1、研發流程及QbD介紹DS研發流程及QbD介紹DS研發流程及QbD介紹DS技術轉化為價值GMP 醫藥化工法規約束穩定的工藝 實施GMP的基礎QbD(質量源于設計）- 工藝開發指導法規符合技術轉化為價值GMP 醫藥化工法規約束穩定的工藝 實施GMP的基礎QbD(質量源于設計）- 工藝開發指導法規符合Quality by Design質量源于設計 前控制質量源于生產 過程控制質量源于檢測 后控制法規符合Quality by Design質量源于設計Definition 定義Systematic approach to development that begins with predefined o

2、bjectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.以合理的科學和質量風險管理為依據的，起始于預定的質量目標，注重對產品和工藝的理解以及對生產工藝過程控制的系統的研發方法Reference: ICH Q8(R)(2) Pharmaceutical Development, 2009法規符合4What is Quality by Design ?什么是質量源于設計 (Reference:

3、ICH Q8 (R2), 2009)法規符合Goals of Implementing QbD應用質量源于設計的目的Achieve meaningful product specifications that are based on clinical performance.根據臨床需求建立有意義的產品質量標準Reduce product variability and detects by increasing product and process understanding通過對產品和其工藝的理解，減少產品質量的變異和瑕疵Enhance product development and

4、manufacturing efficiencies 提高產品開發和生產效率Improve post-approval change management改善和方便批準后更改的管理QbD Terminology Quality Target Product Profile 目標產品質量概況Critical Quality Attributes 關鍵質量屬性Critical Material Attributes 關鍵物料屬性Critical Process Parameters 關鍵工藝參數Risk Assessment 風險評估Design Space 設計空間Control Strateg

5、y 控制策略Continual Improvement 繼續改進7Systematic Approach by QbDPredefined Objective預定的目標Defined Quality Target Product Profile (QTPP)Identify Critical Quality Attributes (CQA)Product and Process Understanding對產品和工藝的理解Define Critical Material Attributes (CMA)Identify Critical Process parameters (CPP)Unde

6、rstanding the relationship between CMA, CPP and CQAProcess Control生產工藝過程控制Establish appropriate control strategyDefine Proven Acceptable Range (PAR) and Operational Range (OR)Sound Science合理的科學LiteraturePrior knowledgeDevelopment studyQuality Risk Management質量風險管理Risk based approach through developm

7、ent to commercial manufacturing, as well as continual improvementOverview of QbD質量源于設計的概括法規符合 Process Comparison 工藝比較1QbD Concept ApproachTraditional Approach QTPP/CQA2Process Route IdentificationProcess Route Identification3Piloting Scale-up and Process OptimizationPiloting Scale-up and Process Opt

8、imization4Process Characterization and Process Understanding CPP, CMA, PAR (OR)5Control strategy(Design Space, etc.)6Process Qualification (Validation)Process Qualification (Validation)10Process Development Procedure - 產品開發流程路線評估工藝開發/路線確定工藝優化工藝確認放大研究工藝驗證明確目標商業化生產QTPP/CQA（雜質、晶型、粒度等）文獻綜述 路線可行性分析（成本、綠色

9、、設備、質量、原料）合理的科學和技術積累 創新起始物料確認，每步考察，最終工藝確定 確定潛在產品質量屬性及初步質量風險評估每步工藝優化 CPP確認/優化工藝 質量風險控制 DoE Design Space(允許/操作范圍) 實驗室三批確認放大工藝/步驟合理性說明/評估驗證方案/驗證報告Continuous Process Improvement11Example Identify CQA in Drug SubstanceQuality AttributesTargetCriticalJustificationSolid StateForm IIYesDirectly link to solu

10、bility & stabilityPSDDefined rangeYes/NoFormulation and process do dependentAssay (purity)100% of label claimYesAssay value will affect safety and efficacySolubilityInformationNoNot control by processDegradation ProductsXXX: NMT 0.5%Any unknown NMT 0.2%Total: NMT 1.0%YesThey may impact safetyWater C

11、ontentNMT 4.0%NoUnlikely to impact safetyQuality Risk Management ProcessProcessDevelopmentControl Strategy DevelopmentContinual Improvement13Risk Assessment Tools風險評估的工具Tools for parameter screeningExamples: Ishikawa (Fishbone) diagrams, What-if Analysis, HAZOP analysisTools for risk rankingExamples

12、: FMEA/FMECA, Pareto analysis,Relative rankingExperimental tools for process understandingExamples: Statistically designed experiments (DOE), mechanistic models14Selected Tools Used in the Risk Assessment 用于風險評估的工具舉例Ishikawa (Fishbone) Diagramto identify all potential variables, such as raw material

13、s, compression parameters, and environmental factors, which can have an impact on a particular CQA, such as tablet hardness.Failure Mode Effect Analysis (FMEA)to rank the variables based on risk (i.e., a combination of probability, severity, and detectability) and to select the process parameters wi

14、th higher risks for further studies to gain greater understanding of their effects on CQAs.15Ishikawa (Fishbone) DiagramsAlso known as Cause & Effect DiagramIncludes all the potential inputs that affect a desired output (CQA)Effective for initial brainstorming of potential design space parametersQua

15、lity Attribute(Effect)Material AttributesProcess ParametersOperational Factors(Causes)16Failure Mode Effects Analysis (FMEA)Cross-functional team evaluation Product and process understanding appliedPotential failure modes identified and related to product quality and performanceProduct and process r

16、isks prioritized Output/results can be used as a basis for design of experiment or further analysisRisk quantitatively assessedRisk = Severity X Likelihood X Detectability嚴重性 X 可能性 X 可測試性 17CriticalQualityAttribute (right)AppearanceChemical IdentityPhysical IdentityResidual Precursors S.M. Related I

17、mpuritiesProcess Related ImpuritiesEnantiomeric PurityPhthalimide ProductsEDC.HCl + urea by-productDMAPmethylamineInorganic SaltsDMFDichloromethaneIsopropanolEthanolAcetic AcidAcetoneAssayParticle SizeStability /StorageProcess Stage (below)Starting Material RIA10Starting Material RIA20RIA30ReactionI

18、solationDryingRIA35ReactionIsolationDryingRIA46ReactionWork-upStarting Material RIA60RIA56ReactionWork-upRIAReactionIsolationPurificationDrying/MillingOverallPreliminary Process Risk Assessment Map18Design Space 設計空間Definition 定義The multidimensional combination and interaction of input variables (e.

19、g., material attributes and process parameters) that have been demonstrated to provide assurance of quality輸入變數(物料屬性和工藝參數)的多維結合和相互作用已證明能提供產品質量的保障Working within the design space is not considered as a change. Movement out of the design space is considered to be a change Design space is proposed by th

20、e drug applicant and is subject to regulatory assessment and approval19Design Space 設計空間 Design space is potentially scale- and equipment-dependent 設計空間與批量和設備有關Design space determined at the laboratory scale may not be relevant to the process at the commercial scale 實驗或小試中取得的設計空間也許與商業生產工藝沒有直接的關聯 The

21、refore, design-space verification at the commercial scale becomes essential unless it is demonstrated that the design space is scale-independent.與生產批量有關的設計空間參數應在商業批生產過程中證實20Important NoteFor generic drug/API applications:Design space is optionalQbD can be implemented without a design space because p

22、roduct and process understanding can be established without a formal design space.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ICH Q8 defines C

23、ontrol Strategy as:A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.基于在對產品和工藝的理解基礎上制定的控制要點以確保工藝穩定和產品質量The controls can include parameters and attributes related to drug substance and drug-product materials and comp

24、onents, 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Control strategy may include:Control of input material attributes (CMAs) Controls for unit operations (C

25、PPs and process endpoints) In-process or real-time release testing Product specifications (CQAs)23CriticalQualityAttribute (right)AppearanceChemical IdentityPhysical IdentityResidual Precursors S.M. Related ImpuritiesProcess Related ImpuritiesEnantiomeric PurityPhthalimide ProductsEDC.HCl + urea by-

26、productDMAPmethylamineInorganic SaltsDMFDichloromethaneIsopropanolEthanolAcetic AcidAcetoneAssayParticle SizeStability /StorageProcess Stage (below)Starting Material RIA10Starting Material RIA20RIA30ReactionIsolationDryingRIA35ReactionIsolationDryingRIA46ReactionWork-upStarting Material RIA60RIA56Re

27、actionWork-upRIAReactionIsolationPurificationDrying/MillingOverallOptimized Process Risk Assessment Map24Critical Quality Control Strategy of Drug SubstanceCritical Quality Attribute(Test Method)DS Confirmation Test Acceptance CriteriaProduct Quality Control TypeDescription of ControlsAppearance(Vis

28、ual)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 ( white to off-white solid); RIA60 Appearance Specification (white to dark b

29、eige 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 corresponding standard.Starting Materials (RIA10, RIA20, RIA60) &General CGMPRIA10

30、, 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 directed in the Assay method.Starting Material (RIA10, RIA60, phthalim

31、ide potassium, ) &General CGMPRIA10, phthalimide potassium & RIA60 Identification Specification.25Process Development Report工藝硏發報吿 All written documents should follow Good Document PracticeDocument numbersAuthor and approver signaturesData traceability (notebook numbers)Individual report can referen

32、ce other reports26Process Development Report工藝硏發報吿 Not a written regulatory requirementAbsence of the report is not a reason for a FDA-483 observationHowever,Companies must produce documented data to justify critical process parameters, controls ranges and specifications, etc.No documented supportiv

33、e data will result in 483 observation (GMP deficiency).27Process Development Report工藝硏發報吿 ObjectiveSummarize development history to support proposed commercial processSupport qualification/validation protocolDemonstrate knowledge and control strategy over the commercial process Prepare for Pre-Approval Inspection (PAI)Reference for future optimization and investigation activities, suc