上海CMC培训QualitybyDesignApproachtoFormulationandProcessDevelopmentCaseStudiesforNDAandANDAFilings.ppt

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 TONYTONGOPTONLINE.NET 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,Extending U.S. leadership to 35% market share,18%,22%,30%,35%,Teva market share,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 provides unparalleled 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,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 Study Example: 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 evalua