Quality Risk Management ICH Q9 Content Disclaimer: This presentation includes the authors views on quality risk management theory and practice. The presentation does not represent official guidance or policy of authorities or industry.

Purpose of this part To guide through the content of the ICH Q9 document Provide some considerations, possible interpretations and where appropriate examples

ICH Q9: Quality Risk Management (QRM) Document is available on the ICH Webpage www.ich.org

Table of contents 1. Introduction 2. Scope 3. Principles of Quality Risk Management 4. General Quality Risk Management Process 5. Risk Management Methodology Annex I: Risk Management Methods and Tools 6. Integration of QRM process into Industry and Regulatory operations Annex II: Potential Applications for QRM 7. Definitions 8. References

Quality Risk Management 1. Introduction Risk Management Quality Risk Management Quality Systems Harm Severity Stakeholder Product Life Cycle GMP Compliance

2. Scope This guideline provides principles & examples of tools of quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products ICH Q9

2. Scope Drug substances, Drug (medicinal) products, CONSIDERATIONS 2. Scope Drug substances, Drug (medicinal) products, Biological and biotechnological products Including the selection and use of Raw materials Solvents Excipients Packaging and labelling materials Components

3. Principles of Quality Risk Management Two primary principles: The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk ICH Q9

4. General Quality Risk Management Process Systematic processes designed to coordinate, facilitate and improve science-based decision making with respect to risk to quality ICH Q9

4. A General Quality Risk Management Process Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the M g e l Team approach ICH Q9

4. General Quality Risk Management Process Decision makers: Person(s) with competence and authority to make a decision Ensuring that ongoing Quality Risk Management processes operate Coordinating quality risk management process across various functions and departments Supporting the team approach Management responsibility ICH Q9

4. General Quality Risk Management Process CONSIDERATIONS 4. General Quality Risk Management Process Team approach Usually, but not always, undertaken by interdisciplinary teams from areas appropriate to the risk being considered e.g. Quality unit Development Engineering / Statistics Regulatory affairs Production operations Business, Sales and Marketing Legal Medical / Clinical &… Individuals knowledgeable of the QRM processes

4. General Quality Risk Management Process When to initiate and plan a QRM Process First define the question which should be answered (e.g. a problem and/or risk question) including pertinent assumptions identifying the potential for risk Then assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the risk Identify a leader and necessary resources Specify a timeline, deliverables and appropriate level of decision making for the QRM process Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

When to apply Quality Risk Management? CONSIDERATIONS When to apply Quality Risk Management? Should risks be assessed? Are there clear rules for decision making? e.g. regulations Yes “no RM“ Risk assessment not required (No flexibility) Follow procedures (e.g. Standard Operating Procedures) Document results, decisions and actions 1. What might go wrong? 2. What is the likelihood (probability) it will go wrong? 3. What are the consequences (severity)? No or justification needed Can you answer the risk assessment questions? Yes “informal RM“ Initiate Risk assessment (risk identification, analysis & evaluation) Run risk control (select appropriate measures) Agree on a team (small project) Select a Risk Management tool (if appropriate e.g. see ICH Q9 Annex I) No “formal RM“ Carry out the quality risk management process Document the steps Based on K. Connelly, AstraZeneca, 2005

4. General Quality Risk Management Process 3 fundamental questions Risk Assessment Risk Identification What might go wrong? Risk Analysis What is the likelihood (probability) it will go wrong? Risk Evaluation What are the consequences (severity)? Note: People often use terms “Risk analysis”, “Risk assessment” and “Risk management” interchangeably which is incorrect! Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

4. General Quality Risk Management Process Risk Assessment: Risk Identification “What might go wrong?” A systematic use of information to identify hazards referring to the risk question or problem historical data theoretical analysis informed opinions concerns of stakeholders Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

4. General Quality Risk Management Process Risk Assessment: Risk Analysis “What is the likelihood it will go wrong?” The estimation of the risk associated with the identified hazards. A qualitative or quantitative process of linking the likelihood of occurrence and severity of harm Consider detectability if applicable (used in some tools) Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

4. General Quality Risk Management Process CONSIDERATIONS 4. General Quality Risk Management Process Risk Assessment: Risk Analysis Often data driven Keep in mind: Statistical approach may or may not be used Maintain a robust data set! Start with the more extensive data set and reduce it Trend and use statistics (e.g. extrapolation) Comparing between different sets requires compatible data Data must be reliable Data must be accessible Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

4. General Quality Risk Management Process Risk Assessment: Risk Evaluation “What is the risk?” Compare the identified and analysed risk against given risk criteria Consider the strength of evidence for all three of the fundamental questions What might go wrong? What is the likelihood (probability) it will go wrong? What are the consequences (severity)? Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

4. General Quality Risk Management Process CONSIDERATIONS 4. General Quality Risk Management Process Risk Assessment: Risk Evaluation A picture of the life cycle = Risk Priority Number Probability x Detectability x Severity Frequency of “occurences” driven by the number of trials Degree of belief Data refers to Can you find it? Impact past today future time

4. General Quality Risk Management Process Risk Control: Decision-making activity Is the risk above an acceptable level? What can be done to reduce or eliminate risks? What is the appropriate balance between benefits, risks and resources? Are new risks introduced as a result of the identified risks being controlled? Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

4. General Quality Risk Management Process CONSIDERATIONS 4. General Quality Risk Management Process Risk Control: Residual Risk The residual risk consists of e.g. Hazards that have been assessed and risks that have been accepted Hazards which have been identified but the risks have not been correctly assessed Hazards that have not yet been identified Hazards which are not yet linked to the patient risk Is the risk reduced to an acceptable level? Fulfil all legal and internal obligations Consider current scientific knowledge & techniques Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

4. General Quality Risk Management Process Risk Control: Risk Reduction Mitigation or avoidance of quality risk Elimination of risks, where appropriate Focus actions on severity and/or probability of harm; don’t forget detectability It might be appropriate to revisit the risk assessment during the life cycle for new risks or increased significance of existing risks Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

4. General Quality Risk Management Process Risk Control: Risk Acceptance Decision to Accept the residual risk Passively accept non specified residual risks May require support by (senior) management Applies to both industry and competent authorities Will always be made on a case-by-case basis Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

4. General Quality Risk Management Process CONSIDERATIONS 4. General Quality Risk Management Process Risk Control: Risk Acceptance Discuss the appropriate balance between benefits, risks, and resources Focus on the patients’ interests and good science/data Risk acceptance is not Inappropriately interpreting data and information Hiding risks from management / competent authorities Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

What is an “acceptable risk”? Risk Control: Risk Acceptance Who has to accept risk? Decision Maker(s) Person(s) with the competence and authority to make appropriate and timely quality risk management decisions Stakeholder Any individual, group or organization that can …be affected by a risk Decision makers might also be stakeholders The primary stakeholders are the patient, healthcare professional, regulatory authority, and industry The secondary stakeholders are patient associations, public opinions, politicians (ICH Q9, definition)

4. General Quality Risk Management Process EXAMPLE 4. General Quality Risk Management Process A Risk Acceptance process 1/3 Finish baseline for risk acceptance decision risk identification, risk analysis, risks evaluation, risks reduction Risk reduction step finished Yes Stakeholders involved as appropiate? Revisit risk assessment step All identified risks assessed? No Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

4. General Quality Risk Management Process EXAMPLE 4. General Quality Risk Management Process Evaluate measures on severity, probability, detectability Check needed resources e.g. employee, money Measures / Actions appropriate? No Yes Revisit risk reduction step Other hazards caused? Is a risk reducible? Measures/ actions needed? A Risk Acceptance process 2/3 Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

4. General Quality Risk Management Process EXAMPLE 4. General Quality Risk Management Process A Risk Acceptance process 3/3 Accept the residual risk? Ready for communication Accept risk Sign off documentation Is a risk reducible? Yes Advantage outweighs risk? No Risk not acceptable Revisit risk assessment step Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

4. General Quality Risk Management Process Risk Communication Bi-directional sharing of information about risk and risk management between the decision makers and others Communicate at any stage of the QRM process Communicate and document the output/result of the QRM process appropriately Communication need not be carried out for each and every individual risk acceptance Use existing channels as specified in regulations, guidance and SOP’s Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l According to ICH Q9

4. General Quality Risk Management Process CONSIDERATIONS 4. General Quality Risk Management Process Risk Communication Exchange or sharing of information, as appropriate Sometimes formal sometimes informal Improve ways of thinking and communicating Increase transparency Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

Quality risk management CONSIDERATIONS Quality risk management Communication facilitates trust and understanding Regulators operation - Reviews - Inspections Industry operation - Submissions - Manufacturing

4. General Quality Risk Management Process Risk review: Review Events Review the output / results of the QRM process Take into account new knowledge and experience Utilise for planned or unplanned events Implement a mechanism to review or monitor events Reconsideration of risk acceptance decisions, as appropriate Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

5. Risk Management Methodology One method “all inclusive”? Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l Cartoon: © Zurich Insurance Inc.

Expectations on methods and tools CONSIDERATIONS Expectations on methods and tools Supports science-based decisions A great variety are listed but other existing or new ones might also be used No single tool is appropriate for all cases Specific risks do not always require the same tool Using a tool the level of detail of an investigation will vary according to the risk from case to case Different companies, consultancies and competent authorities may promote use of different tools based on their culture and experiences

Contributing items to manage quality risks CONSIDERATIONS Contributing items to manage quality risks System Risk (facility & people) e.g. interfaces, operators risk, environment, components such as equipment, IT, design elements System Risk (organisation) e.g. Quality systems, controls, measurements, documentation, regulatory compliance Process Risk e.g. process operations and quality parameters Product Risk (safety & efficacy) e.g. quality attributes: measured data according to specifications

5. Risk Management Methodology Supports a scientific and practical approach to decision-making Accomplishing steps of the QRM process Provides documented, transparent and reproducible methods Assessing current knowledge Assessing probability, severity and sometimes detectability Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

5. Risk Management Methodology Adapt the tools for use in specific areas Combined use of tools may provide flexibility The degree of rigor and formality of QRM Should be commensurate with the complexity and / or criticality of the issue to be addressed and reflect available knowledge Informal ways empirical methods and / or internal procedures Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

Annex I: Risk Management Methods and Tools Provides a general overview of and references for some of the primary tools Might be used in QRM by industry and regulators This is not an exhaustive list No one tool or set of tools is applicable to every situation in which a QRM procedure is used For each of the tools Short description & reference Strength and weaknesses Purely illustrative examples Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

Overview: Some tools and their key words CONSIDERATIONS Overview: Some tools and their key words Failure Mode Effects Analysis (FMEA) Break down large complex processes into manageable steps Failure Mode, Effects and Criticality Analysis (FMECA) FMEA & links severity, probability & detectability to criticality Fault Tree Analysis (FTA) Tree of failure modes combinations with logical operators Hazard Analysis and Critical Control Points (HACCP) Systematic, proactive, and preventive method on criticality Hazard Operability Analysis (HAZOP) Brainstorming technique Preliminary Hazard Analysis (PHA) Possibilities that the risk event happens Risk ranking and filtering Compare and prioritize risks with factors for each risk Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l

5. Risk Management Methodology Supporting statistical tools Acceptance Control Charts (see ISO 7966) Control Charts (for example) Control Charts with Arithmetic Average and Warning Limits (see ISO 7873) Cumulative Sum Charts; “CuSum” (see ISO 7871) Shewhart Control Charts (see ISO 8258) Weighted Moving Average Design of Experiments (DOE) Pareto Charts Process Capability Analysis Histograms Use others that you are familiar with…. Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality M g e l ICH Q9

5. Risk Management Methodology CONSIDERATIONS 5. Risk Management Methodology Q9 does not provide “drivers licences”

6. Integration into Industry and Regulatory Operations Foundation for “science-based” decisions Does not obviate industry’s obligation to comply with regulatory requirements May affect the extent and level of direct regulatory oversight Degree of rigor and formality commensurate with the complexity and/or criticality of the issue Implement QRM principles when updating existing guidelines ICH Q9

Annex II: Potential Applications for QRM This Annex is intended to identify potential uses of quality risk management principles and tools by industry and regulators. However, the selection of particular risk management tools is completely dependent upon specific facts and circumstances. These examples are provided for illustrative purposes and only suggest potential uses of quality risk management. This Annex is not intended to create any new expectations beyond the current regulatory requirements. ICH Q9 Introduction to Annex II

Annex II: Potential Applications for QRM Quality risk management as part of Integrated quality management Documentation Training and education Quality defects Auditing / Inspection Periodic review Change management / change control Continual improvement Competent authorities Industry

Competent authorities Competent authorities Annex II: Potential opportunities for conducting quality risk management Quality risk management as part of Regulatory operations Inspection and assessment activities Competent authorities Industry operations Development Facilities, equipment and utilities Materials management Production Laboratory control and stability testing Packaging and labelling Industry Competent authorities

Quality Risk Management PROCESS ASSESSMENT CONTROL COMMUNICATION IDENTIFICATION ANALYSIS EVALUATION REDUCTION ACCEPTANCE REVIEW EVENTS ACCEPT (RESIDUAL RISK) INTERDISCIPLINARY TEAMS WHAT`? PROBABILITY SEVERITY CRITERIA Failure Mode, Effects & Criticality Analysis TOOLS INFORMAL HACCP HAZOP FMEA FMECA FTA PHA Hazard Analysis & Critical Control Points Preliminary Hazard Analysis Fault Tree Analysis Failure Mode Effect Analysis Hazard Operatibility Analysis QUALITY Mgt. INDUSTRY REGULATORY DOCUMENTATION TRAINING AUDITING CHANGE CONTROL MATERIALS PRODUCTION QU INSPECTION ASSESSMENT APPLICATION ICH Q9 Quality Risk Management RISK PROBABILITY OF HARM SEVERITY CAUSE OF DAMAGE CAUSE OF HARM HAZARD PRINCIPLES PATIENT PROTECTION EFFORT Peter Gough, Stephan Roenninger, ICH Q9 : Quality Risk Management - an update Regulatory Affairs Journal, 16, 2005, 91-93 Bill Paulson, ICH Q9 Provides Implementation Framework for Quality Risk Management Gold Sheet, 39, May 2005 QUALITY SYSTEM © J. Arce, F. Hoffmann-La Roche

Use the right “risk” expression please! Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the M g e l Use the right “risk” expression please!