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1、Quality by Design Approach to Formulation and Process DevelopmentCase Studies for NDA and ANDA FilingsCase Studies for NDA and ANDA Filings Wei-Qin(Tony)Tong,Ph.D.Wei-Qin(Tony)Tong,Ph.D.Teva Pharmaceuticals USA Teva Pharmaceuticals USAAAPS/CPA CMC Workshop AAPS/CPA CMC WorkshopJune 28-29,2010 June 2
2、8-29,2010Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of TevaTotal Rx*Extending U.S.leadership to 35%market share18%22%30%35%TevamarketshareNumber of GGx prescriptions,bnTotal marketTeva4%CAGR14%CAGR139 139 Paragraph IV Paragra
3、ph IV89 89 first-to-file first-to-file$114bn$114bnbrand sales brand sales216 216 ANDAs ANDAs$55bn$55bnbrand sales brand salesTevas scale providesunparalleled leverage$500m R&D investment 1,000+R&D staff Breadth of plants and technologyHow will Teva get there:PipelineWhat is Quality?Quality means doi
4、ng it right when No one is looking.Henry FordQuality is never an accident;it is always the result of high intention,sincere effort,intelligent direction and skillful execution;it represents the wise choice of many alternatives.William A.FosterQuality is not an act,it is a habit.AristotleQuality has
5、to be caused,not Controlled.Philip Cosby Design and develop formulations and manufacturing processes to ensure pre-defined product quality Understand and control formulation and manufacturing process variables affecting the quality of a drug productWhat is Pharmaceutical Quality by Design(QbD)?Quali
6、ty by end product testing Little or no scrutiny on product and process design Product specifications Little or no mechanistic understanding“Overly conservative and often irrelevant specifications”Does not adjust review to the level of scientific understandingCurrent CMC Review:IssuesLawrence Yu,“Imp
7、lementation of Quality-by-Design:Question-based Review”,42th Drug Information Association Annual Meeting,Philadelphia,2006Quality by End Product TestingLawrence Yu,“Implementation of Quality-by-Design:Question-based Review”,42th Drug Information Association Annual Meeting,Philadelphia,2006Unit Opera
8、tionsMixingCompressionCoatingDrug SubstanceExcipientsAssayUniformityImpurityMetalRes SolventsMoistureDissMeetSpec?YesNo10/30 out of 10,000,000CFR 314.70Change GuidanceQuality by End Product Testing vs.Quality by DesignVariable Starting MaterialsFixedManufacturing ProcessVariableFinished ProductMater
9、ial and process variability are covered by the Design SpaceVariable Starting MaterialsControllableManufacturing ProcessConsistentFinished ProductTraditional Manufacturing Process:QbD Manufacturing Process:Critical Steps of Quality by Design(QbD)ApproachDefine Target Product Profile(TPP)Identify CQAs
10、 and CPPsEstablish Design SpaceDevelop Control StrategyContinual ImprovementSolid Dosage Form DevelopmentExcipients Formulation&Process Development(small scale)Formulation&Process Optimization(Pilot scale)Process Prevalidation and ValidationBioperformanceStabilityProcess RobustnessDefining CPP and D
11、esign SpaceConfirming CPP and Design SpaceCQAMonitoring CPP(i.e.PAT)Drug SubstanceDesign Space Concept Design Space The multidimensional combination and interaction of input variables(e.g.material attributes)and process parameters that have been demonstrated to provide assurance of qualityDesign Spa
12、ce:Impact of Scale10 Fold=?Potential Design SpaceDesign SpaceGenerationConfirmationLawrence Yu,“Implementation of Quality-by-Design:Question-based Review”,42th Drug Information Association Annual Meeting,Philadelphia,2006Design Space:Impact of IVIVCPotential Design SpaceFinal Design SpaceIn Vitro An
13、imals Human=?In vitro performance tests Assay Uniformity Purity Dissolution In Vivo performance tests PK/PD Clinical/Therapeutical effects Specs with clinical relevanceHow Do You Judge Quality?-Critical Quality Attribute-Critical Quality AttributeCritical Material Attributes and Process Variables AP
14、I and Excipients Particle size distribution,crystal form and morphologies,hygroscopicity,LOD,surface energy.Manufacturing Facilities Temperature and RH control Blending Blending time and speed,chopper speed,etc.Critical Material Attributes and Process Variables(Continued)Granulation End point,Binder
15、(dry/wet),amount of binder solution and spray rate,mixer/chopper speed and time,etc.Drying Inlet air(volume,temperature,and RH),load level,product initial temperature,end point,etc.Compression Compression force,feeding mechanism,tablet speed,tooling Coating Inlet air(volume,temperature,and RH),equip
16、ment,spray guns,spray rate,coating solution.Process Development by QbD Understand the effect of process parameters on in process material attributes and drug product CQA Conduct risk analysis and assessment to develop risk mitigation strategies Determine critical process parameters and their operati
17、ng ranges Establish appropriate control strategy to minimize effects of both material attribute and process parameter variability on CQAs Process validation is defined by the FDAs new guideline as the collection and evaluation of data,from the process design stage throughout production,which establi
18、shes scientific evidence that a process is capable of consistently delivering quality products.Two key components:Understanding your process Ensuring it remains in a state of controlWhat is Process Validation?Validation and Filing of Design Space Process Validation needs to demonstrate:The process w
19、ill deliver a product of acceptable quality if operated within the design space The small or pilot scale systems,scale-up parameters,or models used to establish the design space accurately model the performance of the manufacturing scale process Regulatory filing would include all CPP Material attri
20、butes(i.e.those included in the design space)Process parameters with acceptable operating rangesDesign Space Creation and ValidationCharacterization RangeAcceptable RangeOperating RangeCharacterization SpaceDesign SpaceOperating SpaceAcceptableVariability inCQAsProcess CharacterizationStudiesDefine
21、Spaces&Validate in Manf.ScaleQbD Tools Process Analytical Technology(PAT):A system for designing,analyzing,and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes,with the goal of ensuring final product qu
22、ality Design of Experiments(DoE)A structured,organized method for determining the relationshipPAT and QbD PAT is an enabler of the concept of QbD:Online,inline,or at-line PAT application to monitor material attributes,critical process parameters In-line analysis means that the analyzer interface is
23、located within the process itself,in-situ,by means of a probe or through a window On-line means automated sampling off the process stream At-line means manual sampling with transport to an analyzer located in the manufacturing area Real time PAT assessments enable continuous feedback and result in i
24、mproved process robustnessCase Study:PAT to Monitor the Dryer Bowl The fluid bed drying process is monitored continuously and moisture content end point determined in read time by Near-Infrared(NIR)sensorsRathore AS et al,“Quality by Design:Industrial Case Studies on Defining and Implementing Design
25、 Space for Pharmaceutical Processes”,BioPharm International,Jan.2009FixedUpper DryerBowlNIRControllerLODComputerCase Study:PAT Applications to the Solid Dosage Form ProcessRathore AS et al,“Quality by Design:Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Process
26、es”,BioPharm International,Jan.2009 Dispersing Blending Granulation(i.e.Roller Compaction)Drying Milling Blending Compression Coating Mixing:NIR in-line monitoring of blend uniformity Granulation and milling:Laser Diffraction for particle size analysis Tabletting:NIR for at-line monitoring of ID,ass
27、ay.Fishbone Diagram:High-Shear Granulation Example Identify all variables that could affect each process step DOE Screening StudyExample:Factor Selection DOE screening study example:Process:wet granulation,fluid bed drying,blending,tabletting Final dosage form:immediate release Critical quality attr
28、ibutes(response):dissolution profile Critical process parameters(factors):Amount of binder or binder addition(wet vs.dry)High-shear mixer wet granulation water amount Drying final LOD Dried granulation milling screen Dried granulation mill type Amount of disintegrant Final blend mixing time or amoun
29、t of lubricantDOE Screening Study Example:Experiment Details DOE screening study example:Factors 7 identified Levels 2(high and low)Number of trials 11 Primary response dissolution profile Additional responses:blend uniformity RSD,final blend PSD,final blend density,tablet hardness,tablet friability
30、,assay,content uniformityQbD for ANDA Filing Current question based review contains QbD components FDA is working on examples for IR and MR QbD filing examples Question Based Review questions will be revised to incorporate QbD for generic drugs Question Based Review and QbD API Does particle size or
31、 morphic form affect solubility or flowability?Excipients What properties of the excipients can affect manufacturing and product performance?Question Based Review and QbD(Continued)Formulation How was the formulation developed and optimized?Was DoE methodology utilized to determine the critical form
32、ulation factors?Manufacturing Process What is the relationship between the properties of the formulation and the optimal manufacturing process?How are the critical process parameters identified and how are they controlled?Quality of Generic Drugs Approved generic drugs meet high quality standards an
33、d are equivalent to their reference products ANDA rejections are weighted equally to ANDA approval in OGD staff evaluations Public recognize the OGDs contribution to product quality OGD encourages industry to implement QbD2012 OGD CMC Strategic GoalsLawrence Yu,“Strategic Planning and Question Based
34、 Review”,FDA/GPhA QbD Workshop on ANDAs,May 2010Risk Assessment ExampleVaithiyalingram SR,“QbD IR Example:Process Development”,FDA/GPhA QbD Workshop on ANDA,May 2010.CPP and Control Strategy Example(Tabletting)(Tabletting)Vaithiyalingram SR,“QbD IR Example:Process Development”,FDA/GPhA QbD Workshop
35、on ANDA,May 2010.Input Criticality Control StrategyRibbon density Critical PAR:0.68-0.81Granule PSD Demonstrated Not Critical PAR:250 500 mGranule uniformity Demonstrated Not Critical PAR:4%RSDPress Geometry Not Critical FixedTooling Geometry Not Critical FixedFeeder Speed Not Critical PAR:10-18 rpm
36、Feeder Fill Depth Not Critical PAR:15-20 mmPre-Compression ForceDemonstrated Not Critical PAR:0.5-3.0 Kn Controlled based on Ribbon DensityCompression Force Critical PAR:6.8-13.5 Kn Controlled based on Ribbon DensityEjection Force Potentially Critical Fixed:0.2 kNPress Speed Demonstrated Not Critica
37、l PAR:1000-7000 TPM More and more companies are applying QbD principle to more and more products Tool and technologies required for QbD are continuously being developed and improving QbD is not just about tool and technologies,it is also about culture and philosophy.The concepts of QbD,Design Space and PAT are inherently&fundamentally linked.Successful implementation of QbD requires Management support and commitment A cross-functional collaboration and a mixture of skills and efforts from various areas of expertise Working together with the regulatorsConcluding Remarks