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1、Quality by Design Approach to Formulation and Process DevelopmentCase Studies for NDA and ANDA Filings Wei-Qin (Tony) Tong, Ph.D. Teva Pharmaceuticals USATONYTONGOPTONLINE.NETAAPS/CPA CMC Workshop June 28-29, 2010Opinions expressed in this presentation are those of the speakerand do not necessarily
2、reflect the views or policies of TevaTotal Rx*Extending U.S. leadership to 35% market share18%22%30%35%Teva market shareNumber of GGx prescriptions, bnTotal marketTeva4% CAGR14% CAGR$114bn$114bn brand salesbrand sales$55bn$55bn brand salesbrand salesTevas scale provides unparalleled leverage $500m R
3、 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 to be caused, not Controlled. Philip Cosby Design and develop form
4、ulations 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)? Quality by end product testing Little or no scrutiny on product and
5、 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, “Implementation of Quality-by-Design: Question-based Review”,
6、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 Operations Mixing Compression CoatingDrug SubstanceExc
7、ipientsAssay Uniformity Impurity Metal Res Solvents Moisture DissMeet Spec? YesNo10/30 out of 10,000,000CFR 314.70 Change GuidanceQuality by End Product Testing vs. Quality by DesignVariable Starting MaterialsFixed Manufacturing ProcessVariable Finished ProductMaterial and process variability are co
8、vered by the Design SpaceVariable Starting MaterialsControllable Manufacturing ProcessConsistent Finished ProductTraditional Manufacturing Process:QbD Manufacturing Process:Critical Steps of Quality by Design (QbD) ApproachDefine Target Product Profile (TPP)Identify CQAs and CPPsEstablish Design Spa
9、ceDevelop Control StrategyContinual ImprovementSolid Dosage Form DevelopmentExcipients Formulation & Process Development (small scale)Formulation & Process Optimization (Pilot scale)Process Prevalidation and ValidationBioperformance Stability Process RobustnessDefining CPP and Design SpaceConfirming
10、 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 Space: Impact of Sc
11、ale10 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 VitroAnimalsHuman
12、 =? 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 AttributeCritical Material Attributes and Process Variables API and ExcipientsParticle size dist
13、ribution, crystal form and morphologies, hygroscopicity, LOD, surface energy. Manufacturing FacilitiesTemperature and RH control BlendingBlending time and speed, chopper speed, etc.Critical Material Attributes and Process Variables (Continued) GranulationEnd point, Binder (dry/wet), amount of binder
14、 solution and spray rate, mixer/chopper speed and time, etc. DryingInlet air (volume, temperature, and RH), load level, product initial temperature, end point, etc. CompressionCompression force, feeding mechanism, tablet speed, tooling CoatingInlet air (volume, temperature, and RH), equipment, spray
15、 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 operating range
16、s 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 establishes scientific evidence that a process is capable of consistently delivering qual
