Quality System Model ICH Q10

Agenda What is ICH Q10 History Why do we need a ‘modern effective Quality System’? The elements and enablers of a Quality System Model of Pfizer’s Quality System Review the website

Pharmaceutical Quality System The ICH Q10 document on Pharmaceutical Quality System was recommended for adoption to the regulatory bodies of the EU, Japan and USA, June 2008. The document establishes a tripartite guideline describing a model for an effective quality management system; a management system to direct and control a pharmaceutical company with regard to quality. The specifics of a pharmaceutical quality system vary depending with the stage of the product lifecycle, but the overall principles and components are the same.

History Evolution of regional GMPs 1970s Evolution of ISO 9000 approaches 1980s FDA 21st Century initiative 2002 ICH Quality Vision / Q8, Q9 2003 Guidance for Industry - Quality System Approach to Pharmaceutical cGMP Regulations 2006 ICH Q10 Pharmaceutical Quality System 2008

Comprehensive Model Based on International Standards Organization (ISO) quality concepts Includes applicable GMP regulations Complements both ICH Q8 Pharmaceutical Development, ICH Q9 Quality Risk Management Not intended to create new expectations beyond current regulatory environment

A ‘Modern Effective Quality System’? Good business practice! Significant changes in external business environment Fewer new products / ‘blockbusters’ Reduced margins / greater competition / low-cost sources Focus of efficient, effective organizations Lean processes Pharmaceutical industry is behind other industries in Quality Management philosophies / practices Marketed products ARE safe and efficacious BUT costs of quality are high Often reactive, not designed-in / preventative

Why do we need a ‘Modern Effective Quality System’? Implementation should Facilitate innovation and continual improvement Inflexible regulatory environment Focus on Compliance, not Science and Risk-Based approach Industry margins did not provide drive for change Strengthen the link between pharmaceutical development and manufacturing GMPs do not provide a ‘full modern’ Quality System Originated in 1970s – incremental additions ISO Quality Management thinking not embedded Need to be complemented with Q8 and Q9 This is in direct alignment with Pfizer’s philosophies and vision

Pharmaceutical Quality System The diagram illustrates the major features of the ICH Q10 Pharmaceutical Quality System model. The model covers the entire lifecycle of a product including pharmaceutical development, technology transfer, commercial manufacturing, and product discontinuation. The diagram also illustrates that GMPs apply to the manufacture of investigational products. The next horizontal bar illustrates the importance of management responsibilities to all stages of the product lifecycle. The following horizontal bar lists the Quality System elements which are the mainstays of a quality system. These elements should be applied appropriately and proportionally to each lifecycle stage. The bottom set of horizontal bars illustrate the enablers: knowledge management and quality risk management, which are applicable throughout the lifecycle stages. These enablers support the quality system goals of achieving product realization, establishing and maintaining a state of control, and facilitating continual

An Effective Quality System GMPs Management Responsibility Elements - Continual Improvement Enablers – Knowledge and Risk Management Lifecycle approach ICH Q10 describes a single comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts. It includes applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management”. ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle. Much of the content of ICH Q10 applicable to manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not intended to create any new expectations beyond current regulatory requirements. The additional content is optional, but its use should facilitate innovation and continual improvement, and strengthen the link between pharmaceutical development and manufacturing activities. It does not restate GMP requirements, ICH Q10 is intended to augment requirements to achieve the Pharmaceutical Quality System objectives Cover Management Responsibility and Continual improvement in a bit more detail

An Effective Quality System GMPs Management Responsibility Elements - Continual Improvement Enablers – Knowledge and Risk Management Lifecycle approach ICH Q10 describes a single comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts. It includes applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management”. ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle. Much of the content of ICH Q10 applicable to manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not intended to create any new expectations beyond current regulatory requirements. The additional content is optional, but its use should facilitate innovation and continual improvement, and strengthen the link between pharmaceutical development and manufacturing activities. It does not restate GMP requirements, ICH Q10 is intended to augment requirements to achieve the Pharmaceutical Quality System objectives Cover Management Responsibility and Continual improvement in a bit more detail

Management Responsibilities Essential component of a Quality System Not just about compliance Visible leadership to establish and maintain a company wide culture and commitment to Quality and improvement Monitor performance of the Quality System for both internal and outsourced activities Quality can not be owned only by the ‘Q’ Unit Management is accountable But independent assessments are key

Management Responsibilities Management Commitment Quality Policy Quality Planning Resource Management Internal Communication Management Review Outsourced Activities Change in Product Ownership Essential component of a Quality system Not just about compliance but Visible leadership to establish and maintain a company wide culture and commitment to Quality and improvement Monitor performance of the Quality System for both internal and outsourced activities Quality can not be owned only by the Q Unit Management is accountable But independent assessments / audits are key

Management Commitment Signed Quality Commitments are commonplace and are not indicative of Management Commitment What is Indicative? Plant Managers aware of the issues Management Team that works together Quality as a Trusted Partner

Clear Roles, Responsibilities, Processes Quality Policy: Sets the standards and direction of organization Quality Planning: Converts into objectives & plans Resources: Allocations and competence Communication: Quality items to appropriate audience Management Reviews Product and Process performance Quality System performance

Quality Policies Comprehensive and Balanced Flexibility/adaptability defined is consistent Interconnectivity of a Quality System requires a comprehensive approach in the design

Quality Plans Written Quality Plans are becoming more common What is Indicative? Quality Planning Process is dynamic Defined process for evaluating issues to bring into the quality planning process. Tracking progress against an agreed upon Quality Plan Adequate resources are made available

Resource Management Adequate resources are made available Resources include time, money, equipment and people What is Indicative? Clear prioritization of resources in line with Reasonable number of projects with Realistic commitment time frames

Internal Communication Issues will occur Escalation of issues, actions, decisions and impact What is Indicative? Trusting relationship between manufacturing & quality assurance Understanding of why timeliness is important Communication uses defined processes and is transparent Escalation of issue is not viewed as punitive The Operations Team is wholly accountable Adequate resources are made available

Management Review Grounded in the device regulations, periodic Management Reviews are becoming more common What is Indicative? Linkage between Quality Plan and Management Reviews Linage between Key Quality Indicators In a hierarchal company, how information flows Depth and frequency of Reviews Attendance at the Management Review How is the information used? Opportunity to align priorities and resources Not punitive

Outsourced Activities and Purchased Materials Pharmaceutical firm (i.e., Management) is ultimately responsible to assure processes are in place Process must be in place to: Assess suitability of contractors / suppliers before use Ensure use of approved suppliers and a defined supply chain Define responsibilities and communication processes for quality related activities Review performance and make improvements Quality System must extend to the control and review of outsourced activities and the quality of purchased materials

An Effective Quality System GMPs Management Responsibility Elements - Continual Improvement Process Performance and Product Quality Corrective Action / Preventive Action Change Management Management Review Enablers – Knowledge and Risk Management Lifecycle approach ICH Q10 describes a single comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts. It includes applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management”. ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle. Much of the content of ICH Q10 applicable to manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not intended to create any new expectations beyond current regulatory requirements. The additional content is optional, but its use should facilitate innovation and continual improvement, and strengthen the link between pharmaceutical development and manufacturing activities. It does not restate GMP requirements, ICH Q10 is intended to augment requirements to achieve the Pharmaceutical Quality System objectives Cover Management Responsibility and Continual improvement in a bit more detail

Continual Improvement Continuous Improvement of product quality is a key objective of the quality system, irrespective of the stage of the lifecycle. Four specific elements of the quality system support achieving continuous improvement: Process performance and product quality monitoring Corrective action and preventative action Change management Management review of process performance and product quality

Product Quality and Process Performance Use knowledge, Quality by Design, Product and Process understanding and QRM to set Control Strategy What and when to monitor / measure / test Based on critical product quality attributes and critical process parameters to deliver them Reduce and control variation to appropriate levels Confirm and maintain a state of control Feed-back and Feed-forward loops Drive continual improvement Continual verification

CAPA System Investigation of non-conformances Reactive → deviations, rejections, complaints, recalls, observations from audits and inspections Proactive → feedback from trends Structured investigations to seek root cause Use QRM to ensure degree and formality is commensurate with level of risk Should result in enhanced knowledge and improvement Not just reacting to non-conformances Focus on preventative actions Need effective tracking / follow up processes

Change Management System Change can be good! Proactively driven by outputs from monitoring / trending / improvement / innovation Not just by reacting to problems Use expert teams and knowledge to evaluate and set success criteria Use QRM commensurate with level of risk Consider impact on regulatory filings Undertake in timely and effective way and tracked Assure no unintended consequences

Management Review Process Performance and Product Quality Results from inspections and assessments Periodic quality reviews Customer satisfaction – complaints, recalls Conclusions of process performance and product quality monitoring Effectiveness of process and product changes Appropriate actions Improvements to manufacturing processes Training and/or realignment of resources Capture and share knowledge All three come together in management review

Continual Improvement of the Quality System Assessment of the Quality System against Internal factors (audits, CAPAs, complaints, recalls, etc.) External factors (regulatory inspectional findings) Emerging regulations New technology Change in business strategies Outcomes of the Assessment Improvements communicated throughout a business Resource reallocation Changes in policies, practices

An Effective Quality System GMPs Management Responsibility Elements - Continual Improvement Enablers – Knowledge and Risk Management Lifecycle approach ICH Q10 describes a single comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts. It includes applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management”. ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle. Much of the content of ICH Q10 applicable to manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not intended to create any new expectations beyond current regulatory requirements. The additional content is optional, but its use should facilitate innovation and continual improvement, and strengthen the link between pharmaceutical development and manufacturing activities. It does not restate GMP requirements, ICH Q10 is intended to augment requirements to achieve the Pharmaceutical Quality System objectives Cover Management Responsibility and Continual improvement in a bit more detail

Knowledge Management Systematic and lifecycle approach to acquiring, analyzing, storing and disseminating knowledge on products, processes, components Provides the basis for science and risk-based approaches in the Quality System Product and process development Manufacturing Change management Continual improvement

Quality Risk Management (Q9) Essential, integrated part of Quality System The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk Proactive use to identify and control risk Support decision through lifecycle Integrate into key parts of Quality System e.g., change management, CAPA, GMPs – Validation, etc. Help set meaningful specification / control parameters to ensure product quality control requirements are met

Key to an Effective Quality System GMPs Management Responsibility Continual Improvement Knowledge Management Quality Risk Management Lifecycle approach ICH Q10 describes a single comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts. It includes applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management”. ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle. Much of the content of ICH Q10 applicable to manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not intended to create any new expectations beyond current regulatory requirements. The additional content is optional, but its use should facilitate innovation and continual improvement, and strengthen the link between pharmaceutical development and manufacturing activities. It does not restate GMP requirements, ICH Q10 is intended to augment requirements to achieve the Pharmaceutical Quality System objectives Cover Management Responsibility and Continual improvement in a bit more detail

Lifecycle Approach Holistic and cover the product lifecycle Design and Development Manufacturing Withdrawal Challenges and removes some traditional organizational silos Within industry Within Regulatory Agencies With outsourcing partners Application of Quality System Elements at each stage of the Product Lifecycle

Pharmaceutical Quality System The diagram illustrates the major features of the ICH Q10 Pharmaceutical Quality System model. The model covers the entire lifecycle of a product including pharmaceutical development, technology transfer, commercial manufacturing, and product discontinuation. The diagram also illustrates that GMPs apply to the manufacture of investigational products. The next horizontal bar illustrates the importance of management responsibilities to all stages of the product lifecycle. The following horizontal bar lists the Quality System elements which are the mainstays of a quality system. These elements should be applied appropriately and proportionally to each lifecycle stage. The bottom set of horizontal bars illustrate the enablers: knowledge management and quality risk management, which are applicable throughout the lifecycle stages. These enablers support the quality system goals of achieving product realization, establishing and maintaining a state of control, and facilitating continual

Pharmaceutical Development Stage Design a product and its manufacturing process to consistently deliver the intended performance and meet the needs of patients, health-care professionals, and regulatory authorities Develop knowledge of product and processes Utilize Quality Risk Management principles to identify and control risk to product quality

Technology Transfer Stage Transfer product and process knowledge between development and manufacturing or between manufacturing units. Develop further knowledge Refine Quality Risk Management and control strategies

Commercial Manufacturing Stage Provide product with appropriate quality attributes consistently in a state of control and facilitating continual improvement. Continually expand product and process knowledge Adjust the Quality Risk Management and control strategy as needed.

Product Discontinuation Stage Manage the terminal stage of the product lifecycle using a pre-defined approach product complaint management stability studies documentation

GMPs over the Product Lifecycle Compliance with applicable GMPs is the foundation of the quality system The intended use and market of any material produced during the lifecycle must be understood and the appropriate GMPs must be met Applicable GMPs must be incorporated into the quality system for each stage of the lifecycle Documentation Quality Unit Responsibilities Facilities and Equipment

Management Controls - Product Lifecycle Essential over all stages of Product Lifecycle Includes: Management Commitment, Policy and Planning, Resource Management, Review and Communication Extends to management controls of outsourced operations

Monitoring CAPA Change Management Management Review Use to provide data and knowledge CAPA Use methodology to identify and implement improvements Change Management Change is inherent part of this phase Change must be documented Increase formality as development progresses Management Review Use to ensure the adequacy of product and process design

Monitoring CAPA Change Management Management Review Use to provide indication of how process performs in manufacturing CAPA Used to make improvements to development and to commercial manufacturing Change Management Proactively manage change and thoroughly Management Review Use to ensure the developed process can be manufactured at scale

Monitoring CAPA Change Management Management Review Well-defined monitoring of process performance & product quality to assure performance within a state of control CAPA CAPA methodology must be used and the effectiveness evaluated Change Management Formal change management must be used Must have oversight by the quality unit Management Review A structured review which identifies and supports continual improvement

Monitoring CAPA Change Management Management Review Relevant monitoring should continue (e.g., completion of stability studies, and product compliant analysis) CAPA Should be used to determine and address any impact on product remaining on the market and on any other products Change Management Should continue for any appropriate changes Oversight by quality unit Management Review Continue reviews and include such activities as stability and complaints

Enablers Over the Product Lifecycle Knowledge increases throughout the product lifecycle and must be captured, transferred and used systematically Quality Risk Management provides proactive approach to identifying and controlling risks throughout the lifecycle

Framework of a Quality System Achieve Product Realization From the start of an idea for a product, to the culmination of the product available for the patients. Manufacturing and release of finished goods so that prodcut is available for patients Establish and Maintain a State of Control Effective monitoring & control systems are in place which assure continued process performance and prodcut quality A confidence when scheduling production, product will be available according to planned dates. Facilitate Continual Improvement Reducing project and process variability Looking for areas of improvement not self-evident but important Start with the End in Mind – Define your objectives

Summary The Quality System defines our Quality Culture Defines the responsibilities and authorities Defines communication models to all levels in the organization Provides a clear governance model defining how quality decisions are made Monitors to assure necessary resources are available for completion of quality plans Assures alignment of the quality objectives with the business strategy Makes life easier

Pfizer Quality System Model

References International Conference on Harmonization, Harmonized Tripartite Guideline, Pharmaceutical Quality System, ICH Q10, Step 4, 04June2008 Kaufman, Zena G., Divisional VP, Quality Center of Excellence, Abbott, “Considerations for Designing a Pharmaceutical Quality System”, Nov 2008 Allen, Barbara, Director, Global Quality Systems, Eli Lilly and Company, “Quality Systems over the Product Lifecycle”, Nov 2008 Wilkinson, Neil, David Begg Associates, “The Elements of a Modern Effective Pharmaceutical Quality System”, Nov 2008