《浅谈质量源于设计》解读概要课件.ppt

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1、浅谈质量源于设计浅谈质量源于设计 -Quality by Design (-Quality by Design (QbDQbD) )重庆药友制药有限责任公司重庆药友制药有限责任公司张彦张彦自我介绍2什么是什么是“质量源于设计质量源于设计” 3 质量源于设计（Quality by Design，QbD) 1992年由著名的美国质量专家Joseph M. Juran 提出来。 Juran相信可以通过合理的计划和设计获得优秀的产品质量。许多产品质量问题都与产品最初的设计蓝图息息相关。 QbD概念已经运用到每一个行业，尤其是自动化程度高的行业。QbDQbD在制药行业的应用在制药行业的应用 4 QbDQ

2、bD被美国FDA采纳，并希望这一概念运用到新药发现、开发及商业化生产中。This FDA imperative is best outlined in its report “Pharmaceutical Quality for the 21st Century: A Risk-Based Approach.”QbDQbD: CMC: CMC先期计划先期计划 52005年6月 FDA ONDQA 宣布启动一项CMC先期计划:v为制药企业提供如何进行CMC的展示(i) QbD 的应用原则 (ii) 产品和生产工艺的理解v使FDA有能力评价那些基于QbD 理念进行开发的新药申请。v在FDA重新起草

3、制药行业质量评估系统时寻求到更多的公众资源和信息。截止2010年底, 共有21项NDAs, 18 INDs, 9 SupplsQbDQbD: : 仿制药仿制药 62005年8月, FDA仿制药审评办公室公开了一个仿制药的审评要求QbR-QoS模板作为21世纪GMP的启动;2008年1月, QbR-QoS 开始启用;2011年12月, FDA仿制药审评办公室发布了一个缓释片的QbD 模板。2013年1月，所有仿制药申请都必须基于QbD理念 。QbDQbD: :配方和工艺开发配方和工艺开发 ICH Q8ICH Q8 7定义：质量源于设计QbD是通过系统性的设计和研究开发产品。在开发过程中通过完善的

4、科学研究和全面的质量风险管理，通过全面的过程控制手段，努力实现既定的产品质量目标。 8设计产品以满足患者需求和满足使用需求；设计过程和工艺以稳定地生产出符合产品关键属性的好产品；通过研究，深刻理解起始物料质量与生产工艺参数对产品质量的影响；持续评估生产工艺，确保始终如一的产品质量；明确和控制引起工艺参数变动的关键原因；制定合理的控制策略。QbDQbD: :配方和工艺开发配方和工艺开发 ICH Q8ICH Q8Significance of Quality by Design 9 10 目标产品质量(QTPP) 产品的关键质量属性(CQAs) 产品设计和对产品的充分理解，包括:对原料、辅料、包材

5、的CQAs的界定 工艺设计和对工艺的充分理解，包括：界定关键工艺参数和中间体属性 对控制策略的合理性给予充分解释例如：PAT，实时放行，设计空间，试验设计，风险评估，统计分析QbDQbD: FDA: FDA的期望的期望关键质量属性关键质量属性 Identification of a CQA is based on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute. 11关键物料属性关键物料属性 12关键工艺参数关键工艺参数 1

6、3 14建立建立CMAs, CPPsCMAs, CPPs和和CQAsCQAs的关系的关系控制策略控制策略 15 基于对现有产品和工艺的理解，为了保障成功的生产过程和产品质量而制定的一系列控制手段。 包括：工艺参数，影响产品质量的物料属性，设备，中间控制，成品质量标准，检测方法，检测频率，等等。 (ICH Q10) 设计空间设计空间 16KnowledgeSpaceDesign SpaceControl SpaceUnexplored SpaceICH Q8设计空间-经过试验和验证确认可以保证产品质量的各种变量（例如：物料属性、工艺参数）的允许范围。在设计空间之内的变化不应被视为真正的变化。设计

7、空间之外的变化则必须要经过正式的研究并需要获得药政部门的批准才能使用。设计空间是由产品开发者提出并经过药政部门充分评估、批准后才能运用。QbDQbD各元素之间的关联各元素之间的关联Lionberger R. et al AAPS J. 10(2):268, 2008 17目前状态目前状态QbDQbD的要求的要求产品开发产品开发经验性的，随机的，重于优化系统性的，多变量试验，重于控制策略生产过程生产过程固定的在健全的质量系统支持下，在设计空间之内可以调整工艺工艺控制工艺控制有少量过程控制运用在线监测技术产品质量标准产品质量标准是工厂QC的主要依据，依靠批放行数据属于系统质量控制策略中的一部分，主

8、要考虑产品的实际功效控制策略控制策略通过监测和检查基于风险评估的控制策略，实时监控、实时放行 18QbDQbD : :配方和工艺开发配方和工艺开发 ICH Q8ICH Q8 19 20I. I. 目标产品质量目标产品质量(QTPP)(QTPP)2122常见的目标产品质量属性表常见的目标产品质量属性表23CQA常见的目标产品质量属性表（续）常见的目标产品质量属性表（续）建立仿制药的建立仿制药的QTPPQTPP第一步：了解已上市对照药第一步：了解已上市对照药2425普通制剂普通制剂QTPPQTPP案例案例: Acetriptan: Acetriptan片片26普通制剂普通制剂QTPPQTPP案例案

9、例: Acetriptan: Acetriptan片片普通制剂普通制剂QTPPQTPP案例案例: : AcetriptanAcetriptan片片2728Make a new Table for CQA普通制剂普通制剂QTPPQTPP案例案例: Acetriptan: Acetriptan片片29建立仿制药的建立仿制药的QTPPQTPP第二步：确定关键质量属性第二步：确定关键质量属性30建立仿制药的建立仿制药的QTPPQTPP第二步：确定关键质量属性第二步：确定关键质量属性31案例：普通制剂的关键质量属性案例：普通制剂的关键质量属性32案例：普通制剂的关键质量属性案例：普通制剂的关键质量属性I

10、I. II. 充分理解你的产品充分理解你的产品33原料药性质原料药性质3435辅料性质辅料性质36原辅料相容性原辅料相容性37配方优化配方优化38配方优化配方优化39.充分理解你的工艺充分理解你的工艺步骤步骤1 1：确定工艺步骤：确定工艺步骤工具工具: : 工艺路径图工艺路径图( (缓释制剂缓释制剂QbDQbD 案例案例) )40步骤步骤1 1：确定工艺步骤：确定工艺步骤寻找关键物料属性、关键工艺参数与关键质量属性的关系寻找关键物料属性、关键工艺参数与关键质量属性的关系4142步骤步骤2 2：确定潜在的高风险参数：确定潜在的高风险参数工具工具: : 风险评估和专业知识风险评估和专业知识43步骤

11、步骤2 2：确定潜在的高风险参数：确定潜在的高风险参数工具工具: : 风险评估和专业知识风险评估和专业知识44步骤步骤2 2：确定潜在的高风险参数：确定潜在的高风险参数工具工具: : 风险评估和专业知识风险评估和专业知识45步骤步骤2 2：确定潜在的高风险参数：确定潜在的高风险参数工具工具: : 风险评估和专业知识风险评估和专业知识46步骤步骤3 3：确定工艺参数范围：确定工艺参数范围工具工具: : 专业知识和生产经验专业知识和生产经验47步骤步骤4 4：设计并完成试验：设计并完成试验工具工具: : 实验设计实验设计(DOE)(DOE)48Updated Process Risk Assess

12、ment Example after the Analysis步骤步骤5 5：分析试验数据：分析试验数据工具工具: : 统计分析统计分析(ANOVA,(ANOVA,数学模型数学模型) )49步骤步骤5 5：分析试验数据：分析试验数据充分解释实验数据充分解释实验数据Step 6: Develop Control Strategy (Example)Step 6: Develop Control Strategy (Example)50步骤步骤6 6：确定控制策略：确定控制策略51IV.风险评估风险评估工具工具: ICH Q9: ICH Q9质量风险管理质量风险管理 52Risk Identifi

13、cationRisk IdentificationRisk AnalysisRisk AnalysisRisk EvaluationRisk EvaluationRisk ReductionRisk ReductionRisk AcceptanceRisk AcceptanceRisk CommunicationRisk CommunicationReview EventsReview EventsRisk AcceptanceRisk AcceptanceOutput/Results of theOutput/Results of theRisk Management ProcessRisk

14、 Management ProcessInitiateInitiateRisk Management ProcessRisk Management ProcessRisk AssessmentRisk AssessmentRisk ControlRisk ControlRiskRisk Communication CommunicationRisk ReviewRisk Review 风险管理工具风险管理工具UnacceptableUnacceptableICHQ9 Quality Risk ManagementICHQ9 Quality Risk Management质量风险评估应基于专业质

15、量风险评估应基于专业知识和对患者的保护意识知识和对患者的保护意识不同级别的风险因素应给不同级别的风险因素应给予不同的关注和监测予不同的关注和监测质量风险管理的原则质量风险管理的原则531)质量风险评估应该建立在专业知识的充分理解和对患者的足够保护基础之上。2) 对不同等级的风险，应该投入不同程度的关注和精力。风险评估：原辅料属性风险评估：原辅料属性54摘自FDA 普通制剂QbD 模板55风险评估：合理性解释风险评估：合理性解释摘自FDA 普通制剂QbD 模板风险转移风险转移56对制剂的关键质量属性而言，原料属性属于高风险因素原料属性原料属性 制剂属性制剂属性 风险转移风险转移固态固态 溶出度

16、QC粒径分布 含量均匀度和溶出 QC和工艺开发部溶解度 溶出度 配方开发和工艺开发化学稳定性 含量和降解 配方开发和工艺开发流动性 含量均匀度 工艺开发摘自FDA 普通制剂QbD 模板57风险评估：配方变量风险评估：配方变量需要做的实验需要做的实验58原辅料相容性试验两两混合配方所有成分的混合物 配方开发试验第一轮DOE：原料 的粒径分布、颗粒内乳糖用量、MCC用量、CMS用量对产品关键质量属性的影响。第二轮DOE ：颗粒外乳糖、滑石粉、硬脂酸镁对产品关键质量属性的影响。及时更新风险评估及时更新风险评估59原料属性的控制策略原料属性的控制策略6061总结总结Q&AQ&AGDUFAGDUFATh

17、e Generic Drug User Fee Act (GDUFA) calls for the generic drug industry to pay $299 million annually in user fees for the next five years, beginning October 1, 2012. This funding is supplemental to what Congress appropriates to FDA each year and will enable the FDAs Office of Generic Drugs to hire t

18、he scientific resources needed to provide timely approval of generic medicines. The new fees also will provide increased funding for generic manufacturer facility inspections, which are required before new generics can be approved.Type of Fees Will be Paid Under GDUFAType of Fees Will be Paid Under

19、GDUFAOne time backlog fee for ANDAs pending on Oct 1, 2012. A notice of amount of fees will be published by 10/31/12 (50MM/#ANDAs). Fee due date in 30 calendar days.DMF fee (same above)ANDA and prior approval supplement filing fee (75% refund if ANDA is not considered to be received).An annual fee f

20、or facility to manufacture API or Generics.Amount of fee published 60 days before each fiscal yearFee due date within 45 days after notification.299MM: 6% DMF; 24% ANDA; 56% Generic facility; 14% API facility (2013-2017) charged from Generic Pharma.Type of Fees Will be Paid Under GDUFAType of Fees W

21、ill be Paid Under GDUFAFacility fee (annual): 100K 125KANDA: 60K 90KPAS: 30K 45KBacklog one time fee: 15K-20KDMF: 15K-20KThis is not official information. Final fees information is available in Oct 2012 IF the Act is passed.New Paradigm of DMF ReviewNew Paradigm of DMF ReviewFDA DMF TeamFDA DMF Team

22、67Review ProcessReview Process68Question Based Review for Question Based Review for DMFsDMFs69Question Based Review for Question Based Review for DMFsDMFs70Proposed Implementation TimelineProposed Implementation Timeline71Expectation for Process Dev & Process Scale-Expectation for Process Dev & Proc

23、ess Scale-up Informationup Information72Proposed Draft Proposed Draft QbRQbR Questions Questions73Proposed Draft Proposed Draft QbRQbR Questions Questions74Proposed Draft Proposed Draft QbRQbR Questions Questions7576Completeness Assessments (“filing Completeness Assessments (“filing review”) for rev

24、iew”) for DMFsDMFs Consistent with language in GDUFADifferent than the administrative “filing” review performed by the Central Document Room Avoid confusion with the ANDA Filing Review process 77Why a Completeness Assessment or “Filing Review” for Type II DMFs? New requirement in the proposed GDUFA

25、legislation Drug substance (Type II) DMFs must be deemed “available for reference” by the HHS Secretary to be referenced by an ANDA Two things must happen for the DMF to be considered “available for reference” 1. DMF Fee must be paid 2. DMF must pass a “completeness assessment” ANDAs can only be fil

26、ed by OGD if all DMFs for the drug substance(s) are “available for reference” 78Which Fee is associated with the Completeness Assessment? Drug Master File Fee paid by the DMF Holder Not to be confused with the facility fee related to the drug substance manufacturing facility One-time Fee paid once i

27、n the DMF lifecycle Fee is due upon the first reference by an ANDA submission under GDUFA Payment of this fee triggers the Completeness Assessment process in OGD 79What are the responsibilities for the Completeness Assessment under GDUFA? vDMF holder Pay the DMF Fee allowing sufficient time for the

28、completeness Assessment to occur Provide a high quality DMF submission Respond to comments in letters and teleconferences quickly vOffice of Generic Drugs Perform a timely Completeness Assessment Issue comments for DMFs found “Incomplete” Communicate comments by teleconference when possible Publish

29、a list of DMFs found “available for reference” (fee paid and complete) on an FDA website Publish our criteria for the Completeness Assessment 80Initial OGD Goals for the Process Should be comprehensive and provide useful feedback to the DMF holder Improve quality of the submission Improve the effici

30、ency of the scientific review Should be performed exclusively by the DMF Team Should be performed by a chemist Enhance efficiency Leverage expertise Should not be a huge workload burden Complete in 2 to 3 hours Should not cross the line into Scientific Review Comments are information requests Review

31、er training 81Work Flow 1 82Work Flow 2 What can DMF holders do to ensure success? 83Stability Expectation For Stability Expectation For Generic DrugsGeneric DrugsProposed Stability GuidanceProposed Stability Guidance85ICH Stability ICH Stability GuidancesGuidances86ICH Q1A Requirements: General Cas

32、e (2.2.7.1)ICH Q1A Requirements: General Case (2.2.7.1)87If significant change occurs during 6 months testing at the accelerated condition, additional testing at the intermediate condition required Initial application should include a minimum of 6 months data from a 12-month study at the intermediat

33、e storage. ICH Q1A Requirement: Selection of Batches ICH Q1A Requirement: Selection of Batches (2.2.3) (2.2.3) 88Stability studies data should be provided on at least three primary batches of the drug product. Two of the three batches should be at least pilot scale batches, and the third one can be

34、smaller if justified. Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied. ICH Q1A : Batch DefinitionsICH Q1A : Batch Definitions89Primary batch: A batch of a drug substance or drug product used in a forma

35、l stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf life, respectively. A primary batch may be a production batch. Production batch: A batch of a drug substance or drug product manufactured at production sc

36、ale by using production equipment in a production facility as specified in the application It is proposed that one of the three batches be an exhibit batch on which ANDA holder has conducted bioequivalence studies comparing to a Reference Listed Drug, where applicable. Guidance StatusGuidance Status

37、90The draft Stability Guidance (ANDAs: Stability Testing of Drug Substances and Products) is currently obtaining clearance for posting OGD has met with Generic Industry representatives during guidance development Industry will have the opportunity to provide comments After evaluation of comments and

38、 revision as appropriate, the guidance will be posted ICH Q8关于关于QbD的三个主要元素的三个主要元素 91“知识管理”structured requirements flow down and cause structured requirements flow down and cause effect overview “ quality function deploymenteffect overview “ quality function deployment过程理解过程理解structured experiments a

39、nd data collection (e.g. structured experiments and data collection (e.g. DoEDoE and modeling) to provide an understanding of cause and and modeling) to provide an understanding of cause and effect and interaction.effect and interaction.质量风险管理质量风险管理Using the assessment of the risk associated with Using the assessment of the risk associated with the cause and effect to remove or control the risk to an the cause and effect to remove or control the risk to an adequate level -PAT, Control Strategyadequate level -PAT, Control Strategy92案例：普通制剂的关键质量属性案例：普通制剂的关键质量属性QbDQbD: FDA: FDA的期望的期望 93