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4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 1 ICH Q9 Quality Risk Management ICH Q9 Quality Risk Management –– An Industry PerspectiveAn Industry Perspective Graham Cook Ph.D. Senior Director, Process Knowledge / Quality by Design Wyeth Pharmaceuticals cookg1@wyeth.com 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 2 Overview of Presentation „ What is Quality Risk Management (QRM)? ‰ Background ‰ Principles ‰ Relationship to ICH Q8 and Q10 „ Why Quality Risk Management? ‰ Benefits for Industry „ When and where can QRM be applied? ‰ Example: QRM in tablet development ‰ Example: QRM in facility design „ How can we implement QRM and who do we need? ‰ Organization „ Summary 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 3 Background „ QRM is not new ‰ Quality Risk Management used by companies and authorities informally or more formally ‰ Used in other related regulated industries e.g. medical devices, food „ QRM is increasingly important ‰ QRM now enshrined in EU GMPs for Human and Veterinary Medicinal Products (Eudralex Vol.4 Part I, Chapter 1, Part II (API) & Annex 20) ‰ Global Boards of Health (BOH) and PIC/S are actively promoting QRM – e.g. FDA’s GMPs for the 21st Century initiative, IMB training initiatives, etc. ‰ BOH inspection and submission review requests regarding quality risk management are increasing 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 4 Definitions Quality Degree to which a set of inherent properties of a product, system or process fulfills requirements combination of the probability of occurrence of harm and the severity of that harm Risk Management QRM Systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 5 Principles of Quality Risk Management „ The evaluation of 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 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 6 ICH Q9 Content „ A common language and process with feedback loops „ Potential methodologies for QRM „ Where QRM can add value „ How to facilitate communication Risk Review 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 Risk Management Process R isk M anagem ent Tools R i s k C o m m u n i c a t i o n ICH Q9 Explains: ICH Q9 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 7 Risk Management Methods and Tools „ Facilitation Tools ‰ Flowcharts ‰ Checksheets ‰ Process mapping ‰ Cause & Effect diagrams (Ishikawa or Fishbone diagrams) „ Supporting statistical tools ‰ Acceptance Control Charts (see ISO 7966) ‰ Control Charts ‰ Design of Experiments (DOE) „ Pareto Charts ‰ Process Capability Analysis ‰ Histograms ICH Q9 Annex I 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 8 Popular Risk Management Tools „ 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 ICH Q9 Annex I 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 9 How Q9 works with Q8 and Q10 High Credit: J. Ramsbotham, Solvay Pharm. NL / EFPIA R i s k f r o m M a n u f a c t u r i n g s i t e Product / Process Risk Low HighLow Using Q9 Quality Risk Management principles c on tin ua l im pr ov em en t Q 1 0 P h a r m . Q u a l i t y S y s t e m s Q8 Pharmaceutical Development 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 10 Advantages of QRM as a Technique „ Improves decision making ‰ Identifies what gives most benefit to the patient „ Is scientific & data-driven ‰ Facilitate communication „ Ranks risk - allows prioritization ‰ Better use of resources „ Improves transparency & trust ‰ Enables regulatory flexibility 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 11 Overview of Presentation „ What is Quality Risk Management (QRM)? ‰ Background ‰ Principles ‰ Relationship to ICH Q8 and Q10 „ Why Quality Risk Management? ‰ Benefits for Industry „ When and where can QRM be applied? ‰ Example: QRM in tablet development ‰ Example: QRM in facility design „ How can we implement QRM and who do we need? ‰ Organization „ Summary 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 12 QRM Benefits our Company Operations „ Improves decision making ‰ Identifies what gives most benefit to the patient ‰ QRM is scientific and data-driven ‰ Reduces subjectivity „ Uses resources better ‰ Ranks risk - allows prioritization of effort ‰ Means of building in Quality ‰ Benefits apply throughout product lifecycle „ Facilitates communication ‰ Matrix team approach ‰ Outputs enhance product and process understanding ‰ Better understanding of risk-based decisions ‰ Acceptance of residual risks „ Encourages a preventive approach ‰ Proactive control of risks and uncertainty ‰ Benefit of knowledge transfer by team approach “Quality risk management can facilitate better use of resources by all parties.” (ICH Q9 Section 6) 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 13 QRM Benefits our Relationships with Global Boards of Health „ Improves transparency and builds trust with competent authorities ‰ Enables regulatory flexibility „ Recognise risks at a desired level ‰ Zero risk not possible „ Provide assurance ‰ Risks are adequately managed ‰ Compliance to external and internal requirements “Effective quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks, and can beneficially affect the extent and level of direct regulatory oversight.” (ICH Q9 Section 1) 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 14 QRM Benefits our Patients „ Quality products ‰ Patient focus ‰ Enhanced assurance of safety & effectiveness „ Consistent supply ‰ Enhanced product, process and systems robustness „ Better value ‰ Focusing our efforts and resources “An effective quality risk management approach can further ensure the high quality of the drug product to the patient by providing a proactive means to identify and control potential quality issues during development and manufacturing.” (ICH Q9 Section 1) 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 15 Overview of Presentation „ What is Quality Risk Management (QRM)? ‰ Background ‰ Principles ‰ Relationship to ICH Q8 and Q10 „ Why Quality Risk Management? ‰ Benefits for Industry „ When and where can QRM be applied? ‰ Example: QRM in tablet development ‰ Example: QRM in facility design „ How can we implement QRM and who do we need? ‰ Organization „ Summary 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 16 QRM: a Critical Component within Product Lifecycle Pharmaceutical Quality System (ICHQ10) QRM identified as one of the two key enablers of effective quality systems Pharmaceutical Development (ICHQ8) QRM and scientific approaches combine to enhance process knowledge Process Materials Design Manufacturing Distribution Patient Facilities Quality Risk Management (ICHQ9) Opportunities to impact risk using quality risk management Credit: G. Claycamp, FDA, June 2006 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 17 Application Areas – Some Examples „ Product Development ‰ Quality by Design: QRM is a key supporting tool „ Marketed Products ‰ Investigations and complaints ‰ Packaging design and labelling controls ‰ Laboratory controls ‰ Materials management „ Systems & Facilities ‰ Validation/Qualification ‰ Equipment & Utilities design and maintenance ‰ Documentation systems ‰ Auditing programmes QRM can provide benefit to operations within all quality systems and throughout the product lifecycle ICH Q9 Annex II 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 18 Application Examples „ QRM in tablet development ‰ EFPIA Mock P2 – ‘Examplain Tablets’ ‰ Drying operation „ QRM in facility design ‰ Biopharmaceutical manufacturing facility ‰ Risk of cross-contamination between adjacent manufacturing suites „ Examples illustrate ‰ Application of common principles in different areas of industry ‰ Different risks: therefore different level of effort ‰ Use of different tools 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 19 ‘Examplain Tablets’ Risk Identification - Manufacturing Process Cause and Effect Diagram for Water Content Credit: EFPIA, Mock P2, 2006 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 20 ‘Examplain Tablets’ Initial Risk Assessment Drying operation may affect product quality Credit: EFPIA, Mock P2, 2006 Initial classification of unit operations potential influence on product quality 1 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 21 Risk Control of Drying Process First Review Risk Assessment Failure modes understood Risk reduction: - Drying end-point control using NIR - Control of drying trajectory - Particle size monitored using laser diffraction Third Review Risk Assessment Experimental work to develop process understanding leads to risk reduction Credit: EFPIA, Mock P2, 2006 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 22 ‘Examplain Tablets’ Updated Risk Assessment Unit operations / Quality attributes Dispensing (Raw Material Properties) Granulation Drying Blending (Magnesium Stearate) Tableting Packaging Dissolution Particle size API Power consumption Prior knowledge Not critical to quality Not critical to quality Prior knowledge Disintegration Particle size API water amount and feed rate Prior knowledge Not critical to quality Not critical to quality Prior knowledge Hardness Prior knowledge Prior knowledge Prior knowledge Not critical to quality Not critical to quality Prior knowledge Assay Prior knowledge Prior knowledge Prior knowledge Prior knowledge NIR measurement Prior knowledge Content uniformity Prior knowledge Power consumption Not critical to quality Not critical to quality NIR measurement Prior knowledge Degradation Prior knowledge Water amount and feed rate Not critical to quality Prior knowledge Prior knowledge Prior knowledge Stability Prior knowledge Prior knowledge Control water content Prior knowledge Prior knowledge Prior knowledge Appearance Prior knowledge Prior knowledge Not critical to quality Prior knowledge Not critical to quality Prior knowledge Identification NIR of raw material Prior knowledge Prior knowledge Prior knowledge Prior knowledge Prior knowledge Water Prior knowledge Prior knowledge Control water content Prior knowledge Prior knowledge Prior knowledge Microbiology Specification of starting material Purified water used Prior knowledge Prior knowledge Prior knowledge Prior knowledge low Process understanding Control Strategy Unit operation Q u a l i t y A t t r i b u t e s Credit: EFPIA, Mock P2, 2006 - Process understanding gained during development 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 23 Example: Cross-contamination Prevention „ Proposed ‘Non-traditional’ biopharmaceutical facility utilization: ‰ Concurrent mammalian cell and bacterial (BL2) cell manufacturing processes in adjacent dedicated suites „ Facility design review identified the following concerns: ‰ Potential for cross-contamination between mammalian & bacterial processes through shared Production Service areas ‰ Operations for control and containment of the process within manufacturing suites Cross contamination hazards include: Raw materials Product Cell culture & fermentation components Process byproducts (ex: effluents, isoforms, etc.) Process support (cleaning agents, etc.) 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 24 Risk Management Strategy „ Cross contamination between processes is dependent upon three events occurring: ‰ Release hazard in Suite 1 + Transport hazard + Ingress hazard to Suite 2 „ Approach: systematic risk assessment of the internal operations and flows for each component at each facility interface gate Release of a hazard out of a manufacturing area due to deviations in internal area operations Ingress of a hazard into a manufacturing process due to deviations in internal area operations Transport of a hazard between manufacturing areas due to deviations in controls of the flow of components at interface gates Suite 1 Suite 2 Shared Services Shared Corridor Prevent or control each of these events and cross- contamination cannot occur 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 25 Risk Assessment „ Identify the complete array of release, transport, and ingress risks within scope „ Hazard Operability Analysis (HAZOP) used as the risk assessment tool for detailed analysis ‰ Suitable for facilities, equipment, and processes ‰ Capable of assessing process systems and their physical and operational environments ‰ Capable of assessing operational and procedural controls 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 26 Risk Analysis: Risk Rating System No Action Required One or More Controls Required One or More Controls Required More Than One Control Required More Than One Control Required More Than One Control Required More Than One Control Required More Than One Control Required Engineering Or Design Control Required High D e v i a t i o n O c c u r r e n c e Medium Controls may be procedural, training, or engineering / facility design controls and may consider the ability to detect deviations or hazard components as part of a mitigating control. Low Low Medium High Deviation Severity 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 27 Risk Control „ Risk Reduction – based on HAZOP outputs ‰ Facility design changes ‰ Process design and control enhancements ‰ Facility operating procedure and control enhancements „ Risk Acceptance ‰ Reduce residual risks to As Low As Reasonably Practicable (ALARP) ‰ ALARP – stop when risk reduction benefits disproportionately low for resources used ‰ Accept residual risks Risk Rating 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 28 Risk Communication & Risk Review „ Risk Communication ‰ Continuous reporting of process outcomes and progress to key stakeholders and management ‰ Regular updates prepared Senior Management for efficient decision-making on risk mitigation and regulatory submission strategies ‰ Meetings with Regulatory Agency to solicit feedback and facilitate understanding „ Risk Review ‰ Endorsed controlling actions were assessed to ensure no further negative impact ‰ Ongoing assessment may be performed as necessitated by changes 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 29 Outcomes & Benefits of QRM Process „ Summary report ‰ Extensive documentation package, basis for regulatory submissions ‰ QRM process was easily replicated with less effort for a similar risk assessment at a different facility „ Enhanced communication and transparency ‰ Quality Risk Management results showed multiple layers of control in place to prevent cross-contamination between suites ‰ Regular communication facilitated efficient, objective decision- making by Senior Management ‰ Enhanced understanding of facility design and controls for Regulatory Agency „ Continual improvement ‰ Opportunities identified for continual improvement of site-wide and global facility management and operational processes 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 30 Overview of Presentation „ What is Quality Risk Management (QRM)? ‰ Background ‰ Principles ‰ Relationship to ICH Q8 and Q10 „ Why Quality Risk Management? ‰ Benefits for Industry „ When and where can QRM be applied? ‰ Example: QRM in tablet development ‰ Example: QRM in facility design „ How can we implement QRM and who do we need? ‰ Organization „ Summary 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 31 What does Senior Management need to do? „ Ensure organisation is aware of ICH Q9 and the opportunity it affords ‰ Appropriate education and training „ Encourage open, risk aware culture ‰ Establish & support “QRM leaders” across organisations „ Encourage integration of Quality Risk Management with existing Quality systems ‰ Do NOT set up as a separate department ‰ Coordinate implementation and resource allocation ‰ Prioritise; start small, learn as you go 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 32 QRM Roles and Responsibilities „ Facilitator / Team Lead ‰ Guide the QRM process „ Team Members ‰ Can include Subject Matter Experts / process representative or owner, Quality, Regulatory Affairs, Operators & Technicians and others as needed ‰ Provide expertise, input, and perspective „ Internal Stakeholders ‰ Can include direct line management, senior management ‰ Can affect (or can be affected by) the QRM process „ Reviewers & Approvers ‰ Review and access outcome of the QRM process 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 33 An Approach to Implementation of QRM Sharing best practices, leading industry Replications, sharing proven practices Initial QRM efforts QRM Policies and SOPs in place Most advanced InitialInitial RepeatableRepeatable DefinedDefined ManagedManaged OptimizingOptimizing InitialInitial RepeatableRepeatable DefinedDefined ManagedManaged OptimizingOptimizing Disciplined process Continually improving process Standard process Predictable process 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 34 Summary – What QRM Is and Is Not „ Quality Risk Management is NOT ‰ Making do with insufficient time, money, or people ‰ Providing an excuse not to do the right things ‰ Deciding what to do based on what might be observed during an inspection ‰ Providing an excuse to be out of compliance with applicable regulations „ Quality Risk Management IS ‰ Knowing our processes (manufacturing and business) ‰ Understanding what is truly important ‰ Focusing our money, time, energy, and people on the important things that provide quality assurance to our patients ‰ Facilitating communication 4 December 2008 JCCT Workshop on Implementation of ICH Q8/Q9/Q10 35 ICH Q9 briefing pack is available On the ICH Q9 Document „ Background „ History „ Content „ Tools „ Applications Additional features „ Executive Summary „ Frequently Asked Questions (Q&A) See www.ich.org Q9 documen