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1 Guidance for Industry Q10 Pharmaceutical Quality System U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) April 2009 ICH

2 Guidance for Industry Q10 Pharmaceutical Quality System Additional copies are available from: Office of Communication Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave.,Bldg. 51, Room 2201 Silver Spring, MD 20993-0002 (Tel) 301-796-3400 Office of Communication, Outreach and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 (Tel) 1-800-835-4709 or 301-827-1800 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) April 2009 ICH

3 TABLE OF CONTENTS I. INTRODUCTION (1, 1.1) ... 1 II. PHARMACEUTICAL QUALITY MANAGEMENT SYSTEM ... 2 Scope (1.2) ... 2 A. Relationship of ICH Q10 to Regional GMP Requirements, ISO Standards, B. 3 ... ... and ICH Q7 (1.3) 3 ... Relationship of ICH Q10 to Regulatory Approaches (1.4) C. 3 ... D. ICH Q10 Objectives (1.5) 4 E. Enablers: Knowledge Management and Quality Risk Management (1.6) ... 4 F. Design and Content Considerations (1.7) ... 5 ... Quality Manual (1.8) G. 5 ... MANAGEMENT RESPONSIBILITY (2) III. 5 ... Management Commitment (2.1) A. Quality Policy (2.2) B. 6 ... C. ( 2.3) ... 6 Quality Planning D. 7 ... ... Resource Management (2.4) Internal Communication (2.5) E. ... ... 7 7 ... F. Management Review (2.6) ... Management of Outsourced Activities and Purchased Materials (2.7)... 7 G. 8 ... Management of Change in Product Ownership (2.8) H. CONTINUAL IMPROVEMENT OF PROCESS PERFORMANCE AND IV. PRODUCT QUALITY (3) ... 8 8 ... Goals (3.1) Lifecycle Stage A. Pharmaceutical Quality Syst B. 9 ... em Elements (3.2) V. CONTINUAL IMPROVEMENT OF THE PHARMACEUTICAL QUALITY ... SYSTEM (4) 13 eutical Quality System (4.1) 13 A. ... Management Review of the Pharmac B. Monitoring of Internal and External Fa ctors That Can Have an Impacton the 13 Pharmaceutical Quality System (4.2) ... 14 C. Outcomes of Management Review and Monitoring (4.3) ... VI. GLOSSARY (5) ... 15 Annex I: Potential Opportunities To Enha nce Science- and Risk-Based Regulatory Approaches * ... 18 Annex 2: Diagram of the ICH Q10 Ph armaceutical Quality System Model...19 i

4 1 Guidance for Industry Q10 Pharmaceutical Quality System s (FDA’s) current thinking on this topic. It This guidance represents the Food and Drug Administration' does not create or confer any rights for or on any pe rson and does not operate to bind FDA or the public. satisfies the requirements of the applicable statutes You can use an alternative approach if the approach and regulations. If you want to discuss an alterna tive approach, contact the FDA staff responsible for the appropriate FDA staff, call the appropriate implementing this guidance. If you cannot identify number listed on the title page of this guidance. 2 I. INTRODUCTION (1, 1.1) This internationally harmonized guidance is in tended to assist pharmaceutical manufacturers by describing a model for an effective management system for the pharmaceutical industry, quality referred to as the . Throughout this guidance, the term pharmaceutical quality system pharmaceutical quality system refers to the ICH Q10 model. effective pharmaceutical quality system that ICH Q10 describes one comprehensive model for an nization for Standardization (IS is based on International Orga O) quality concepts, includes applicable good manufacturi ng practice (GMP) regulations , and complements ICH “Q8 3 ICH Q10 is a model H “Q9 Quality Risk Management.” Pharmaceutical Development” and IC 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. IC H Q10 is not intended to create any new y, the content of ICH Q10 that expectations beyond current regula tory requirements. Consequentl is additional to current regiona l GMP requirements is optional. 1 This guidance was developed within the Expert Working Group (Quality) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at of the process, the final Step 4 of the ICH process, June 2008. At Step 4 . draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States 2 ed by the ICH Steering Committee at tional breakdown of the document endors Arabic numbers reflect the organiza Step 4 of the ICH process, June 2008. 3 . We update These guidances are available on the Internet at guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at 1

5 ICH Q10 demonstrates industry and regulator y authorities’ support of an effective pharmaceutical quality system to enhance the qua lity and availability of medicines around the ublic health. Implementation of ICH Q10 throughout the product world in the interest of p and innovation facilitate lifecycle should and strengthen the link between continual improvement pharmaceutical development and manufacturing activities. FDA's guidance documents, including this guida nce, do not establish legally enforceable e Agency’s current thinki responsibilities. Instead, guidances describe th ng on a topic and should ific regulatory or stat be viewed only as recommendations, unless spec utory requirements are should in Agency guidances means that something is suggested or cited. The use of the word recommended, but not required. II. PHARMACEUTICAL QUAL ITY MANAGEMENT SYSTEM A. Scope (1.2) upporting the development and manufacture of This guidance applies to the systems s pharmaceutical drug substances (i.e., active pharmaceutical ingredients (APIs)) and drug nd biological products, throughout the product lifecycle. products, including biotechnology a The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to among, and the different goals each of the product lifecycle st ages, recognizing the differences of, each stage (see section IV (3)). ce, the product lifecycle includes For the purposes of this guidan the following technical activities for new and existing products: • Pharmaceutical Development Drug substance development o ng container/closure system) Formulation development (includi o o Manufacture of investigational products o Delivery system development (where relevant) o Manufacturing process development and scale-up o Analytical method development • Technology Transfer lopment through manufacturing New product transfers during deve o o and testing sites for marketed products Transfers within or between manufacturing Commercial Manufacturing • o Acquisition and control of materials Provision of facilities, utilities, and equipment o aging and labeling) Production (including pack o o Quality control and assurance o Release Storage o 2

6 Distribution (excluding wholesaler activities) o • Product Discontinuation Retention of documentation o Sample retention o Continued product assessment and reporting o Relationship of ICH Q10 to Regional GMP Requirements, ISO Standards, B. and ICH Q7 (1.3) Regional GMP requirements, the ICH guidance “Q7 Good Manufacturing Pr actice Guidance for Active Pharmaceutical Ingredients,” and ISO qua lity management system guidelines form the described below, ICH Q10 augments GMPs by foundation for ICH Q10. To meet the objectives management responsibilities. ICH Q10 provides describing specific quality system elements and a harmonized model for a pharmaceutical quality system throughout the lifecycle of a product and is intended to be used togeth er with regional GMP requirements. ss all stages of the The regional GMPs do not explicitly addre product lifecycle (e.g., management responsibilities described in this development). The quality system elements and ience- and risk-based approaches at each guidance are intended to encourage the use of sc lifecycle stage, thereby promo ting continual improvement acro ss the entire product lifecycle. C. Relationship of ICH Q10 to Regulatory Approaches (1.4) should be commensurate manufacturing facility Regulatory approaches for a specific product or cess understanding, the results of , and with the level of product and pro quality risk management the effectiveness of the pharmaceutical quality system. When implemented, the effectiveness of evaluated during a regulatory inspection at the pharmaceutical quality system can normally be the manufacturing site. Potential opportunities to enhance science- and risk-based regulatory approaches are identified in Annex 1. Regulat ory processes will be determined by region. ICH Q10 Objectives (1.5) D. Implementation of the Q10 model should result in achievement of three main objectives that complement or enhance regional GMP requirements. 1. Product Realization Achieve (1.5.1) To establish, implement, and maintain a system that allows the deliver y of products with the quality attributes appropriate to meet the needs of patients, health care professionals, regulatory authorities (including compliance with approve d regulatory filings) a nd other internal and external customers. (1.5.2) 2 Establish and Maintain a State of Control 3

7 control systems for process performance and To develop and use effective monitoring and capability of processes nce of continued suitability and product quality, thereby providing assura . Quality risk management can be useful in identifying the monitoring and control systems. Facilitate Continual Improvement (1.5.3) 3 To identify and implement appr opriate product quality improve ments, process improvements, variability reduction, innovations, and pharmaceutic al quality system enhancements, thereby increasing the ability to fulfill a pharmaceutical manufacturer’s own quality needs consistently. Quality risk management can be useful for id entifying and prioritizing areas for continual improvement. E. : Knowledge Management and Quality Risk Management (1.6) Enablers and quality risk management Use of knowledge management will enable a company to implement ICH Q10 effectively a nd successfully. These enablers will facilitate achievement of ove by providing the means for science- and risk- the objectives described in section II.D (1.5) ab based decisions related to product quality. Knowledge Management (1.6.1) 1. Product and process knowledge should be mana ged from development through the commercial n. For example, development life of the product up to and including product discontinuatio dge for product and process understanding. ientific approaches provide knowle activities using sc alyzing, storing, and oach to acquiring, an Knowledge management is a systematic appr disseminating information related to products, manufacturing processes, and components. Sources of knowledge include, but are not lim ited to, prior knowledge (public domain or ent studies; technology transfer activities; internally documented); pharmaceutical developm process validation studies over manufacturing experience; innovation; the product lifecycle; continual improvement; and change management activities. Quality Risk Management (1.6.2) 2. Quality risk management is integral to an effective pharmaceutical quality system. It can ntifically evaluating, and controlling potential provide a proactive approach to identifying, scie risks to quality. It facilitates continual improve ment of process performance and product quality H Q9 provides principles and ex amples of tools for quality throughout the product lifecycle. IC risk management that can be applied to di fferent aspects of pharmaceutical quality. F. Design and Content Considerations (1.7) (a) The design, organization, and documentation of the pharmaceutical quality system should be well structured and clear to f acilitate common understanding and consistent application. d in a manner that is appropriate and (b) The elements of ICH Q10 should be applie proportionate to each of the product lifecycl e stages, recognizing the different goals 4

8 and knowledge available for each stage. tivities should be taken into consideration The size and complexity of the company’s ac (c) system or modifying an existing one. when developing a new pharmaceutical quality quality system should incorporate appropriate risk The design of the pharmaceutical management principles. While some aspect s of the pharmaceutical quality system can be company wide and others site specific , the effectiveness of the pharmaceutical quality system is normally demonstrated at the site level. The pharmaceutical quality system should in clude appropriate processes, resources, (d) and and responsibilities to provide assurance of the quality of outsourced activities purchased materials as described in section III.G (2.7). (e) Management responsibilities, as described in section III (2), should be identified within the pharmaceutical quality system. The pharmaceutical quality system should include the following elements, as (f) performance and product quality monitoring, described in section IV (3): process , change management, and management review. preventive action corrective and (g) Performance indicators , as described in section V (4), should be identified and used to ithin the pharmaceutical quality system. monitor the effectiveness of processes w G. Quality Manual (1.8) Quality Manual A should be established and should or equivalent documentation approach ality system. The description should include: contain the description of the pharmaceutical qu (a) (see section III (2)). quality policy The (b) The scope of the pharmaceutical quality system. system processes, as well as their Identification of the pharmaceutical quality (c) sequences, linkages, and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting pharmaceutical quality system processes in a visual manner. Management responsibilities within the pharmaceutical quality system (see (d) section III (2)). MANAGEMENT RESPONSIBILITY (2) III. Leadership is essential to establish and maintain a company-wide commitment to quality and for the performance of the pha rmaceutical quality system. Management Commitment (2.1) A. has the ultimate responsibility to ensure an effective (a) Senior management pharmaceutical quality system is in place to achieve the quality objectives, and that 5

9 roles, responsibilities, an d authorities are defined, communicated, and implemented throughout the company. (b) Management should: (1) Participate in the design, implementation, monitoring, and maintenance of an effective pharmaceutical quality system. (2) Demonstrate strong and visible support for the pharmaceutical quality system throughout their organization. and ensure its implementation Ensure a timely and effective communicat ion and escalation process exists to (3) opriate levels of management. raise quality issues to the appr (4) responsibilities, authorities, and inter- Define individual and collective roles, relationships of all organizational unit s related to the pharmaceutical quality system. Ensure these interactions are communicated and understood at all levels of the organization. An independe nt quality unit/structure with authority stem responsibilities is required by to fulfill certain pharmaceutical quality sy regional regulations. (5) Conduct management reviews of proce ss performance and product quality and of the pharmaceutical quality system. Advocate continual improvement. (6) (7) Commit appropriate resources. B. Quality Policy (2.2) (a) Senior management should establish a quality policy that describes the overall intentions and direction of th e company related to quality. tion to comply with applicable regulatory The quality policy should include an expecta (b) requirements and should facilitate continual improvement of the pharmaceutical quality system. The quality policy should be communicated (c) to and understood by personnel at all levels in the company. (d) The quality policy should be reviewed periodically for continuing effectiveness. C. Quality Planning ( 2.3) (a) Senior management should ensure the quality objectives to implement the quality policy are defined and communicated. (b) Quality objectives should be supported by a ll relevant levels of the company. (c) Quality objectives should align with the comp any’s strategies and be consistent with the quality policy. resources and training to achieve the (d) Management should provide the appropriate 6

10 quality objectives. Performance indicators that measure progress against quality objectives should be (e) ly, and acted upon as appropriate as established, monitored, communicated regular 4.1) of this document. described in section V.A ( Resource Management (2.4) D. Management should determine and provide adequate and appropriate resources (a) nd equipment) to implement and maintain the (human, financial, materials, facilities, a pharmaceutical quality system and continually improve its effectiveness. lied to a specific (b) Management should ensure that resources are appropriately app product, process, or site. Internal Communication (2.5) E. (a) Management should ensure appropriate comm unication processes are established and implemented within the organization. flow of appropriate information between Communications processes should ensure the (b) all levels of the company. (c) e appropriate and timely escalation of Communication processes should ensure th certain product quality and pharmaceutical quality system issues. F. Management Review (2.6) sible for pharmaceutical quality system (a) Senior management should be respon ensure its continuing suitability and governance through management review to effectiveness. Management should assess the conclusions of periodic reviews of process (b) performance and product quality and of the pharmaceutical quality system, as described in sections IV (3) and V (4). G. Management of Outsourced Activities and Purchased Materials (2.7) The pharmaceutical quality system, including the management responsibilities described in this ntrol and review of any outsourced activities and quali ty of purchased section, extends to the co materials. The pharmaceutical company is ultimatel y responsible to ensure processes are in place to assure the control of outsour ced activities and quality of purchased materials. These processes should incorporate quality risk management and include: al suppliers, the suitability (a) Assessing prior to outsourcing operations or selecting materi and competence of the other party to carry out the activity or provide the material 7

11 using a defined supply chain (e.g., audits, material evaluations, qualification). (b) Defining the responsibilities and communi cation processes for quality-related ced activities, this should be included in a activities of the involved parties. For outsour written agreement between the contract giver and contract acceptor. (c) Monitoring and review of the performance of the contract acceptor or the quality of the material from the provider, and the identification and implementation of any essential improvements. (d) Monitoring incoming ingredients and materials to ensure they are from approved sources using the agre ed supply chain. Management of Change in Product Ownership (2.8) H. sitions), management should consider the When product ownership changes (e.g., through acqui complexity of this and ensure: The ongoing responsibilities are defined for each company involved (a) The essential information is transferred (b) CONTINUAL IMPROVEMENT OF PROCESS PERFORMANCE AND IV. PRODUCT QUALITY (3) This section describes the lifecycle stage goals and the four specific pharmaceutical quality system elements that augment regional requirements to achieve the ICH Q10 objectives, as restate all regional GMP requirements. defined in section II.D (1.5). It does not Lifecycle Stage Goals (3.1) A. The goals of each product lifecycle stage are described below. 1. Pharmaceutical Development (3.1.1) s is to design a product and its manufacturing The goal of pharmaceutical development activitie process to consistently deliver the intended pe rformance and meet the needs of patients and healthcare professionals, and regulatory authori ties and internal customers’ requirements. Approaches to pharmaceutical development are desc ribed in ICH Q8. The re sults of exploratory the scope of this guidance, are inputs to and clinical development studies, while outside pharmaceutical development. Technology Transfer (3.1.2) 2. The goal of technology transfer ac tivities is to transfer produc t and process knowledge between development and manufacturing, and within or between manufacturing s ites to achieve product 8

12 realization. This knowledge forms the ba sis for the manufacturing process, control strategy , process validation approach, and ongoing continual improvement. Commercial Manufacturing (3.1.3) 3. The goals of manufacturing activ ities include achieving product realization, es tablishing and itating continual improvement. The pharmaceutical maintaining a state of control, and facil quality system should assure that the desired pr oduct quality is routinely met, suitable process performance is achieved, the se , improvement opportunities are t of controls are appropriate knowledge is continually expanded. identified and evaluated, and the body of Product Discontinuation (3.1.4) 4. activities is to manage the terminal stage of the product The goal of product discontinuation a predefined approach should be used to lifecycle effectively. For product discontinuation, umentation and samples and continued product manage activities such as retention of doc ) and reporting in accordance with regulatory assessment (e.g., complaint handling and stability requirements. System Elements (3.2) B. Pharmaceutical Quality red in part under regional GMP regulations. The elements described below might be requi However, the Q10 model’s intent is to enhance th ese elements to promote the lifecycle approach to product quality. These four elements are: Process performance and product quality monitoring system • and • preventive action (CAPA) system Corrective action Change management system • • Management review of process performance and product quality is appropriate and proportionate to each of the These elements should be applied in a manner that product lifecycle stages, recognizi and the different goals of ng the differences among the stages each stage. Throughout the product lifecycle, companies are encouraged to evaluate opportunities for innovative approach es to improve product quality. e element to the stages of the Each element is followed by a tabl e of example applications of th pharmaceutical lifecycle. 1. Process Performance and Product Quality Monitoring System 3.2.1 Pharmaceutical companies should plan and exec ute a system for the monitoring of process performance and product quality to ensure a st ate of control is maintained. An effective monitoring system provides assurance of the cont inued capability of processes and controls to produce a product of desired quality and to id entify areas for continual improvement. The ity monitoring system should: process performance and product qual 9

13 Use quality risk management to establish the control strategy. This can include (a) ug substance and drug product materials and parameters and attributes related to dr components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and gy should facilitate timely feedback/feedforward and control. The control strate appropriate corrective acti on and preventive action. Provide the tools for measurement and analysis (b) of parameters and attributes identified in the control strategy (e.g., data ma nagement and statistical tools). to verify continued in the control strategy (c) Analyze parameters and attributes identified operation within a state of control. Identify sources of variation affecting pr (d) ocess performance and product quality for ies to reduce or control variation. potential continual improvement activit Include feedback on product (e) quality from both internal and external sources (e.g., complaints, product rejections, nonconformances, recalls, deviations, audits and regulatory inspections, and findings). design space (where (f) Provide knowledge to enhance pr ocess understanding, enrich the established), and enable innovative a pproaches to process validation. ce and Product Quality Monitoring System Table I: Application of Process Performan Throughout the Product Lifecycle Technology Product Commercial Pharmaceutical Manufacturing Discontinuation Transfer Development Process and product Monitoring during A well-defined system Once manufacturing scale-up activities can knowledge generated ceases, monitoring for process and process and provide a preliminary performance and such as stability testing product monitoring indication of process product quality should continue to performance and the conducted throughout completion of the monitoring should be applied to assure successful integration studies. Appropriate development can be used to establish a into manufacturing. performance within a action on marketed state of control and to product should control strategy for Knowledge obtained continue to be executed identify improvement during transfer and manufacturing. according to regional areas. scale-up activities can regulations. be useful in further developing the control strategy. Action (CAPA) System (3.2.2) 2. Corrective Action and Preventive em for implementing corrective actions and The pharmaceutical company should have a syst preventive actions resulting from the inve stigation of complain ts, product rejections, nonconformances, recalls, deviations, audits, regu latory inspections and findings, and trends from process performance and product quality monitoring. A structur ed approach to the 10

14 of determining the root cause. The level investigation process should be us ed with the objective mmensurate with the vestigation should be co of effort, formality, and documentation of the in H Q9. CAPA methodology should re sult in product and process level of risk, in line with IC t and process understanding. improvements and enhanced produc Table II: Application of Corrective Action and Preventive Action System Throughout the Product Lifecycle Commercial Product Technology Pharmaceutical Transfer Manufacturing Discontinuation Development CAPA should continue CAPA should be used, CAPA can be used as Product or process after the product is and the effectiveness of an effective system for variability is explored. the actions should be discontinued. The feedback, feedforward, CAPA methodology is evaluated. impact on product and continual useful where corrective remaining on the improvement. actions and preventive market should be actions are incorporated considered, as well as into the iterative design other products that and development might be affected. process. 3. Change Management System (3.2.3) of process performance and product quality Innovation, continual improvement, the outputs monitoring, and CAPA drive change. To eval uate, approve, and implement these changes system. There is generally a properly, a company should have an effective change management processes prior to the initial regulatory difference in formality of change management the regulatory filing might be required under submission and after submission, where changes to regional requirements. The change management system ensures continua l improvement is undertaken in a timely and effective manner. It should provide a high de gree of assurance th ere are no unintended consequences of the change. The change management system should include the following, as appropriate for the stage of the lifecycle: (a) Quality risk management should be utilized to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk. (b) Proposed changes should be evaluated re lative to the marketing authorization, including design space, where established, and/or current product and process understanding. There should be an assessment to determine 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 filing perspective). However, from a pharmaceutical quality system standpoint, all changes s change management system. should be evaluated by a company’ (c) Proposed changes should be evaluated by e xpert teams contributing the appropriate 11

15 eas (e.g., Pharmaceutical Development, expertise and knowledge from relevant ar y Affairs, and Medical) to ensure the change is Manufacturing, Quality, Regulator criteria for a proposed change should be technically justified. Prospective evaluation set. change should be undertaken to confirm the (d) After implementation, an evaluation of the change objectives were achieved and that there was no deleterious impact on product quality. Table III: Application of Change Management System Throughout the Product Lifecycle Commercial Pharmaceutical Product Technology Manufacturing Development Discontinuation Transfer Any changes after A formal change The change Change is an inherent product discontinuation management system management system part of the development should go through an should be in place for should provide process and should be appropriate change commercial management and documented; the management system. manufacturing. documentation of formality of the change Oversight by the adjustments made to management process quality unit should the process during should be consistent provide assurance of technology transfer with the stage of appropriate science- activities. pharmaceutical and risk-based development. assessments. Management Review of Process Pe rformance and Product Quality (3.2.4) 4. assurance that process perf ormance and product quality are Management review should provide and complexity of the company, management managed over the lifecycle. Depending on the size ews at various levels of manage ment and should include a timely review can be a series of revi ty issues to senior raise appropriate quali and effective communication and escalation process to levels of management for review. (a) The management review system should include: and findings, audits and other (1) The results of regulatory inspections de to regulatory authorities assessments, and commitments ma (2) Periodic quality reviews, that can include: Measures of customer satisfaction such as product quality complaints (i) and recalls (ii) Conclusions of process performance and product quality monitoring The effectiveness of process and product changes including those (iii) on and preventive actions arising from corrective acti (3) Any follow-up actions from previous management reviews The management review system should identify appropriate actions, such as: (b) Improvements to manufacturing processes and products (1) (2) Provision, training, and/or realignment of resources 12

16 (3) Capture and dissemination of knowledge Table IV: Application of Management Revi ew of Process Performance and Product Quality Throughout the Product Lifecycle Commercial Pharmaceutical Product Technology Transfer Discontinuation Development Manufacturing Management review Management review Aspects of Aspects of management should include such should be a structured management review review can be items as product system, as described should be performed to performed to ensure stability and product above, and should ensure the developed adequacy of the product quality complaints. support continual product and process and process design. improvement. can be manufactured at commercial scale. V. CONTINUAL IMPROVEMENT OF THE PHARMACEUTICAL QUALITY SYSTEM (4) This section describes activities that should be conducted to mana ge and continually improve the pharmaceutical quality system. armaceutical Quality System (4.1) A. Management Review of the Ph cal quality system on a reviewing the pharmaceuti Management should have a formal process for periodic basis. The review should include: Measurement of achievement of pharmaceutical quality system objectives (a) be used to monitor the effectiveness of Assessment of performance indicators that can (b) cal quality system, such as: processes within the pharmaceuti Complaint, deviation, CAPA and change management processes (1) Feedback on outsourced activities (2) (3) Self-assessment processes including risk assessments, trending, and audits (4) External assessments such as regulatory inspections and findings and customer audits Factors That Can Have an Impacton B. Monitoring of Internal and External the Pharmaceutical Quality System (4.2) Factors monitored by management can include: (a) Emerging regulations, guidance, and quality issues that can have an impact on the Pharmaceutical Quality System Innovations that might enhance the pharmaceutical quality system (b) (c) Changes in business environment and objectives 13

17 Changes in product ownership (d) Outcomes of Management Review and Monitoring (4.3) C. rmaceutical quality system and monitoring of The outcome of management review of the pha internal and external factors can include: system and related processes (a) Improvements to the pharmaceutical quality Allocation or realloca or personnel training (b) tion of resources and/ Revisions to quality policy and quality objectives (c) (d) Documentation and timely and effective communication of the results of the lation of appropriate issues to senior management review and actions, including esca management 14

18 VI. GLOSSARY (5) ICH and ISO definitions are used in ICH Q10 where they exist. For the purpose of ICH Q10, where the words “requirement”, “requirements,” or “necessary” appear in an ISO definition, they do not necessarily reflect a regulatory requirement. The source of the definition is identified in te ICH or ISO definition was available, an parentheses after the definition. Where no appropria ICH Q10 definition was developed. Capability of a Process: Ability of a process to real ize a product that will fulfill the cess capability can also be defined in statistical requirements of that product. The concept of pro terms. (ISO 9000:2005) A systematic approach to proposing, evaluating, approving, Change Management: implementing, and reviewing changes. (ICH Q10) Continual Improvement: ility to fulfill requirements. (ISO Recurring activity to increase the ab 9000:2005) Control Strategy: A planned set of controls, deri ved from current product and process ess performance and product quali understanding, that assures proc ty. The controls can include parameters and attributes related to drug substance and drug product materials and components, nished product specifications, conditions, in-process controls, fi facility and equipment operating and the associated methods and frequency of monitoring and control. (ICH Q10) Action to eliminate the cause of Corrective Action: a detected nonconformity or other undesirable situation. NOTE: Corrective action is taken to prevent recurrence whereas preventive action is taken to preven t occurrence. (ISO 9000:2005) interaction of input variables (e.g., The multidimensional combination and Design Space: trated to provide assurance of material attributes) and process pa rameters that have been demons quality. (ICH Q8) A tool or process that provides the means to achieve an objective. (ICH Q10) Enabler: Feedback/Feedforward: Feedback: The modification or control of a process or system by its results or effects. The modification or control of a pro cess using its anticipated results or Feedforward: effects. (Oxford Dictionary of Eng lish by Oxford University Press, 2003) Feedback/feedforward can be applied technically in process control strate gies and conceptually in quality management. (ICH Q10) ies or methodologies. (ICH Q10) Innovation: The introduction of new technolog 15

19 ring, analyzing, storing, and Systematic approach to acqui Knowledge Management: disseminating information related to products, manufacturing processes, and components. (ICH Q10) Outsourced Activities: Activities conducted by a contract a cceptor under a written agreement with a contract giver. (ICH Q10) Measurable values used to quantify quality objectives to reflect the Performance Indicators: in some performance metrics performance of an organization, process, or system, also known as regions. (ICH Q10) Pharmaceutical Quality System (PQS): Management system to direct and control a pharmaceutical company with regard to quality. (ICH Q10 based upon ISO 9000:2005) Action to eliminate the cause of a potential nonconformity or other Preventive Action: undesirable potential situation. NO TE: Preventive action is taken to prevent occurrence whereas event recurrence. (ISO 9000:2005) corrective action is taken to pr Product Realization: appropriate to meet ith the quality attributes Achievement of a product w the needs of patients, health ca re professionals, and regulatory authorities (including compliance with marketing authorization) and inte rnal customers requirements. (ICH Q10) The degree to which a set of inherent propert ies of a product, system, or process fulfils Quality: requirements. (ICH Q9) Quality Manual: Document specifying the quality management system of an organization. (ISO 9000:2005) A means to translate the quality pol Quality Objectives: icy and strategies into measurable activities. (ICH Q10) Quality Planning: Part of quality management focu sed on setting quality objectives and specifying necessary operational processes and rela ted resources to fulfill the quality objectives. (ISO 9000:2005) ted to quality as formally ction of an organization rela Quality Policy: Overall intentions and dire expressed by senior management. (ISO 9000:2005) Quality Risk Management: A systematic process for the assessment, control, communication, ty of the drug (medicinal) pro and review of risks to the quali duct across the product lifecycle. (ICH Q9) Senior Management: Person(s) who direct and control a co mpany or site at the highest levels ity to mobilize resources within the company or site. (ICH Q10 with the authority and responsibil based in part on ISO 9000:2005) 16

20 State of Control: A condition in which the set of controls consisten tly provides assurance of continued process performance and product quality. (ICH Q10) 17

21 Enhance Science- and Risk-Based Annex I: Potential Opportunities To Regulatory Approaches * ential opportunities to enhance regul *Note: This annex reflects pot atory approaches. The actual regulatory process will be determined by region. Potential Opportunity Scenario Compliance – status quo 1. Comply with GMPs Opportunity to: 2. Demonstrate effective pharmaceutical quality system, increase use of risk-based • including effective use of quality approaches for regulatory risk management principles (e.g., inspections ICH Q9 and ICH Q10). 3. Demonstrate product and process Opportunity to: understanding, including effective facilitate science-based • use of quality risk management pharmaceutical quality assessment principles (e.g., ICH Q8 and ICH • enable innovative approaches to Q9). process validation establish real-time release • mechanisms 4. Demonstrate effective Opportunity to: pharmaceutical quality system and increase use of risk-based • product and process understanding, approaches for regulatory including the use of quality risk inspections; management principles (e.g., ICH facilitate science-based • Q8, ICH Q9, and ICH Q10). pharmaceutical quality assessment; optimize science- and risk-based • postapproval change processes to maximize benefits from innovation and continual improvement; • enable innovative approaches to process validation; • establish real-time release mechanisms. 18

22 Annex 2 Diagram of the ICH Q10 Pharmaceutical Quality System Model ICH Q10 Pharmaceutical Quality System Pharmaceutical Commercial Product Technology Manufacturing Discontinuation Transfer Development Investigational products GMP Management Responsibilities Process Performance & Product Quality Monitoring System Corrective Action / Preventive Action (CAPA) System PQS Change Management System elements Management Review Knowledge Management Enablers Quality Risk Management This diagram illustrates the major features of the ICH Q10 Pharmaceutical Quality System (PQS) model. The PQS covers the entire lif ecycle of a product including pharmaceutical development, technology transf facturing, and product discontinuation as er, commercial manu illustrated by the upper portion of the diagram. The PQS augments regional GMPs as illustrated in the diagram. The diagram also illustrates th at regional GMPs apply to the manufacture of investigational products. The next horizontal bar illustrates the importan ce of management respon sibilities explained in the product lifecycle. The fo section III (2) to all stages of llowing horizontal bar lists the PQS elements that serve as the major pillars under th e PQS model. These elements should be applied izing opportunities to identify appropriately and proportionally to each lifecycle stage, recogn areas for continual improvement. e enablers: knowledge management and quality The bottom set of horizontal bars illustrates th risk management, which are applicable throughou t the lifecycle stages. These enablers support the PQS goals of achieving product realization, esta blishing and maintaining a state of control, and facilitating continual improvement. 19

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