fda更新关于实施质量源于设计药业公司宣传文案资料.ppt

FDA Update on Implementation of Quality by Design (QbD) FDA更新关于实施质量源于设计,Richard (Rik) Lostritto, Ph.D.Director, DPAMSOffice of New Drug Quality AssessmentCDER/FDA,The New Jersey Pharmaceutical AssociationFor Science and Technology新泽西州制药协会科学和技术September 17, 2009,Outline大纲,FDA quality initiatives backgroundFDA 质量措施背景QbD guidances QbD 指导QbD activities and initiativesQbD 活动和建议Remaining challenges and gaps挑战和差距Concluding comments结论性意见,In 2002, FDA assessed the ongoing problems and issues in pharmaceutical manufacturing2002年，FDA评估药品生产的持续存在的问题The final report issued in 2004, recommended:在2004年发行的最后报告，建议:Outreach and collaboration with industryEncourage risk-based pharmaceutical quality management systems for industry鼓励制药质量管理系统的风险为主Implement quality management systems within FDA实施质量管理系统在食品及药物管理局(FDA)Introduce new manufacturing science into regulatory paradigm介绍新制造科学监管模式Science and risk based approaches基础科学和风险的方法Change the CMC review process更改CMC的审查过程Harmonize concepts internationally统一国际概念,FDA Initiatives: “Pharmaceutical Quality for the 21st Century” FDA的倡议：“面向21世纪药品质量”,The Desired State理想状态,A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight.最大效率，敏捷，灵活的医药制造业，可靠的生产高品质的药物产品，没有广泛的监管。,Janet Woodcock, M.D.Pharmaceutical Quality Assessment WorkshopOctober 5, 2005,Characteristics of Desired State,Janet Woodcock, M.D.Deputy Commissioner/Chief Medical Officer, FDAPharmaceutical Quality Initiatives WorkshopMarch 2, 2007,Manufacturers have extensive knowledge about critical product and process parameters and quality attributes制造商有关关键产品和工艺参数和质量属性广博的知识Manufacturers control process through quality systems over life cycle and strive for continuous improvement厂家通过质量体系控制生命周期的过程和不断求进FDA Role: Initial verification, subsequent auditFDA的作用：初步核实，后续审计No manufacturing supplements (may be needed for formulation change)没有制造业的补充（可能需要制定改变),What is Quality by Design (QbD)?什么是QbD,Systematic approach to development系统发展Begins with predefined objectives 开始预订的目标 Emphasizes product and process understanding and process control强调产品和过程的理解和过程控制Based on sound science and quality risk management基于健全的科学和质量风险管理from ICH Q8(R1),What are the elements of QbD?什么是QbD的成分,Define desired product performance upfront;identify product CQAs前面定义产品的理想性能，确定产品关键质量属性（CQA）,Design formulation and process to meet product CQAs设计可以重复稳健地符合产品关键质量属性的处方和工艺,Understand impact of material attributes and process parameters on product CQAs理解物料及工艺参数的属性对产品关键质量属性（CQA）的影响,Identify and control sources of variability in material and process确定并控制物料和工艺的变异性的来源,Continually monitor and update process to assure consistent quality对工艺进行持续监测与升级以确保产品质量的一贯性,Risk assessment and risk control风险评估和风险控制,Product & process design and development 生产或工艺设计与开发,Why QbD?为什么要实施QbD,Higher level of assurance of product quality for patient确保病人有更高水平质量保证的产品Improved product and process design and understanding Quality risk management in manufacturing 提高产品和工艺设计，理解在制造方面质量风险管理Monitoring, tracking and trending of product and process监控跟踪和趋势分析产品和生产过程的需要Continual improvement 持续改进的机会Cost saving and efficiency for industry节省开支，提高企业的生产效率Increase efficiency of manufacturing process提高工艺的效率Minimize/eliminate potential compliance actions最小化/排除潜在法规问题。Provide opportunities for continual improvement提供不断改进的机会Facilitate innovation促进创新More efficient regulatory oversight更有效的监督管理Streamline post approval manufacturing changes and regulatory processes便捷的验收后工艺变化及调整,What are some barriers to QbD?什么是QbD的阻碍,Culture challenges 文化差异的挑战Move from prescriptive approachMore sharing of scientific and risk information更多的分享科学和风险的信息Business Challenges商业的挑战Business justification商业理由Management Support管理支持Budgeting silos across business unitsImplementation Challenges执行中的挑战Collaboration between functions 功能间的协调Experience with new concepts经验与新概念Workload and resource limitations工作量和资源的限制International harmonization国际协调,How can we break down barriers?如何消除障碍,New guidances on quality对质量新的指导原则International participation国际参与New review processes新的审核流程Greater information sharing in application在应用程序的信息共享Enhanced communication between regulator and applicant加强监管机构和申请人之间的沟通Enhanced interactions between review and field investigator加强审查和实地调查之间的相互作用Gain experience through working together获得经验,通过一起工作Regulatory sponsored pilot programsIndustry consortium, mock submission documents, etc.行业协会，模拟提交文件等Sharing information and experience分享信息和经验Regulators sharing with industry through meetings and conferences通过会议，监管机构与业界分享Sharing amongst industry through publications and presentations通过在行业出版物共享和演示,Recent Quality Guidance and Initiatives,2004,2005,2006,2007,2008,2009,Recent ICH Quality Guidance,ICH Q8 Pharmaceutical Development药品开发Describes good practices for pharmaceutical product development介绍医药产品开发的良好做法Introduces concepts of design space and flexible regulatory approaches推出概念设计空间和灵活的监管办法ICH Q8(R1) Annex merged with original document附件与原始文件合并Includes concepts of Quality by Design and examples of design space包括设计和质量的概念设计空间的例子,Recent ICH Quality Guidance (cont.),ICH Q9 Quality Risk Management质量风险管理Describes a systematic process for the assessment, control, communication and review of quality risks对药品质量风险进行评估、控制、沟通和审评的系统过程Applies over product lifecycle: development, manufacturing and distribution应用于产品的生命周期：开发、生产和流通Includes principles and examples of tools for quality risk management包括质量风险管理原则和质量风险管理工具的例子ICH Q10 Pharmaceutical Quality Systems医药质量体系Describes systems that facilitate establishment and maintainence of a state of control for process performance and product qualityFacilitates continual improvementApplies to drug substance and drug product throughout product lifecycle,Target the product profileDetermine critical quality attributes (CQAs)Link raw material attributes and process parameters to CQAs and perform risk assessmentDevelop a design spaceDesign and implement a control strategyManage product lifecycle, including continual improvement,Product profile,Example QbD Approach (Q8R1),Design Space,Definition The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of qualityRegulatory flexibilityWorking within the design space is not considered a changeImportant to noteDesign space is proposed by the applicant and is subject to regulatory assessment and approval,Design Space Determination,First-principles approachcombination of experimental data and mechanistic knowledge of chemistry, physics, and engineering to model and predict performanceNon-mechanistic/empirical approach statistically designed experiments (DOEs)linear and multiple-linear regression Scale-up correlationstranslate operating conditions between different scales or pieces of equipmentRisk Analysisdetermine significance of effectsAny combination of the above,Surface Plot,Contour Plot,Design Space(linear ranges),Design space proposed by the applicantDesign space can be described as a mathematical function or simple parameter rangeOperation within design space will result in a product meeting the defined quality attributes,Design Space Example,Design Space and Quality Control Strategy,Process (or Process Step),InputProcessParameters,Input Materials,Product (or Intermediate),ProcessVariability,Quality Risk Management Process (Q9),Example of Risk Assessment Toolsin Product & Process Development,Tools for parameter screeningExamples: Ishikawa diagrams, What-if analysis, HAZOP analysisTools for risk rankingExamples: FMEA/FMECA, Pareto analysis,Relative rankingExperimental tools for process understandingExamples: Statistically designed experiments (DOE), mechanistic models,Role of Quality Risk Management inDevelopment & Manufacturing,Manufacturing,Process Scale-up & Tech Transfer,Process Development,Product Development,The regulatory flexibility provided with a design space approach requires effective change management at the manufacturing siteTrack and trend product qualityRespond to process trends before they become problemsMaintain and update models as neededInternally verify that process changes are successful,Why Focus on Quality Systems? (Q10),ICH Where do we go from here?,ICH Q11 Drug SubstanceProposed harmonized guidance for development and manufacture of drug substance Guidance to includes both small molecule and biotechnology productsICH Implementation Work Group (IWG)Provide clarity and resolve ambiguity regarding ICH quality topic (e.g., terminology, documentation)Provide examples for implementation for training purposesEvaluate progress of implementation,FDA Review Office Programs,Office of New Drug Quality Assessment (ONDQA)Pharmaceutical Quality Assessment System (PQAS)2005 CMC Pilot programOffice of Biotechnology Products2008 Biotechnology Pilot Program Office of Generic DrugsQuestion Based Review (QBR),ONDQAs Pharmaceutical Assessment System,Introduced in 2004 as part of FDA Quality initiativesObjectivesFacilitate product innovation and continuous improvement Provide regulatory flexibility for specification setting and post-approval changes Streamline the submission and review processesKey ElementsMore relevant information on critical quality attributes and how they relate to clinical safety and effectivenessCritical steps and in-process controls identified and justified to demonstrate product knowledge and process understandingSources of variability in manufacturing identified and controlledLess documentation of data not directly relevant to scientific evaluation of product quality,ONDQA Restructuring,ONDQA was restructured in 2005, coincident with move to White Oak campusConsolidation of CMC reviewers into single locationSeparation of post-marketing review activitiesShift from small review teams to larger, integrated review BranchesIntroduction of CMC project managersIntroduction of Pharmaceutical Assessment Leads (PALs)Proposed ONDQA Realignment in 2009Better alignment of CMC review functionsShould be imperceptible to applicants,ONDQAs CMC Pilot Program,ObjectivesTo provide participating firms an opportunity to submit CMC information demonstrating QbDTo enable FDA to implement new QbD concepts Status9 original and 2(3) supplemental NDAs acceptedAll submitted to date: 11 approved, 1 under review (as of August 2009)Common factorsSubmission of design spaceUse of risk assessmentProposals of regulatory flexibility under firms quality system,CMC Pilot Observations,Wide variety of design spaces proposed:Most included drug product, some included drug substanceMost included process parameters, some included formulation componentsDeveloped using varied experimental techniques & mathematical modelsSeveral utilized risk assessment in developmentWide variety of control strategies utilized, includingOn-line analyzersIn-process testing in lieu of end-product testsReal time release using PAT,Example Control Strategy forReal Time Release Testing,Tablet Compression,Pan Coating,Sifting,Roller compaction,Blending,Dispensing,Findings from CMC Pilot Program,Provided valuable experience for industry and FDA in implementing QbDElements of QbD in submissionsRisk assessmentsDesign spaces Proposals for flexible regulatory approachesRisk-based regulatory decisions were enabledLearning has been incorporated into ICH Q8(R1)Refinement of concepts still ongoingQbD applications within and outside of pilot program,Recent QbD Experiences,Number of QbD meetings and applications have been increasingApplications containing QbD elements, outside of pilot (as of May 2009):12 NDAs18 INDs3 supplemental NDAsNew proposals have contained challenging concepts for regulatory