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1、Product Development:Case Study Overview,© ICH, November 2010,Disclaimer,The information within this presentation is based on the ICH Q-IWG members expertise and experience, and represents the views of the ICH Q-IWG

2、 members for the purposes of a training workshop.,© ICH, November 2010,Outline of Presentation,Key Steps for Quality by DesignCase Study OrganizationIntroducing API and Drug Product Discussion of concepts of Qual

3、ity Target Product Profile, processes, compositionDescription of API & Drug Product process development Discussion of illustrative examples of detailed approaches from the case studyBatch release,© ICH, Novem

4、ber 2010,Key Steps for a product under Quality by Design (QbD),,,,Product/Process Development,Pharmaceutical Development,PQS & GMP,Local Environment,Commercial Manufacturing,Quality Unit (QP,..) level support by PQS

5、,Manage product lifecycle, including continual improvement,Design Space (DS), RTR testing,Link raw material attributes and process parameters to CQAs and perform Risk Assessment Methodology,Potential CQA (Critical Quali

6、ty Attribute) identified & CPP (Critical Process Parameters) determined,QTPP : Definition of intended use & product,Quality TargetProduct Profile,CPP : CriticalProcess Parameter,CQA : CriticalQuality Attribut

7、e,Risk Management,Opportunities,Design to meet CQA using Risk Management & experimental studies (e.g. DOE),DOE : Design of Experiment,Control Strategy,Technology Transfer,Batch ReleaseStrategy,,,Prior Knowledge (sci

8、ence, GMP, regulations, ..),,,,,Continualimprovement,,,,Product/Process Understanding,,,,QRM principle apply at any stage,,Marketing Authorisation,,Quality System PQS,© ICH, November 2010,Purpose of Case Study,Illu

9、strative exampleCovers the concepts and integrated implementation of ICH Q8, 9 and 10Not the complete content for a regulatory filingNote: this example is not intended to represent the preferred or required approac

10、h.,© ICH, November 2010,Case Study Organization,© ICH, November 2010,Basis for Development Information,Fictional active pharmaceutical ingredient (API) Drug product information is based on the ‘Sakura’ Tablet

11、case studyFull Sakura case study can be found at http://www.nihs.go.jp/drug/DrugDiv-E.html Alignment between API and drug productAPI Particle size and drug product dissolutionHydrolytic degradation and dry granulatio

12、n /direct compression,© ICH, November 2010,Organization of Content,Quality Target Product Profile (QTPP)API properties and assumptionsProcess and Drug product composition overviewInitial risk assessment of unit o

13、perationsQuality by Design assessment of selected unit operations,© ICH, November 2010,Quality attribute focus,,Technical Examples,APIDrug Product,,,Compression,Real Time Release testing(Assay, CU, Dissolution)

14、,,Blending,APICrystallization,- Final crystallization step,- Blending- Direct compression,- Particle size control,- Assay and content uniformity - Dissolution,Process focus,,© ICH, November 2010,,Process Step Ana

15、lysis,For each exampleRisk assessmentDesign of experimentsExperimental planning, execution & data analysisDesign space definitionControl strategyBatch release,Design ofExperiments,,Design Space,,Control Stra

16、tegy,,Batch Release,QRM,© ICH, November 2010,QbD Story per Unit Operation,,,,Process Variables,Design ofExperiments,QualityRisk Management,Illustrative Examples of Unit Operations:,QTPP & CQAs,,Design Space

17、,,Control Strategy,,Batch Release,,,,Compression,Real Time Release testing(Assay, CU, Dissolution),,Blending,APICrystallization,© ICH, November 2010,Introducing API and Drug Product,© ICH, November 2010,As

18、sumptions,API is designated as AmokinolSingle, neutral polymorphBiopharmaceutical Classification System (BCS) class II – low solubility & high permeabilityAPI solubility (dissolution) affected by particle sizeDeg

19、rades by hydrolytic mechanismIn vitro-in vivo correlation (IVIVC) established – allows dissolution to be used as surrogate for clinical performanceDrug product is oral immediate release tablet,© ICH, November 20

20、10,Assumptions & Prior Knowledge,API is designated as AmokinolSingle, neutral polymorphBiopharmaceutical Classification System (BCS) class II – low solubility & high permeabilityAPI solubility (dissolution) af

21、fected by particle sizeCrystallization step impacts particle sizeDegrades by hydrolytic mechanismHigher water levels and elevated temperatures will increase degradationDegradates are water soluble, so last processing

22、 removal point is the aqueous extraction stepDegradates are not rejected in the crystallization stepIn vitro-in vivo correlation (IVIVC) established – allows dissolution to be used as surrogate for clinical performance

23、Drug product is oral immediate release tablet,© ICH, November 2010,Quality Target Product Profile (QTPP) Safety and Efficacy Requirements,QTPP may evolve during lifecycle – during development and commercial m

24、anufacture - as new knowledge is gained e.g. new patient needs are identified, new technical information is obtained about the product etc.,,© ICH, November 2010,API Unit Operations,Coupling Reaction,Aqueous Extract

25、ions,Distillative Solvent Switch,Semi ContinuousCrystallization,Centrifugal Filtration,Rotary Drying,Coupling of API Starting Materials,Removes water, prepares API for crystallization step,Addition of API in solution a

26、nd anti-solvent to a seed slurry,Filtration and washing of API,Drying off crystallization solvents,Removes unreacted materials. Done cold to minimize risk of degradation,Understand formation & removal of impuriti

27、es,Example from Case Study,© ICH, November 2010,Tablet Formulation,,© ICH, November 2010,Drug Product Process,Blending,Lubrication,Compression,Film coating,,,,API and ExcipientsAmokinolD-mannitolCalcium hydr

28、ogen phosphate hydrateSodium starch glycolate,LubricantMagnesium Stearate,,,CoatingHPMC，Macrogol 6000titanium oxideiron sesquioxide,,,© ICH, November 2010,Overview of API and Drug Product Case Study Elements

29、Representative Examples from the full Case Study,© ICH, November 2010,Overall Risk Assessment for Process,Process Steps,CQA,Example from Case Study,© ICH, November 2010,Overall Risk Assessment for Process,Proce

30、ss Steps,CQA,,© ICH, November 2010,,API Semi-Continuous Crystallization,Designed to minimize hydrolytic degradation (degradate below qualified levels)Univariate experimentation exampleFMEA of crystallization proce

31、ss parametersHigh risk for temperature, feed time, water levelTest upper end of parameter ranges (represents worst case) with variation in water content only and monitor degradationProven acceptable upper limits defin

32、ed for above parametersNote that in this case study, the distillative solvent switch prior to crystallization and crystallization itself are conducted at lower temperatures and no degradation occurs in these steps,

33、9; ICH, November 2010,,API Semi-Continuous Crystallization,Designed to control particle sizeMultivariate DOE example leading to predictive modelFMEA of parameters using prior knowledgeHigh risk for addition time, % se

34、ed, temperature, agitationDOE: half fraction factorial using experimental ranges based on QTPP, operational flexibility & prior knowledgeDesign space based on predictive model obtained by statistical analysis of D

35、OE dataParticle size distribution (PSD) qualified in formulation DOE and dissolution studies,© ICH, November 2010,Risk Assessment: Particle Size Distribution (PSD) Control,,,,,To be investigatedin DOE,© ICH,

36、 November 2010,Options for Depicting a Design Space,Large square represents the ranges tested in the DOE.Red area represents points of failureGreen area represents points of success.,Oval = full design space represe

37、nted by equation Rectangle represent rangesSimple, but a portion of the design space is not utilizedCould use other rectangles within ovalExact choice of above options can be driven by business factors,For purposes

38、of this case study, an acceptable design space based on ranges was chosen,Seed wt%,© ICH, November 2010,Options for Expanding a Design Space,Why expand a Design Space?Business drivers can change, resulting in a dif

39、ferent optimum operating spaceWhen is DS Expansion possible?Case A: When the original design space was artificially constrained for simplicityCase B: When some edges of the design space are the same as edges of th

40、e knowledge space,© ICH, November 2010,API Crystallization: Design Space & Control Strategy,Control Strategy should address:Parameter controls Distillative solvent switch achieves target water contentCrystal

41、lization parameters are within the design space TestingAPI feed solution tested for water contentFinal API will be tested for hydrolysis degradate Using the predictive model, PSD does not need to be routinely tested

42、since it is consistently controlled by the process parameters,© ICH, November 2010,Design Space / Control StrategyParameter controls & Testing,Particle size will be tested in this example, since the result is i

43、ncludedin the mathematical model used for dissolution.,Example from Case Study,© ICH, November 2010,Drug Product,Immediate release tablet containing 30 mg AmokinolRationale for formulation composition and process

44、 selection providedIn vitro-in vivo correlation (IVIVC) determinationCorrelation shown between pharmacokinetic data and dissolution resultsRobust dissolution measurement neededFor a low solubility drug, close monito

45、ring is important,© ICH, November 2010,Drug Product Direct Compression Manufacturing Process,Focus of Story,Example from Case Study,Lubrication,,© ICH, November 2010,Initial Quality Risk Assessment,Impact of Fo

46、rmulation and Process unit operations on Tablet CQAs assessed using prior knowledgeAlso consider the impact of excipient characteristics on the CQAs,Example from Case Study,,,,,© ICH, November 2010,Drug Product CQA

47、 – Dissolution Summary,Quality risk assessmentHigh impact risk for API particle size, filler, lubrication and compressionFillers selected based on experimental work to confirm compatibility with Amokinol and acceptable

48、 compression and product dissolution characteristicsAPI particle size affects both bioavailability & dissolutionMultivariate DOE to determine factors that affect dissolution and extent of their impactPredictive ma

49、thematical model generatedConfirmed by comparison of results from model vs. actual dissolution testingPossible graphical representations of this design space,© ICH, November 2010,Predictive Model for DissolutionA

50、 mathematical representation of the design space,Factors include: API PSD, lubricant (magnesium stearate) specific surface area, lubrication time, tablet hardness (via compression force),Confirmation of model,Example fr

51、om Case Study,Continue model verification with dissolution testing of production material, as needed,© ICH, November 2010,Dissolution: Control Strategy,Controls of input material CQAsAPI particle sizeControl of cr

52、ystallisation stepMagnesium stearate specific surface areaSpecification for incoming materialControls of process parameter CPPsLubrication step blending time within design spaceCompression force (set for tablet hard

53、ness) within design spaceTablet press force-feedback control systemPrediction mathematical modelUse in place of dissolution testing of finished drug productPotentially allows process to be adjusted for variation (e.g

54、. in API particle size) and still assure dissolution performance,© ICH, November 2010,Drug Product CQA -Assay & Content Uniformity Summary,Quality risk assessmentPotential impact for API particle size, moistur

55、e control, blending, and lubricationMoisture will be controlled in manufacturing environmentConsider possible control strategy approachesExperimental plan to develop design space using input material and process facto

56、rsIn-process monitoringAssay assured by weight control of tablets made from uniform powder blend with acceptable API content by HPLCBlend homogeneity by on-line NIR to determine blending endpoint, includes feedback lo

57、opAPI assay in blend tested by HPLCTablet weight by automatic weight control with feedback loop,© ICH, November 2010,Blending Process Control Options,Decision on conventional vs. RTR testing,Example from Case Stud

58、y,© ICH, November 2010,Process Control Option 2 Blend uniformity monitored using a process analyser,On-line NIR spectrometer used to confirm scale up of blendingBlending operation complete when mean spectral std.

59、dev. reaches plateau regionPlateau may be detected using statistical test or rulesFeedback control to turn off blenderCompany verifies blend does not segregate downstreamAssays tablets to confirm uniformityConducts

60、studies to try to segregate API,Data analysis model will be providedPlan for updating of model available,Acknowledgement: adapted from ISPE PQLI Team,Example from Case Study,© ICH, November 2010,Conventional automa

61、ted control of Tablet Weight using feedback loop:Sample weights fed into weight control equipment which sends signal to filling mechanism on tablet machine to adjust fill volume and therefore tablet weight.,Tablet Weigh

62、t Control in Compression Operation,© ICH, November 2010,Batch Release Strategy,Finished product not tested for assay, CU and dissolution Input materials meet specifications and are testedAPI particle size distribu

63、tionMagnesium stearate specific surface areaAssay calculationVerify (API assay of blend by HPLC) X (tablet weight)Tablet weight by automatic weight control (feedback loop), %RSD of 10 tabletsContent UniformityOn-li

64、ne NIR criteria met for end of blending (blend homogeneity)Tablet weight control results checkedDissolutionPredictive model using input and process parameters calculates for each batch that dissolution meets acceptanc

65、e criteriaInput and process parameters used are within the filed design spaceCompression force is monitored for tablet hardnessWater content NMT 3% in finished product (not covered in this case study),© ICH, Nov

66、ember 2010,Drug Product Specifications,Use for stability, regulatory testing, site change, whenever RTR testing is not possibleInput materials meet specifications and are testedAPI PSDMagnesium stearate specific surfa

67、ce areaAssay calculation (drug product acceptance criteria 95-105% by HPLC)Verify (API assay of blend by HPLC) X (tablet weight)Tablet weight by automatic weight control (feedback loop)For 10 tablets per sampling poi

68、nt, <2% RSD for weightsContent Uniformity (drug product acceptance criteria meets compendia)On-line NIR criteria met for end of blending (blend homogeneity)Tablet weight control results checkedDissolution (drug pr

69、oduct acceptance criteria min 85% in 30 minutes)Predictive model using input and process parameters for each batch calculates whether dissolution meets acceptance criteriaInput and process parameters are all within the