Pharmaceuticals Quality Management System
A quality management system (QMS) can be defined as a set of policies, processes, and procedures required for planning and execution (production/development/service) in the core business area of an organization. A QMS integrates the various internal processes within the organization and provides a process approach for project execution. The QMS enables organizations to identify, measure, control, and improve the various core business processes, which ultimately leads to improved business performance.
The design and implementation of a QMS will vary depending on the type, size, and products of the organization. Implementing a QMS within an organization needs to be a decision by top management. Continued support by top management is critical to the ongoing success of the QMS.
The objectives of the QMS need to be clearly defined so that the system can be effective. QMS objectives must be measurable and reflect the overall company objectives. The QMS must be managed properly, and adequate resources must be allocated. The system must be practical and accessible to all employees within the organization. The system also must be reviewed regularly and measured for effectiveness, and adjustments must be made to reflect major changes to the organization and business practices.
Each company will have its own objectives for implementing a QMS; however, enhancing company effectiveness and profitability are often cited as primary drivers for implementation. A QMS can assist a company by managing costs and risks, increasing effectiveness and productivity, identifying improvement opportunities, and increasing customer satisfaction. A well-managed QMS will have an impact on customer loyalty and repeat business, market share, operational efficiencies, and flexibility and the ability to respond to market opportunities. It also helps in the effective and efficient use of resources and reducing costs, provides competitive advantages, and can increase participation and motivation of human resources, industry reputation, and control on all processes.
ESTABLISHING A QUALITY MANAGEMENT SYSTEM
A QMS must ensure that the products/services conform to customer needs and expectations and, at the same time, meet the objectives of the organization. Factors to be considered when setting up a QMS include design and build, deployment and implementation, control, measurement, review, and improvement.
Design and build include the structure of the QMS, the process, and its implementation. The design should be led by senior managers and ideally is accomplished using a framework to lead the thinking. Design of the QMS should result from determining the organization’s core processes and well-defined goals and strategies, and be linked to the needs of the stakeholders. The process for designing and building the QMS must be clear. The quality function plays a key role in the design and build of the QMS, but involvement and buy-in to the system must come from all other functions as well.
Deployment and implementation are best achieved using process packages, where each core process is broken down into subprocesses and described by a combination of documentation, education, training, tools, systems, and metrics.
Control of the QMS will depend on the size and complexity of the organization. Local control, where possible, is effective, and good practice is found where key stakeholders are documented within the process and where the process owner is allowed to control all of the process. Ideally, process owners/operators are involved in writing the procedures that document the QMS.
Measurement determines the effectiveness and efficiency of each process toward attaining its objectives. It should include the contribution of the QMS to the organization’s goals, and could be achieved by measuring policy definition completeness, business coverage, reflection of policies, deployment, usage, opinion regarding helpfulness of the QMS by staff, speed of change of the QMS, and relevance of QMS architecture to the job at hand. A form of scorecard deployed throughout the organization down to the individual objective level can be used, and the setting of targets at all levels is vital.
Review of the effectiveness, efficiency, and capability of the QMS is vital, and the outcome of these reviews should be communicated to all employees, including senior management. Reviewing and monitoring should be conducted whether or not improvement activities have achieved their expected outcomes.
Improvement should follow as a result of the review process, with the aim of seeking internal best practice. It is part of the overall improvement activities and an integral part of managing change within the organization.
QUALITY MANAGEMENT SYSTEM PRINCIPLES
ISO 9001:2008 (Quality management systems—Requirements) is an internationally recognized standard that specifies the requirements for a QMS that may be used by organizations for internal application, certification, or contractual purposes. ISO 9001:2008 and ISO 9004:2009 (Managing for the sustained success of an organization—A quality management approach) are QMS standards that complement each other, but also may be used independently. ISO 9001 emphasizes a need for management commitment, customer focus, a quality policy, quality planning, communication of responsibility and authority, and the need for a review of the organization’s QMS.
Monitoring of customer satisfaction is necessary to evaluate and validate whether customer requirements have been met. Reference is made in the standard to a methodology known as plan–do–check–act (PDCA) that can be applied to all processes.
The standard suggests that an effective QMS must be a strategic tool designed to deliver business objectives and must have, at its core, a process approach, with each process transforming one or more inputs to create an output of value to the customer. The key business processes may be supported by procedures and work instructions in those cases where it is judged necessary to rigidly define what rules are to be followed when undertaking a task. Most organizations will have core business processes that define those activities that directly add value to the product or service for the external customer, and supporting processes that are required to maintain the effectiveness of the core processes.
The understanding of the many interrelationships between these processes demands that a systems approach to management is adopted. The processes must be thoroughly understood and managed so that the most efficient use is made of available resources to ensure that the needs of all the stakeholders—customers, employees, shareholders, and the community—are met.
Customer satisfaction is a constantly moving target depending on changes in technology and the marketplace, so an effective QMS must be in a state of continual improvement. For this goal to be achieved, attention needs to be given to both the voice of the customer—through complaint analysis, opinion surveys, and regular contacts— and the voice of the processes—through measurement, monitoring, and analysis of both process and product data.
QUALITY MANAGEMENT SYSTEM PRACTICES
Audits, Reviews, and Assessments
A good QMS will not function or improve without adequate audits and reviews. Audits are done to ensure that actual practices adhere to documented procedures. System reviews should be done periodically and methodically to ensure that the system achieves the required effect.
A schedule for audits, with different activities requiring different frequencies, should be established. An audit should not be conducted solely for the purpose of revealing defects or irregularities; it should be conducted to establish the facts rather than to find fault. Audits may indicate necessary improvement and corrective actions, but also are intended to determine whether processes are effective and responsibilities have been correctly assigned. The emphasis on process improvement and enhancing customer satisfaction in the revised ISO 9001:2008 standard will require a more thoughtful approach to auditing. Typically, a QMS review should take place once a year, and should cover:
• Results of audits
• Customer feedback
• Process and product conformity
• Status of preventive and corrective actions
• Follow-up actions from previous management reviews
• Changes that could affect the QMS
• Recommendations for improvements
Outputs should include improvements to the QMS and processes, product improvements related to customer requirements, and identification of resource needs. In addition, the procedures for conducting audits and reviews, and the results from them, should be documented and be subject to review. Internal system audits and reviews should be positive and conducted as part of the preventive strategy, and not as a matter of expediency resulting from problems.
The assessment of a quality system against a standard or set of requirements by internal audit and review is known as a first-party assessment or approval scheme. If an external customer makes the assessment of a supplier against its own requirements, or a national or international standard, a second-party scheme is in operation. The assessment by an independent organization, not connected with any contract between the customer and supplier, but acceptable to them both, is an independent, third-party assessment scheme.
ICH Q10: Pharmaceutical Quality System
ICH Q10 describes one comprehensive model for an effective pharmaceutical quality management system that is based on International Organization for Standardization (ISO) quality concepts, includes applicable good manufacturing practices (GMP) regulations, and complements ICH Q8 Pharmaceutical Development and ICH Q9 Quality Risk Management.
ICH Q10 is a model for a pharmaceutical QMS that can be implemented throughout the different stages of a product life cycle. Much of the content of ICH Q10 applicable to manufacturing sites is currently specified by regional GMP requirements and ICH Q7
Good Manufacturing Practice Guidance for Active Ingredients.
ICH Q10 demonstrates industry and regulatory authorities’ support of an effective pharmaceutical QMS to enhance the quality and availability of medicines globally in the interest of public health. Implementation of ICH Q10 throughout the product life cycle should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and commercial manufacturing activities. The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product life cycle stages, recognizing the differences between, and the different goals of, each stage (Table 8.1).
ICH Q10 Objectives
Implementation of the Q10 model should result in achievement of three main objectives that complement or enhance regional GMP requirements:
• Achieve product realization. To establish, implement, and maintain a system that allows the delivery of products with the quality attributes appropriate to meet the needs of patients, healthcare professionals, regulatory authorities (including compliance with approved regulatory filings) and other internal and external customers.
• Establish and maintain a state of control. To develop and use effective monitoring and control systems for process performance and product quality, thereby providing assurance of continued suitability and capability of processes. Quality risk management can be useful in identifying monitoring and control systems.
• Facilitate continual improvement. To identify and implement appropriate product quality improvements, process improvements, variability reduction, innovations, and pharmaceutical quality system enhancements, thereby increasing the ability to fulfill quality needs consistently. Quality risk management can be useful for identifying and prioritizing areas for continual improvement.
Enablers: Knowledge Management and Quality Risk Management
Use of knowledge management and quality risk management enables a company to implement ICH Q10 effectively and successfully. These enablers facilitate achievement of the three regional GMP requirements objectives by providing the means for science- and risk-based decisions related to product quality.
Knowledge Management. Knowledge management is a systematic approach to acquiring, analyzing, storing, and disseminating information related to products, manufacturing processes, and components. Sources of knowledge include, but are not limited to, public domain or internally documented knowledge, pharmaceutical development studies, technology transfer activities, process validation studies over the product life cycle, manufacturing experience, innovation, continual improvement, and change management activities. Product and process knowledge should be managed from development through the commercial life of the product up to and including product discontinuation. For example, development activities using scientific approaches provide knowledge for product and process understanding.
Quality Risk Management. Quality risk management is integral to an effective pharmaceutical QMS. It can provide a proactive approach to identifying, scientifically evaluating, and controlling potential risks to quality. It facilitates continual improvement of process performance and product quality throughout the product life cycle. ICH Q9 provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceuticals quality
Design and Content Considerations, Quality Manual
The design, organization, and documentation of the pharmaceutical QMS should be well structured and clear to facilitate common understanding and consistent application. The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product life cycle stages, recognizing the different goals and knowledge available for each stage. The size and complexity of the company’s activities should be taken into consideration when developing a new pharmaceutical QMS or modifying an existing one.
The design of the pharmaceutical QMS should incorporate appropriate risk management principles. While some aspects of the pharmaceutical QMS can be companywide and others site specific, the effectiveness of the pharmaceutical QMS normally is demonstrated at the site level. The pharmaceutical QMS should include appropriate processes, resources, and responsibilities to provide assurance of the quality of outsourced activities and purchased materials. The pharmaceutical QMS should include process performance and product quality monitoring, corrective and preventive action, and change management and management review. Performance indicators should be identified and used to monitor the effectiveness of processes within the pharmaceutical QMS. Finally, management responsibilities should be identified within the pharmaceutical QMS. A quality manual or equivalent documentation approach should be established and should contain the description of the pharmaceutical QMS (Figure 8.1).
MANAGEMENT RESPONSIBILITY
Leadership is essential to establish and maintain a companywide commitment to quality and for the performance of the pharmaceutical QMS
Management Commitment
Senior management holds the ultimate responsibility to ensure that an effective pharmaceutical QMS is in place to achieve the quality objectives. They are responsible for ensuring that the roles, responsibilities, and authorities are defined, communicated, and implemented throughout the company. Management should:
• Participate in the design, implementation, monitoring, and maintenance of an effective pharmaceutical QMS.
• Demonstrate strong and visible support for the pharmaceutical QMS and ensure its implementation throughout their organization.
• Ensure that a timely and effective communication and escalation process exists to raise quality issues to the appropriate levels of management.
• Define individual and collective roles, responsibilities, authorities, and interrelationships of all organizational units related to the pharmaceutical QMS.
• Ensure that these interactions are communicated and understood at all levels of the organization. An independent quality unit or structure with authority to fulfill certain pharmaceutical quality system responsibilities is required by regional regulations.
• Conduct management reviews of process performance and product quality, and of the pharmaceutical QMS.
• Advocate continual improvement.
• Commit appropriate resources.
Quality Policy
Senior management should establish a quality policy that describes the overall intentions and direction of the company related to quality. The quality policy should include an expectation to comply with applicable regulatory requirements and should facilitate continual improvement of the pharmaceutical QMS. The quality policy should be communicated to, and understood by, personnel at all levels in the company. The quality policy should be reviewed periodically to ensure continued effectiveness.
Quality Planning
Senior management should ensure that the quality objectives needed to implement the quality policy are defined and communicated. Quality objectives should be supported by all relevant levels of the company. Quality objectives should align with the company’s strategies and be consistent with the quality policy. Management should provide the appropriate resources and training to achieve the quality objectives. Performance indicators that measure progress against quality objectives should be established, monitored, communicated regularly, and acted on as appropriate.
Resource Management
Management should determine and provide adequate and appropriate resources (human financial, materials, facilities, equipment to implement and maintain the pharmaceutical quality system and continually improve its effectiveness. Management should ensure that resources are appropriately applied to a specific product, process, or site.
Internal Communication
Management should ensure that appropriate communication processes are established and implemented within the organization. Communication processes should ensure the flow of appropriate information between all levels of the company and should ensure the appropriate and timely escalation of certain product quality and pharmaceutical quality system issues.
Management Review
Senior management should be responsible for pharmaceutical QMS governance through management review to ensure its continued suitability and effectiveness. Management should assess the conclusions of periodic reviews of process performance and product quality, and of the pharmaceutical QMS.
Management of Outsourced Activities and Purchased Materials
The pharmaceutical QMS, including the management responsibilities, extends to the control and review of any outsourced activities and quality of purchased materials. The pharmaceutical company is responsible to ensure that processes are in place to assure the control of outsourced activities and quality of purchased materials (Figure 8.2).
Management of Change in Product Ownership
When product ownership changes (for example, through acquisitions or divestitures), management should consider the complexity of these events and ensure that ongoing responsibilities are defined for each company involved and the necessary information is shared or transferred.
CONTINUAL IMPROVEMENT OF PROCESS PERFORMANCE AND PRODUCT QUALITY
Life cycle stage goals and four specific pharmaceutical quality system elements augment regional requirements to achieve the ICH Q10 objectives.
Life Cycle Stage Goals
Pharmaceutical Development. The goal of pharmaceutical development activities is to design a product and its manufacturing process to consistently deliver intended performance and meet the needs of patients, healthcare professionals, and regulatory authorities, and internal customers’ requirements. Approaches to pharmaceutical development are described in ICH Q8. The results of exploratory and clinical development studies, while outside the scope of this guidance, are inputs to pharmaceutical development.
Technology Transfer. The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and ongoing continual improvement.
Commercial Manufacturing. The goals of manufacturing activities include achieving product realization, establishing and maintaining a state of control, and facilitating continual improvement. The pharmaceutical quality system should assure that the desired product quality is routinely met, suitable process performance is achieved, the set of controls is appropriate, improvement opportunities are identified and evaluated, and the body of knowledge is continually expanded.
Product Discontinuation. The goal of product discontinuation activities is to manage the terminal stage of the product life cycle effectively. For product discontinuation, a predefined approach should be used to manage activities such as retention of documentation and samples and continued product assessment (for example, complaint handling, adverse event reporting, and stability) and reporting in accordance with regulatory requirements.
Pharmaceutical Quality Management System Elements
Four elements are required, in part, under regional GMP regulations; however, the Q10 model’s intent is to enhance these elements to promote the life cycle approach to product quality. These four elements are process performance and product quality monitoring system, corrective action and preventive action (CAPA) system, change management system, and management review of process performance and product quality. These elements should be applied in a manner that is appropriate and proportionate to each of the product life cycle stages, recognizing the differences between, and the different goals of, each stage. Throughout the product life cycle, companies are encouraged to evaluate opportunities for innovative approaches to improve product quality.
Process Performance and Product Quality Monitoring System. Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure that a state of control is maintained. An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality and to identify areas for continual improvement. The process performance and product quality monitoring system should:
• Use quality risk management to establish the control strategy, which can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. The control strategy should facilitate timely feedback/feed forward and appropriate corrective action and preventive action.
• Provide the tools for measurement and analysis of parameters and attributes identified in the control strategy (for example, data management and statistical tools).
• Analyze parameters and attributes identified in the control strategy to verify continued operation within a state of control.
• Identify sources of variation affecting process performance and product quality for potential continual improvement activities to reduce or control variation.
• Include feedback on product quality from both internal and external sources, for example, complaints, product rejections, nonconformances, recalls, deviations, audits, and regulatory inspections and findings.
• Provide knowledge to enhance process understanding, enrich the design space (where established), and enable innovative approaches to process validation.
Corrective Action and Preventive Action (CAPA) System. The pharmaceutical company should have a system for implementing corrective actions and preventive actions resulting from the investigation of complaints, product rejections, nonconformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring. A structured approach to the investigation process should be used with the objective of determining the root cause. The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9. CAPA methodology should result in product and process improvements and enhanced product and process understanding.
Change Management System. Innovation, continual improvement, the outputs of process performance and product quality monitoring, and CAPA drive change. To evaluate, approve, and implement these changes properly, a company should have an effective change management system. Generally, a difference in formality of change management processes exists before the initial regulatory submission and after submission, where changes to the regulatory submission might be required under regional requirements. The change management system ensures that continual improvement is undertaken in a timely and effective manner. It should provide a high degree of assurance that no unintended consequences will occur because of the change. As part of the change management system, as appropriate for the stage of the life cycle:
• Quality risk management should be used to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk.
• Proposed changes should be evaluated relative to the marketing authorization, including design space, where established, and/or current product and process understanding. An assessment determines whether a change to the regulatory filing is required under regional requirements. As stated in ICH Q8, working within the design space is not considered a change (from a regulatory submission perspective); however, from a pharmaceutical QMS standpoint, all changes should be evaluated by a company’s change management system.
• Proposed changes should be evaluated by subject matter expert teams contributing the appropriate expertise and knowledge from relevant areas (for example, Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs, and Medical) to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set.
• After implementation, an evaluation of the change should be undertaken to confirm that the change objectives were achieved and that there was no deleterious impact on product quality.
Management Review of Process Performance and Product Quality. Management review should provide assurance that process performance and product quality are managed over the product life cycle. Depending on the size and complexity of the company, management review can be a series of reviews at various levels of management, and should include a timely and effective communication and escalation process to raise appropriate quality issues to senior levels of management for review. The management review system should include:
• The results of regulatory inspections and findings, audits and other assessments, and commitments made to regulatory authorities.
• Periodic quality reviews that can include measures of customer satisfaction such as product quality complaints and recalls, conclusions of process performance and product quality monitoring, and the effectiveness of process and product changes, including those arising from corrective action and preventive actions.
• Any follow-up actions from previous management reviews. The management review system should identify appropriate actions, such as improvements to manufacturing processes and products, provision, training, and/or realignment of resources, and capture and dissemination of knowledge.
CONTINUAL IMPROVEMENT OF THE PHARMACEUTICAL QUALITY SYSTEM
Management Review
Management should have a formal process for reviewing the pharmaceutical QMS on a periodic basis. The review should include measurement of achievement of pharmaceutical quality system objectives, and assessment of performance indicators that can be used to monitor the effectiveness of processes within the pharmaceutical quality system (that is, complaint, deviation, CAPA, and change management processes, feedback on outsourced activities, self-assessment processes, including risk assessments, trending, and audits, and external assessments such as regulatory inspections and findings and customer audits).
Monitoring of Internal and External Factors
Management can monitor several factors that impact the QMS, including emerging regulations, guidance, and quality issues, innovations, changes in business environment and objectives, and changes in product ownership.
Outcomes of Management Review and Monitoring
The outcome of management review of the pharmaceutical QMS and monitoring of internal and external factors can include improvements to the pharmaceutical quality system and related processes, allocation or reallocation of resources and/or personnel training, revisions to quality policy and quality objectives, and documentation and timely and effective communication of the results of the management review and actions, including escalation of appropriate issues to senior management.