Frederick Razzaghi
ICH Q9 EWG/WSMI/CHPA
1
Agenda
2
Quality Risk Management (Q9)
4
Prior dialogue
5
OPS objective (April AC meeting)
6
Background of the Q9 working group
7
Approach
8
Considerations for moving ahead in
ICH
“Develop a harmonized pharmaceutical quality
system applicable across the life cycle of the
product emphasizing an integrated approach to
risk management and science.” July 2003.
Requiring consensus among all regions and
developing a guideline to be used by all ICH
parties.
Proceeding with a process oriented, practical,
applicable, predictive, flexible, consistent and
integrated approach in mind.
9
What is the problem being solved
Product may not be available to patients, when needed
May increase the potential for the release of unacceptable
product to the market
New product introductions to the marketplace may be delayed
Delays may occur during implementation of changes and
improvements to processes
Safe and effective drugs may be discarded or recalled from the
market
Manufacturers may be reluctant to implement new technologies
or continuous improvements to the products or processes
Scarce resources may not be optimally allocated
Lack of appropriate data to evaluate risk most effectively
10
Benefits
11
Scope
12
Process
1. Initiate Process
2. Assess
3. Control
4. Communicate
5. Review
13
Guiding principles
The evaluation of the risk should ultimately link back to
the potential risk to the patient.
The extent of the risk management process should be
commensurate with the level of risk associated with the
decision.
A more robust data set will lead to lower uncertainty.
It is essential to have a clear delineation of the risk
question.
Risk management should be an iterative process.
People who apply risk management should have the
appropriate training, skills and experience.
The risk management process should be appropriately
documented and verifiable.
14
Guide to initiating risk management
Defining specifically the risk management problem or
question, including the assumptions leading to the
question.
Assembling background information and data on the
hazard, harm or human health impact relevant to the
assessment.
Defining how the assessment information and
conclusions will be used by the decision makers.
Identifying the necessary resources, members of the
team who have the appropriate expertise, with the
leader clearly identified.
Asking the right risk assessment question(s)
Stating clearly the assumptions in the risk assessment
Assessing the quality and sufficiency of relevant data
Specifying a timeline and deliverables for the risk
assessment
15
Risk Assessment
What can go wrong?
What is the likelihood (probability) it would go
wrong?
What are the consequences?
Risk analysis is a systematic use of
information to identify specific sources of
harm (hazards) and to estimate the risk.
Risk evaluation compares the estimated risk
against given risk criteria using a
quantitative or qualitative scale to determine
the significance of the risk.
16
Risk Control
Risk control describes the actions of implementing risk
management decisions.
18
Risk monitoring and review
19
Process flow
Initiate
Risk Management Process
Risk Assessment
Risk Analysis
Risk Management tools & statistic toolbar
Risk Evaluation
(Resources, Interfaces & Line functions)
Risk Control
Risk Mitigation
(incl. elimination and avoidance)
[Severity]
Risk Reduction
[Probability]
Risk Acceptance
Risk Communication
No additional risk 20
Risk management Tools
1. Process mapping
2. Preliminary Hazard Analysis (PHA)
3. Hazard Analysis of Critical Control Points (HACCP)
4. Hazard Operability Analysis (HAZOP
5. Fault tree analysis (FTA)
6. Failure Mode Effects Analysis (FMEA)
7. Failure Mode, Effects and Criticality Analysis (FMECA)
8. Risk Ranking and Filtering
9. Informal Risk Management
10. Taguchi, variation risk management method
21
Supporting Statistical Tools
22
Integration of Quality Risk Management into
operations
1. Development (e.g. Specification Setting, Test Method Selection
and process development).
2. Regulatory scrutiny during pre and post approval.
3. As a component of Quality systems ( e.g. Auditing,
Deviations/Discrepancies, Complaints & Recall Management,
Change management)
4. Facility systems management ( e.g. Design, Hygiene,
Qualification, environmental control, Preventative
maintenance and Computerized systems)
5. Materials Management (e.g. Supply chain, Assessment and
evaluation of suppliers and contract manufacturers,
procurement and release of material)
23
Integration of Quality Risk Management into
operations (Continued)
6. Production (e.g. PAT, Validation, in-process sampling, testing,
reporting and trending)
7. Laboratory controls (e.g. validation, testing, methods
development, stability).
8. Packaging and labeling (e.g. Selection of container closure system
and label controls).
9. Regulatory Authority Activities
24
Next steps
25
Organizations represented on the
Expert Working Group
EU regulators: EMEA (European Medicines Evaluation Agency) and the French Health
Products Safety Agency (AFSSAPS)
EFPIA: F. Hoffmann-La Roche Ltd. And Eli Lilly &Co.
Japan regulators: Division of drugs, National Institute of Health Sciences ;and Compliance
and Narcotics Division, Pharmaceutical and Food Safety Bureau, Ministry of Health,
Labour and Welfare.
Japan Pharmaceutical Manufacturers Association: Eisai Co., Ltd and Mochida
Pharmaceutical Co., Ltd.
US regulators: Office of Compliance, CDER ;and office of scientific support, CVM, Food
and Drug Administration.
Pharmaceutical Research and Manufacturers of America: Merck & Co inc. and Centocor,
Inc
Canada Regulators: Compliance and Enforcement Coordination Division
Health Products and Food Branch Inspectorate Health Canada.
Swiss regulators (EFTA): Swiss medic, Swiss Agency for Therapeutic Products.
World regulators: Quality Assurance & Safety: Medicines, World Health Organization.
Generic Industry: Barr Laboratories, Inc.
World Self Medication Industry: CHPA Consumer Healthcare Products Association
26
Definitions
Decision Maker - process owner of risk management process
Dynamic / Iterative Process - TBD
Harm – Damage to health, including the damage that can occur from loss of product efficacy, safety,
quality or availability
Hazard - the source of harm. Can be a chemical, biological or physical substance, or an event that can
cause harm.
Product Lifecycle – All phases in the life of a product covering both the inherent characteristics of the
product and how these may change over time. The lifecycle is from the initial development through
pre- and post-approval until the product’s discontinuation and includes the associated regulatory
processes.
Quality – Degree to which a set of inherent characteristics of a product, system or process fulfills
requirements
Quality System – A formalized system that documents the structure, responsibilities and procedures
required to achieve effective quality management.
Requirements – Needs or expectations that are stated, generally implied or obligatory by the patients
or their surrogates (e.g. health care professionals, regulators and legislators)
Risk – Combination of the probability of occurrence of harm and the severity of that harm (from
ISO/IEC Guide 51)
Risk Management – Process consisting of well-defined steps which, when taken in sequence, support
better Decision Making by contributing to a greater insight into risks and their impacts.
It includes elements such as risk identification, assessment, mitigation, elimination and
communication.
Severity – Measure of possible consequence of a potential source of harm
Stakeholder - Any individual, group or organization that can affect, be affected by, or perceive itself to
be affected by a risk. The decision makers might also be stakeholders. For the purposes of this
guideline, the primary stakeholders are the patient, healthcare professional, authority, regulator,
industry, business, customer.
27
References
Ayyub, B.M. (2002) Elicitation of Expert Opinions for Uncertainty and Risks. Boca Raton, FL: CRC
Press.
Ayyub, B.M. (2003) Risk Analysis in Engineering and Economics. Boca Raton, FL: Chapman &
Hall/CRC
Chowdhry, S. (2002). Design for Six Sigma: The Revolutionary Process for Achieving Extraordinary
Profits. Dearborn, MI: Dearborn Trade.
Davies, J.C. (Ed.), (1996). Comparing Environmental Risks. Tools for Setting Government Priorities.
Washington, DC: Resources for the Future.
Haimes, Y.Y. (1998). Risk Modeling, Assessment and Management. New York: John Wiley and Sons,
Inc.
Konisky, D.M. (1999) “Comparative Risk Projects: A Methodology for Cross-Project Analysis of
Human Health Risk Rankings.” Discussion Paper 99-46, August 1999. Washington, DC: Resources
for the Future.
Morgan, G.M., and Henrion, M.C. (1990) Uncertainty. A Guide to Dealing with Uncertainty in
Quantitative Policy Analysis. Cambridge, England: Oxford University Press.
Morgan, G.M., Florig, H.K, DeKay, M.L., and Fischbeck, P. (2000) Categorizing risks for risk ranking.
Risk Analysis 2: 49-58.
National Research Council (1994). Understanding Risk. Informing Decisions in a Democratic Society.
Washington, DC: National Academy Press
Ross, T. and Sumner, J. (2002). A simple spreadsheet-based food safety risk assessment tool. Int. J.
Food Micro. 77:39-53.
Sparrow, M.K. (2000) The Regulatory Craft
Thornton, A. C. (2004). Variation Risk Management. Focusing Quality Improvements in Product
Development and Production. Hoboken, NJ: John Wiley and Sons, Inc.
28
Thank you
29