1、技术转化为价值GMP 医药化工法规约束稳定的工艺 实施GMP的基础QbD(质量源于设计）- 工艺开发指导法规符合法规符合Quality by Design质量源于设计 前控制质量源于生产 过程控制质量源于检测 后控制法规符合法规符合3Quality by Design质量源于设计质量源于设计Definition 定义定义Systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process cont
2、rol, based on sound science and quality risk management.以以合理的科学和质量风险管理合理的科学和质量风险管理为依据的，起始于为依据的，起始于预定的预定的质量目标质量目标，注重，注重对产品和工艺的理解以及对生产工艺过对产品和工艺的理解以及对生产工艺过程控制程控制的的系统的研发方法系统的研发方法Reference: ICH Q8(R)(2) Pharmaceutical Development, 2009法规符合法规符合What is Quality by Design ?什么是质量源于设计什么是质量源于设计 (Reference: ICH
3、Q8 (R2), 2009)法规符合法规符合Goals of Implementing QbD应用质量源于设计的目的应用质量源于设计的目的q Achieve meaningful product specifications that are based on clinical performance.根据临床需求建立有意义的产品质量标准根据临床需求建立有意义的产品质量标准q Reduce product variability and detects by increasing product and process understanding通过对产品和其工艺的理解，减少产品质量的变异和瑕
4、疵通过对产品和其工艺的理解，减少产品质量的变异和瑕疵q Enhance product development and manufacturing efficiencies 提高产品开发和生产效率提高产品开发和生产效率q Improve post-approval change management改善和方便批准后更改的管理改善和方便批准后更改的管理6QbD Terminology nQuality Target Product Profile 目标产品质量概况目标产品质量概况nCritical Quality Attributes 关键质量属性关键质量属性nCritical Material
5、 Attributes 关键物料属性关键物料属性nCritical Process Parameters 关键工艺参数关键工艺参数nRisk Assessment 风险评估风险评估nDesign Space 设计空间设计空间nControl Strategy 控制策略控制策略nContinual Improvement 继续改进继续改进Systematic Approach by QbDPredefined Objective预定的目标预定的目标 Defined Quality Target Product Profile (QTPP) Identify Critical Quality At
6、tributes (CQA)Product and Process Understanding对产品和工艺的理解对产品和工艺的理解 Define Critical Material Attributes (CMA) Identify Critical Process parameters (CPP) Understanding the relationship between CMA, CPP and CQAProcess Control生产工艺过程控制生产工艺过程控制 Establish appropriate control strategy Define Proven Acceptabl
7、e Range (PAR) and Operational Range (OR)Sound Science合理的科学合理的科学 Literature Prior knowledge Development studyQuality Risk Management质量风险管理质量风险管理 Risk based approach through development to commercial manufacturing, as well as continual improvementOverview of QbD质质量源于量源于设计设计的概括的概括法规符合法规符合9 Process Comp
8、arison 工艺比较工艺比较1QbD Concept ApproachTraditional Approach QTPP/CQA2Process Route IdentificationProcess Route Identification3Piloting Scale-up and Process OptimizationPiloting Scale-up and Process Optimization4Process Characterization and Process Understanding v CPP, CMA, PAR (OR)5Control strategy(Des
9、ign Space, etc.)6Process Qualification (Validation)Process Qualification (Validation)10Process Development Procedure - 产品开发流程产品开发流程路线评估路线评估工艺开发工艺开发/ /路线确定路线确定工艺优化工艺优化工艺确认工艺确认放大研究放大研究工艺验证工艺验证明确目标明确目标商业化商业化生产生产QTPP/CQAQTPP/CQA（杂质、晶型、粒度等）（杂质、晶型、粒度等）文献综述文献综述 路线可行性分析（成本、绿色、设备、质路线可行性分析（成本、绿色、设备、质量、原料）合理的科
10、学和技术积累量、原料）合理的科学和技术积累 创新创新起始物料确认，每步考察，最终工艺确定起始物料确认，每步考察，最终工艺确定 确定确定潜在产品质量属性及潜在产品质量属性及初步质量风险评估初步质量风险评估每步工艺优化每步工艺优化 CPPCPP确认确认/ /优化工艺优化工艺 质量风险控制质量风险控制 DoE DoE Design Space(Design Space(允许允许/ /操作范围操作范围) ) 实验室三批确认实验室三批确认放大工艺放大工艺/步骤合理性说明步骤合理性说明/评估评估验证方案验证方案/验证报告验证报告Continuous Process ImprovementExample I
11、dentify CQA in Drug SubstanceQuality AttributesTargetCriticalJustificationSolid StateForm IIYesDirectly link to solubility & stabilityPSDDefined rangeYes/NoFormulation and process do dependentAssay (purity)100% of label claimYesAssay value will affect safety and efficacySolubilityInformationNoNot co
12、ntrol by processDegradation ProductsXXX: NMT 0.5%Any unknown NMT 0.2%Total: NMT 1.0%YesThey may impact safetyWater ContentNMT 4.0%NoUnlikely to impact safety12Quality Risk Management ProcessProcessDevelopmentControl Strategy DevelopmentContinual Improvement13Risk Assessment Tools风险评估的工具风险评估的工具p Tool
13、s for parameter screeningExamples: Ishikawa (Fishbone) diagrams, What-if Analysis, HAZOP analysisp Tools for risk rankingExamples: FMEA/FMECA, Pareto analysis,Relative rankingp Experimental tools for process understandingExamples: Statistically designed experiments (DOE), mechanistic models14Selecte
14、d Tools Used in the Risk Assessment 用于风险评估的工具举例用于风险评估的工具举例p Ishikawa (Fishbone) Diagram to identify all potential variables, such as raw materials, compression parameters, and environmental factors, which can have an impact on a particular CQA, such as tablet hardness.p Failure Mode Effect Analysis
15、(FMEA) to rank the variables based on risk (i.e., a combination of probability, severity, and detectability) and to select the process parameters with higher risks for further studies to gain greater understanding of their effects on CQAs.15Ishikawa (Fishbone) DiagramsAlso known as Cause & Effect Di
16、agramIncludes all the potential inputs that affect a desired output (CQA)Effective for initial brainstorming of potential design space parametersQuality Attribute(Effect)Material AttributesProcess ParametersOperational Factors(Causes)16Failure Mode Effects Analysis (FMEA)Cross-functional team evalua
17、tion Product and process understanding appliedPotential failure modes identified and related to product quality and performanceProduct and process risks prioritized Output/results can be used as a basis for design of experiment or further analysisRisk quantitatively assessednRisk = Severity X Likeli
18、hood X Detectability严重性严重性 X 可能性可能性 X 可可测试性测试性 17CriticalQualityAttribute (right) AppearanceChemical IdentityPhysical IdentityResidual Precursors S.M. Related ImpuritiesProcess Related ImpuritiesEnantiomeric PurityPhthalimide ProductsEDC.HCl + urea by-productDMAPmethylamineInorganic SaltsDMFDichloro
19、methaneIsopropanolEthanolAcetic AcidAcetoneAssayParticle SizeStability /StorageProcess Stage (below)Starting Material RIA10 Starting Material RIA20 RIA30Reaction Isolation Drying RIA35Reaction Isolation Drying RIA46Reaction Work-up Starting Material RIA60 RIA56Reaction Work-up RIAReaction Isolation
20、Purification Drying/Milling Overall Preliminary Process Risk Assessment Map18Design Space 设计空间设计空间 Definition 定义定义The multidimensional combination and interaction of input variables (e.g., material attributes and process parameters) that have been demonstrated to provide assurance of quality输入变数输入变数
21、( (物料属性和工艺参数物料属性和工艺参数) )的多维结合和相互作用已证明能的多维结合和相互作用已证明能提提供产品质量的保障供产品质量的保障v Working within the design space is not considered as a change. Movement out of the design space is considered to be a change v Design space is proposed by the drug applicant and is subject to regulatory assessment and approval19
22、Design Space 设计空间设计空间 Design space is potentially scale- and equipment-dependent 设计空间与批量和设备有关设计空间与批量和设备有关Design space determined at the laboratory scale may not be relevant to the process at the commercial scale 实验或小试中取得的设计空间也许与商业实验或小试中取得的设计空间也许与商业生产工艺没有直接的关联生产工艺没有直接的关联 Therefore, design-space verif
23、ication at the commercial scale becomes essential unless it is demonstrated that the design space is scale-independent.与生产批量有关的设计空间参数应在商业批生产过程中证实与生产批量有关的设计空间参数应在商业批生产过程中证实20Important NoteFor generic drug/API applications:p Design space is optionalp QbD can be implemented without a design space becau
24、se product and process understanding can be established without a formal design space.p Implementation of QbD is strongly encouraged by FDA. For some complex drug substances or drug products, implementation of QbD is considered a required component of the application.21Control Strategy控制策略控制策略ICH Q8
25、 defines Control Strategy as:q A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.基于在对产品和工艺的理解基础上制定的控制要点以确保工艺稳定基于在对产品和工艺的理解基础上制定的控制要点以确保工艺稳定和产品质量和产品质量 The controls can include parameters and attributes related to dru
26、g 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.22Control Strategy控制策略控制策略Control strategy may include:Control of input materia
27、l attributes (CMAs) Controls for unit operations (CPPs and process endpoints) In-process or real-time release testing Product specifications (CQAs)23CriticalQualityAttribute (right) AppearanceChemical IdentityPhysical IdentityResidual Precursors S.M. Related ImpuritiesProcess Related ImpuritiesEnant
28、iomeric PurityPhthalimide ProductsEDC.HCl + urea by-productDMAPmethylamineInorganic SaltsDMFDichloromethaneIsopropanolEthanolAcetic AcidAcetoneAssayParticle SizeStability /StorageProcess Stage (below)Starting Material RIA10 Starting Material RIA20 RIA30Reaction Isolation Drying RIA35Reaction Isolati
29、on Drying RIA46Reaction Work-up Starting Material RIA60 RIA56Reaction Work-up RIAReaction Isolation Purification Drying/Milling Overall Optimized Process Risk Assessment Map24Critical Quality Control Strategy of Drug SubstanceCritical Quality Attribute(Test Method)DS Confirmation Test Acceptance Cri
30、teriaProduct Quality Control TypeDescription of ControlsAppearance(Visual)White to off-white powderStarting Materials (RIA10, RIA60) &RIA Process: RIA35 Isolation & RIA CrystallizationRIA10 Appearance Specification (white to light brown solid);Filtered & washed, RIA35 Appearance Specification ( whit
31、e to off-white solid); RIA60 Appearance Specification (white to dark beige solid);Filter cake wash of crude RIA and crystallized RIA ensures colour removal.Chemical Identification(IR)The IR absorption spectrum of the sample exhibits the maxima only at the same wavelengths as that of the correspondin
32、g standard.Starting Materials (RIA10, RIA20, RIA60) &General CGMPRIA10, RIA20 & RIA60 Identification Specification; Chemical Identification(HPLC) The retention time of the principle peak in the chromatogram of the sample preparation conforms to that of the reference standard preparation obtained as
33、directed in the Assay method.Starting Material (RIA10, RIA60, phthalimide potassium, ) &General CGMPRIA10, phthalimide potassium & RIA60 Identification Specification. 25Process Development Report工艺硏发报吿工艺硏发报吿 qAll written documents should follow Good Document Practice Document numbers Author and appr
34、over signatures Data traceability (notebook numbers) Individual report can reference other reports26Process Development Report工艺硏发报吿工艺硏发报吿 q Not a written regulatory requirementq Absence of the report is not a reason for a FDA-483 observationHowever,v Companies must produce documented data to justif
35、y critical process parameters, controls ranges and specifications, etc.v No documented supportive data will result in 483 observation (GMP deficiency).27Process Development Report工艺硏发报吿工艺硏发报吿 q Objective Summarize development history to support proposed commercial process Support qualification/valid
36、ation protocol Demonstrate knowledge and control strategy over the commercial process Prepare for Pre-Approval Inspection (PAI) Reference for future optimization and investigation activities, such as OOS and deviations Support CMC/DMF filing (Section 3.2.S.2.6)281.Introduction: Drug Substance Identi
37、ty and Attributes2. Synthetic Route Development Evaluation3.Potential Quality Attributes of the Drug Substance4.Preliminary Risk Assessment for Critical Quality Attributes5.Starting Material Discussion6.Optimization of Manufacturing Process7.Manufacturing7.1.Brief Description7.2.Synthetic Scheme7.3.
38、Detailed Description of the Process Control8.Critical Quality Control Strategy of Drug Substance9.History of Manufacturing ProcessProcess Development Report - 产品开发报告产品开发报告29Attachments: Supplier Specifications for Starting MaterialSpecifications for Starting Material and IntermediatesProcess Control
39、 Map Detailed Risk AssessmentC of A Summary of Manufactured BatchesGlossary of AbbreviationsProcess Development Report - 产品开发报告产品开发报告30QbD - 产品开发流程产品开发流程 工艺开发报告工艺开发报告 比较比较QbD工艺开发工艺开发产品开发报告产品开发报告QTPP / CQA目标产品质量标准目标产品质量标准引言引言-产品介绍产品介绍及要求及要求工艺设计与风险评估工艺设计与风险评估工艺路线评估工艺路线评估/路线选择路线选择与确定与确定路线选择与开发路线选择与开发潜在质量属性确定潜在质量属性确定初步风险评估初步风险评估起始物料确定起始物料确定风险控制策略风险控制策略工艺优化工艺优化/确认确认/放大放大/验证验证生产工艺优化生产工艺优化生产工艺控制生产工艺控制产品质量控制策略产品质量控制策略持续改进持续改进商业化生产商业化生产生产批次历史生产批次历史/年年报报分析分析Quality by Design质量源于设计目标：设计和开发的工艺能够在可控风险的情况下生产出符合质量标准的产品满足产品质量要求的工艺开发是执行GMP全过程的基础 - 全程可全程可控控法规符合法规符合
