
the decision makers,
stakeholders and
others.
21 August 2019 47
Risk Communication
Report for every risk

assessment, but ….

21 August 2019 48
Risk Review
ONGOING PART
WHY?

21 August 2019 49
Risk Review
All records and

documents
signed and dated by
Who?
21 August 2019 50
Risk Review
Verification of QRM process and
methodologies activities:
1. Review of the QRM process

and its records;
2. Review of deviations and

product dispositions;
3. Confirmation that identified

risks is kept under control

21 August 2019 51
Risk Review
Information reviewed to verify
the QRM process should
include:
1. Expert advice and scientific

studies;
2. In-plant observations,
measurements and
evaluations.

21 August 2019 52
RISK MANAGEMENT METHODOLOGY
 Basic risk management facilitation methods

(flowcharts, check sheets etc.);
 Failure Mode Effects Analysis (FMEA);
 Failure Mode, Effects and Criticality Analysis (FMECA);
 Fault Tree Analysis (FTA);
 Hazard Analysis and Critical Control Points (HACCP);
 Hazard Operability Analysis (HAZOP);
 Preliminary Hazard Analysis (PHA);
 Risk ranking and filtering;
21 August
Supporting
2019
statistical tools.
53
Remember
 The use of Quality Risk Management is not mandatory
However, if you don’t use it,

you will not gain the benefits

21 August 2019 54
Change in behaviour
Sharing information

21 August 2019 55
Change in behaviour
From tick-box
approach for compliance
towards
systematic
risk-based thinking
21 August 2019 56
Integration of QRM
into existing systems
and
regulatory processes
will take time, trust and
communication
21 August 2019 57

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Quality

WHO & ICH Q9

21 August 2019 Quality Risk Management Prepared by Fuad Hassan Amer 1

Quality Risk Management

Managing the risk of drug (medicinal)

Quality Risk Management

Quality Risk Management

Quality Risk Management (Q9)

Pharmaceutical Quality Systems (Q10)

A Vision of the future becomes fact

What does it mean?

Quality Risk Management

Managing risk is a behavior

“The investigation of risks

Kasperson, Renn, Slovic et al. (1988)

Quality Risk Management

Risk Management as a discipline

Different meaning of risk

Quality Risk Management Based on G. Claycamp, FDA, September 2005

Parameters for “calculating” risks

= Risk Priority Number

(Dis)Advantage calculated numbers & data

Quality Risk Management

Risk and Uncertainty Tomorrow ?

Upper Specification Limit (USL) Uncertainty

Lower Specification Limit (LSL)

Risk and Uncertainty

Upper Specification Limit (USL)

Lower Specification Limit (LSL)

RISK: Control options are scenarios for risk management. Note

Risk and Uncertainty

Upper Specification Limit (USL)

Lower Specification Limit (LSL)

Time  Take a cut today

Has QRM already been implemented?

Yes, however we need to firm-up and

 An then focus efforts and communicate in order to…

Risk Management tools

Output / Result of the

Quality Risk Management

 Writing half the truth (e.g. in an investigation report)

 A means of removing industry’s obligation to comply

Quality Risk Management

Prior use of QRM may

Quality management as function of time

The weakest chain will no longer be a problem

Say, what you do

 Over all: Positive Contribution to patient protection

 Ongoing change in behaviour

 The evaluation of the risk to quality

Quality Risk Management

> Assure that a quality risk management process is defined,

Quality Risk Management

Quality Risk Management

Quality Risk Management

Quality Risk Management

Quality Risk Management

1. What might go wrong?

2. What is the likelihood

3. What are the

Quality Risk Management

1. Is the risk above an acceptable

2. What can be done to reduce or

3. What is the appropriate balance