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1、Implementation of Quality-by-Design: Question-based Review Lawrence X. Yu, Ph.D. Director for Science Office of Generic Drugs Food and Drug AdministrationThe Washington PostGeneric Drugs Hit Backlog At FDA No Plans to Expand Review CapabilitiesBy Marc Kaufman Washington Post Staff Writer“ the Food a
2、nd Drug Administration has a backlog of more than 800 applications to bring new generic products to the market - an all-time high.”“Rep. Henry A. Waxman (D-Calif.), This is the time for the FDA to be ramping up its generic reviews, not to be falling so badly behind.“Saturday, February 4, 2006Receipt
3、s of ANDAs0200400600800100020012002200320042005ANDAsEmployeesReceipts of Supplements (ANDAs)200025003000350040002001200220032004The Desired State: A Mutual Goal of Industry, Society, and the RegulatorsA maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces h
4、igh-quality drug products without extensive regulatory oversightPharmaceutical Quality in the 21st Century Janet Woodcock, M.D. Deputy Commissioner for OperationsCharacteristics of Desired State Manufacturers have extensive knowledge about critical product and process parameters and quality attribut
5、es Manufacturers strive for continuous improvement FDA role: Initial verification, subsequent audit No manufacturing supplements neededPharmaceutical Quality in the 21st Century Janet Woodcock, M.D. Deputy Commissioner for OperationsCurrent CMC Review: Issues Quality by end product testing Little or
6、 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 understandingQuality by End Product TestingUnit Operations Mixing Compression CoatingAs
7、say Uniformity Impurity Metal Res Solvents Moisture DissMeet Spec?YesDrug SubstanceNo10/30 out of 10,000,000ExcipientsCFR 314.70 Change GuidanceWhy Question-based Review? Workload Number of applications is quickly growing Number of reviewers is slowly growing Each application leads to supplements Qu
8、ality FDA cGMP Initiative; Pharmaceutical Quality in the 21st Century Issues with current CMC reviewQuestion-based Review Question-based Review is a new review system for a science and risk-based assessment of product quality Contains the important scientific and regulatory review questions to Compr
9、ehensively assess critical formulation and manufacturing process variables Set regulatory specifications relevant to quality Determine the level of risk associated with the manufacture and design of the productQuestion-based Review SystemQuality by DesignQuality Overall SummaryNovel Risk AssessmentQ
10、bR QuestionsPost Approval ChangesQuestion-based Review Incorporates Quality by Design to Assure Product QualityWhat is Quality? Fitness for intended use Free of contamination and reproducibly deliver the therapeutic benefit promised in the label to the consumer (Janet Woodcock) Consumer expectation
11、Pharmaceutical Quality = (drug substance, excipients, manufacturing)How Do You Judge Quality? Quality can be evaluated by in vivo or in vitro performance tests In Vivo: PK, PD, Clinical In Vitro: Assay, Uniformity, Purity, and/or DissolutionHow Does Quality Relate to Product Performance? Quality by
12、design assures in vitro product performance In vitro product performance provides assurance of in vivo product performanceDoseQuality by DesignUnit Operations Mixing Compression CoatingAssay Uniformity Purity DissAlways Meet SpecDrug SubstancePATClinical RelevanceExcipientsWhat is Quality by Design?
13、 Pharmaceutical Quality by Design (QbD) QbD means designing and developing formulations and manufacturing processes to ensure predefined product quality Understanding and controlling formulation and manufacturing process variables affecting the quality of a drug productWhere Does Design of Quality B
14、egin? Target product quality profile Beginning drug development with the end in mind What performance is needed to get clinical benefit and meet consumer expectation Pharmaceutical Quality = (drug substance, excipients, manufacturing)What Does QbD Constitute? Define target product quality profile Th
15、e performance needed to get clinical benefit and meet consumer expectation Design and develop product and manufacturing process to meet target product quality profile Identify and control critical raw material attributes, process parameters, and sources of variability The process is monitored and adapted to produce consistent quality over timeDesign Space Design Space The multidimensional combination and interaction of input variables (eg. Material attributes) and process parameters that have been demonstrated to provide assurance of quality Design of Experiments A structured, organized m
