Quality Risk Management: & Its Application in Sterile Processing

Quality Risk Management
& its application in sterile processing
Ian R Thrussell, MHRA, UK
,Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009
 To provide information on the background
of the ICH Q9 document
 Give an aid by providing some points of

discussions on the understanding of the quality
risk management concept
 Illustrations of how Risk Mamangement can be

applied in sterile product manufacture
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

2|
 The ICH process
 ICH Q9 and other ICH guidelines
 From “Risk” to “Quality Risk Management”
 Opportunities, Challenges and Benefit

3|
 The ICH process

4|
International Conference on
Harmonisation
of Technical Requirements
for Registration of
Pharmaceuticals
for Human Use

5|
• Guidelines on
Expert Working • Quality
Groups (EWG) • Chemical and pharmaceutical QA
• Safety
• In vitro and in-vivo pre-clinical

studies
• Efficacy
• Clinical studies
in human subject
• Multidisciplinary
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors General topics
6|
 The ICH process

7|
 Q1 Stability
 Q2 Analytical Validation
 Q3 Impurities
 Q4 Pharmacopoeias
 Q5 Quality of Biotechnological Products
 Q6 Specifications
Different:
 Q7 Good Manufacturing Practice - not a recipe
 Q8 Pharmaceutical Development - not a “SOP”
just a guidance
 Q9 Quality Risk Management
 Q10 Pharmaceutical Quality Systems
8|
LINK TO PATIENT RISK
Opportunities to impact
risk using quality risk
Design management
Process
Materials Manufacturing
Facilities
Distribution
Patient

9|
Research
Preclinical
Phase
Clinical
Phases End of
life cycle
Launch
Manufacturing
& Distribution
GLP Safety
GCP Efficacy
GMP/GDP ICH Q9
Quality
10 |
Managing the risk of drug 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
Manufacture
Source: of sterile
basic model medicines
adapted– Advanced
from FDAworkshop for SFDA
(1999). GMP inspectors
Managing the Risks from Medical Product Use.
11 |
 ICH Regulators:
– FDA: New paradigm with the 21st Century
GMP initiative
– EMEA: Revised EU directives
– MHLW: Revised Japanese law (rPAL)
 EU & Japan became involved at ICH

GMP Workshop in July 2003: 5 year vision agreed:
“Develop a harmonised pharmaceutical quality system applicable across the
life cycle of the product emphasizing an integrated approach to quality risk
management and science”
 Consequent ICH Expert Working Groups (EWG):
 ICH Q8, on Pharmaceutical Development, doc. approved 2005

– ICH Q9, on Quality Risk Management, doc. approved 2005
– ICH Q10, on Quality Systems, topic accepted 2005

12 |
The new paradigm
“risk-based”
concepts and
principles
Q8 Q9 Q10
13 |
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)
Q10
Q8
Past: GMP checklist

Q9
Future: Quality Systems across product

life cycle

14 |
Product and process risk
Risk from Manufacturing site
High
Q10 Pharm. Quality Systems
t
en
em
ov
pr
m
li
ua
Using Q9
in
nt
Quality Risk
co
Management
Low Q8 Pharmaceutical Development
principles
Low High
15 |
Opportunities to impact
risk using quality risk
Design management Q9
Process
Materials Manufacturing
Facilities
Distribution
Patient
Q8 Q10
16 |
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") .

17 |
Process
Understanding Process Process
Understanding Understanding
CMCCMC
regulatory
regulatory
Oversight CMCCMCregulatory
(Submission)
oversight regulatory
Oversight
(Submission)
oversight CMC
regulatory
oversight
cGMP cGMP
regulatory
regulatory
oversight Q8 cGMPcGMP
regulatory
regulatory
oversight Q10 cGMP
regulatory
(Inspection)
oversight
& (Inspections)
oversight
& oversight
Company’s
Quality system
Q9 Company’s Q9 Company’s
Quality system
Quality system
Post
Approval
approval
Change Continuous
PAC
PAC toto Improvement
(PAC)
change
Continuous
Continuous
Risk Improvement Risk
Improvement
(perceived & real)
(P/R) Risk

18 |
What does it mean?
What is it worth?
Where does it lead?

19 |
“The investigation of risks
is at once
a scientific activity and
an expression of culture”
Kasperson, Renn, Slovic et al. (1988)

20 |
 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

21 |
The hurdles
Increasing
external Growing
requirements complexity
and scope of risks
?
for best practice,
transparency and
compliance • Globalisation
• Public / Community
“Multinational”
• Governments
• Multi-factor approaches
• Regulators
• Regulatory expectations
• Patients Investors /
• Acceptance of
Creditors
Increasing risk and uncertainty
• Documentation
efforts and costs • Projects
for sustainability • Systems
• Interfaces

22 |
Empowerment & Flexibility
• An appropriate integrated approach
helps to meet requirements more efficiently
Proactive Quality Improve

communication
disclosure Risk through sharing best
build trust and
understanding Management practice and science
based knowledge
Master complexity
Convert data into knowledge
e.g. by using methodology and tools
23 |
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
24 |
 Organizations might use many different meanings of risk
– Depending on the type of risk management program
 In general, "probability" and "severity" must be considered

– In a given program definitions will fine-tune the concepts
so that a risk management program can be created
and applied
– Make the detail in the definition fit the objective
of the program
 Accept the different "realities" among the stakeholders

– Harmonized guidance needs to focus concepts
into useful terms for the purpose (e.g. protection of patient [Q9])

25 |
Severity and Probability are simple
concepts?
 Which consequence is more severe?

– 300 lives lost in single, fiery plane crash.
– 300 lives lost on roads over a weekend.
– 300 lives potentially lost from cancer within the next 20 years
 Which probability is probable?

What does a “30% chance of rain tomorrow” mean?
– 30% of the days like tomorrow will have at least a trace of rain.
– 30% of the area will have rain tomorrow.
– 30% of the time tomorrow, it will rain. Gigerenzer, et. al (2005)
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors G. Claycamp, FDA, September 2005
26 |
ty
ili
ab
ct
te
de
Parameters hi
gh
probability
for
evaluating risks
m
ed
iu
m
lo
w
ri s severity
k
27 |
 A picture of the life cycle
= Risk Priority Number

Probability x Detectability x Severity
Refers to
Refers to
Refers to
past today future time

28 |
How can Q9 be implemented?
ICH Q9
Existing a s ed
internal is k-b ach
ng
R pro r
s
Where ap
al risk
documentation de
eci for thin t

ki
residu ble
n
to be in i
se me
system n s Q9
E A ta
future?
Co CH
ba le
(Mission, Policy)
s
k- Imp
I
l
too
M
What to do?
e.g. F
fic
s
(e.g. Directives)
ris
ple
l i st o f
us Exam
How to do?
sp
(e.g. Guidelines)
ing
Detailed instructions Records
(e.g. Standard Operating Procedures)
Rules & Procedures Records &

(internal regulations) Reports

29 |
 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

30 |
Anything
that has the potential to
Potential threat harm patients,
- chemical reaction
- manufacturing issues
product quality or
- facilities and equipment the business
(loss, interruption, image)
hazard
Failure
- technical breakdown System defect
- human breakdown - not detected
- extrinsic effect - insufficiently prevented
- emerges by degree

31 |
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?

32 |
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.
33 |
Tomorrow ?
Upper Specification Limit (USL)
Uncertainty

Take a cut at a moment in
Time  time: today
Risk has a distribution.

34 |
Lack of, or inadequate knowledge
uncertainty Hazard
Hazard
may may not
cause harm cause harm
Manage risks
in relation to
probability &
severity
Hazard
is less likely to
cause harm
35 |
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
of risks to the quality of the drug (medicinal)
QRM product across the product lifecycle
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors ICH Q9
36 |
HAS NOT 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 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

37 |
 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

38 |
ISO 14971(medical devices) vs 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

39 |
ICH Q9 document
 Main body explains the “What?”
 Annex I give ideas on the “How?”
 Annex II give ideas on the “Where?

 It can be implemented by industry and regulators
– Pharmaceutical development (ICH Q8) and Quality Systems (ICH
Q10) will facilitate the “What?”, “How?” and “Where?”
 “It helps prevent overly restrictive and unnecessary requirements
being imposed by either industry or regulators” (ICH Q9)

40 |
 To show how it can be applied by regulators and industry to
quality of pharmaceuticals (including API)
– We already do a lot of quality risk management
activities without identifying them as such
 To enable manufacturing and regulatory flexibility
 Provides the “What?” “How?” and “Where?” for quality risk

management
– Pharmaceutical development (ICH Q8) and Quality
Systems (ICH Q10) facilitate the
“What?”, “How?” and “Where?”

41 |
Concerns regarding QRM
 Hiding risks
 Writing half the truth (e.g. in an investigation

report)
 A means of removing industry’s obligation to

comply with regulatory requirements
 Both Companies & Inspectors have to think and

not simply follow black and white rules

42 |
What happens to regulatory expectations
when things go wrong?
Based on Prof. M. Haller, University St. Gallen, Switzerland
What if
disaster happens?
Consequences
Prior use of QRM may

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

43 |
 The weakest linkin the chain will no longer be a problem

44 |
Integrate QRM during product life cycle
Gain experience
Analyse root cause: (Risk of) Failure ?
Continuous Quality Manufacture
improvement Risk for market
Managem
ent
Improve it (QRM) Do, what you say
Update Approval
documentation
Say, what you do
45 |
 Definitions of “Compliance”:
– Conformity in fulfilling official requirements
– The act or process of complying to a
desire, demand, or proposal or to coercion
– A disposition to yield to others
 The ability of an object to yield elastically

when a force is applied: flexibility
Definition of “Flexibility”:
– characterised by a ready capability
to adapt to new, different, or changing requirements
Source: www.webster.com, 01. Nov.04

46 |
QRM may help to define acceptable quality
levels
Use
“science-based” and
“risk-based” behavior
 Not every single detail can nor should be covered by

– Specifications (product quality)
– Documents (quality systems)
 Set priorities and allocate resources

according to the potential for protection of patients

47 |
Opportunity for the Industry &
Regulators
 Using the same guideline apply QRM to
– Industry (development, manufacture and distribution)
– Competent authorities (reviewer and inspectorate)
 Facilitates common approaches to quality risk
management in our every day jobs
 Supports science-based decision making
 Focus resources based on risks to patients
 Avoids restrictive and unnecessary requirements
 Facilitates communication and transparency
48 |
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!

49 |
Way Forward for Industry and
Regulators
 Improve communication and transparency

 Adapt existing
structures, organizations and systems
– Raise awareness of rationales for decision making
– Develop training on methods and tools, as appropriate
– Do not create new QRM organisations
– Do not create new requirements
 Adapt existing requirements using quality risk
management behaviors
50 |
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
51 |
 The use of Quality Risk Management is
mandatory is an expectation of EU & PICs
GMP – but ICH Q9 is not
However, if you don’t use it,

you will not gain the benefits

52 |
Change in behaviour
Sharing information

53 |
Change in behaviour
From tick-box
approach for compliance
towards
systematic
risk-based thinking
54 |
Change in behaviour
Doing things,
that do not matter
for the patient
55 |
Integration of QRM
into existing systems
and
regulatory processes
will take time, trust and
communication
56 |

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Quality Risk Management

& its application in sterile processing

Ian R Thrussell, MHRA, UK

,Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

 Give an aid by providing some points of

 Illustrations of how Risk Mamangement can be

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

 ICH Q9 and other ICH guidelines

 From “Risk” to “Quality Risk Management”

 Opportunities, Challenges and Benefit

 ICH Q9 and other ICH guidelines

 From “Risk” to “Quality Risk Management”

 Opportunities, Challenges and Benefit

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Expert Working • Quality

Groups (EWG) • Chemical and pharmaceutical QA

• In vitro and in-vivo pre-clinical

 ICH Q9 and other ICH guidelines

 From “Risk” to “Quality Risk Management”

 Opportunities, Challenges and Benefit

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

 EU & Japan became involved at ICH

 Consequent ICH Expert Working Groups (EWG):

 ICH Q8, on Pharmaceutical Development, doc. approved 2005

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Quality Risk Management (Q9)

Pharmaceutical Quality Systems

Past: GMP checklist

Future: Quality Systems across product

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Where does it lead?

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

 Create awareness and a culture

 Supports an effective pro-active behaviour

 Recognise risks at a desired level

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Proactive Quality Improve

 In general, "probability" and "severity" must be considered

 Accept the different "realities" among the stakeholders

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

 Which consequence is more severe?

 Which probability is probable?

= Risk Priority Number

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

eci for thin t

Rules & Procedures Records &

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Upper Specification Limit (USL) Uncertainty

Lower Specification Limit (LSL)

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Upper Specification Limit (USL)

Lower Specification Limit (LSL)

RISK: Control options are scenarios for risk management. Note

Upper Specification Limit (USL)

Lower Specification Limit (LSL)

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Risk combination of the