上海CMC培训 Quality by Design Approach to Formulation and Process Development Case Studies for NDA and ANDA Filings

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Quality by Design Approach to Formulation and Process Development,Case Studies for NDA and ANDA Filings,Wei-Qin (Tony) Tong, Ph.D.,Teva Pharmaceuticals USA,AAPS/CPA CMC Workshop,June 28-29, 2010,Opinions expressed in this presentation are those of the speaker,and do not necessarily reflect the views or policies of Teva,Total Rx*,Extending U.S. leadership to 35%,market share,18%,22%,30%,35%,Tevamarketshare,Number of GGx prescriptions, bn,Total market,Teva,4%CAGR,14%CAGR,139,Paragraph IV,89,first-to-file,$114bn,brand sales,216,ANDAs,$55bn,brand sales,Tevas scale providesunparalleled leverage,$500m,R&D investment,1,000+,R&D staff,Breadth of plants and technology,How will Teva get there: Pipeline,What is Quality?,Quality means doing it right when,No one is looking.,Henry Ford,Quality 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. Foster,Quality is not an act,it is a habit.,Aristotle,Quality has 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 product,What is Pharmaceutical Quality by Design (QbD)?,Quality 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 understanding,Current CMC Review: Issues,Lawrence Yu, “Implementation of Quality-by-Design: Question-based Review”, 42th Drug Information Association Annual Meeting, Philadelphia, 2006,Quality by End Product Testing,Lawrence Yu, “Implementation of Quality-by-Design: Question-based Review”, 42th Drug Information Association Annual Meeting, Philadelphia, 2006,Unit,Operations,Mixing,Compression,Coating,Drug Substance,Excipients,Assay,Uniformity,Impurity,Metal,Res Solvents,Moisture,Diss,Meet,Spec?,Yes,No,10/30 out of 10,000,000,CFR 314.70,Change Guidance,Quality by End Product Testing vs. Quality by Design,Variable,Starting,Materials,Fixed,Manufacturing,Process,Variable,Finished,Product,Material and process variability are covered by,the,Design Space,Variable,Starting,Materials,Controllable,Manufacturing,Process,Consistent,Finished,Product,Traditional Manufacturing Process:,QbD Manufacturing Process:,Critical Steps of Quality by Design (QbD) Approach,Define Target Product Profile (TPP),Identify CQAs and CPPs,Establish Design Space,Develop Control Strategy,Continual Improvement,Solid Dosage Form Development,Excipients,Formulation & Process Development,(small scale),Formulation & Process Optimization,(Pilot scale),Process Prevalidation and Validation,Bioperformance,Stability,Process Robustness,Defining CPP and Design Space,Confirming CPP and Design Space,CQA,Monitoring CPP (i.e. PAT),Drug Substance,Design 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 quality,Design Space: Impact of Scale,10 Fold,=,?,Potential Design Space,Design Space,Generation,Confirmation,Lawrence Yu, “Implementation of Quality-by-Design: Question-based Review”, 42th Drug Information Association Annual Meeting, Philadelphia, 2006,Design Space: Impact of IVIVC,Potential Design Space,Final Design Space,In Vitro,Animals,Human,=,?,In vitro performance tests,Assay,Uniformity,Purity,Dissolution,In Vivo performance tests,PK/PD,Clinical/Therapeutical effects,Specs with clinical relevance,How Do You Judge Quality?,- Critical Quality Attribute,Critical Material Attributes and Process Variables,API 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 (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), equipment, 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 operating 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 establishes 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 control,What is Process Validation?,Validation and Filing of Design Space,Process Validation needs to demonstrate:,The process will 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 attributes (i.e. those included in the design space),Process parameters with acceptable operating ranges,Design Space Creation and Validation,Characterization Range,Acceptable Range,Operating Range,Characterization Space,Design Space,Operating Space,Acceptable,Variability in,CQAs,Process,Characterization,Studies,Define Spaces &,Validate in Manf.,Scale,QbD 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 quality,Design of Experiments (DoE),A structured, organized method for determining the relationship,PAT 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 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 improved process robustness,Case 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) sensors,Rathore AS et al, “Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes”, BioPharm International, Jan. 2009,Fixed,Upper Dryer,Bowl,NIR,Controller,LOD,Computer,Case Study: PAT Applications to the Solid Dosage Form Process,Rathore AS et al, “Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes”, 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, assay.,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 attributes (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 amount of lubricant,DOE 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, assay, content uniformity,QbD 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 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 formulation 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 and 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 QbD,2012 OGD CMC Strategic Goals,Lawrence Yu, “Strategic Planning and Question Based Review”, FDA/GPhA QbD Workshop on ANDAs, May 2010,Risk Assessment Example,Vaithiyalingram SR, “QbD IR Example: Process Development”, FDA/GPhA QbD Workshop on ANDA, May 2010.,CPP and Control Strategy Example,(Tabletting),Vaithiyalingram SR, “QbD IR Example: Process Development”, FDA/GPhA QbD Workshop on ANDA, May 2010.,Input,Criticality,Control Strategy,Ribbon density,Critical,PAR: 0.68-0.81,Granule PSD,Demonstrated Not Critical,PAR: 250 500 m,Granule uniformity,Demonstrated Not Critical,PAR: 4% RSD,Press Geometry,Not Critical,Fixed,Tooling Geometry,Not Critical,Fixed,Feeder Speed,Not Critical,PAR: 10-18 rpm,Feeder Fill Depth,Not Critical,PAR: 15-20 mm,Pre-Compression Force,Demonstrated Not Critical,PAR: 0.5-3.0 Kn Controlled based on Ribbon Density,Compression Force,Critical,PAR: 6.8-13.5 Kn Controlled based on Ribbon Density,Ejection Force,Potentially Critical,Fixed: 0.2 kN,Press Speed,Demonstrated Not Critical,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 regulators,Concluding Remarks,