辉瑞质量风险管理.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Managing Pharmaceutical Quality:Risk or Uncertainty Management?,Ajaz S.Hussain,Ph.D,.,Office of Pharmaceutical Science,CDER,FDA,PQRI Workshop February 1,2005,What is Quality?,What is pharmaceutical quality?,consistent delivery of the label performance and lack of contamination.,operationalzed via a set of pre-specified quality attributes(e.g.,specifications,limits)and through the CGMP regulations.,FDA,in its quality definition,is,standing in for the customer,and it is apparent that health care practitioners and patients highly value an additional drug attribute:,product availability,Good pharmaceutical quality,represents an acceptably low risk of failing to achieve the desired clinical attributes.,http:/,Management Goals,Improving quality and ensuring availability,Optimal use of our resources,A systems approach to CMC review and CGMP investigations,Based on knowledge and process understanding,Achieving“quality by design”,Demonstrating“science of design”,Continuous learning and improvement through“manufacturing science”,An Approach for Quality Risk Connection,Concept of,Quality by Design,(QbD),Product and process performance characteristics are,scientifically designed to meet specific objectives,not merely empirically derived from performance of test batches,Characteristics important to desired performance must be derived from a,combination of prior knowledge and experimental assessment during product development,.,From this knowledge and data,a,multivariate model linking product and process measurements and desired attributes may be constructed,.,Clinical study would then be viewed as confirmatory performance testing of the model,.,Woodcock,2004,A Systems Approach,CMC Reveiw,CGMP Investigations,Science of Design,Manufacturing Science,Deliver,Quality by Design,State of Control&,Continuous Improvement,Quality can not be tested into a product;it has to be by design,“Market Standards”,Science of Design+Manufacturing Science=Quality by Design,Risk/Benefit and Quality,Harm,Acceptable,Risk/Benefit,Quality,Label,No benefit(placebo effect),Managing Pharmaceutical Quality,Quality of a new molecular entity(a potential drug),Intrinsic pharmacological&toxicological attributes,Identity,Complexity,A range of uncertainty with respect to identity of“active moiety”,purity and stability of materials used in evaluation of pharmacological and toxicological attributes(if a mixture;variability adds additional uncertainty),Variability in the extent and rate of delivery of“active moiety”to the sites of action and variability in the pharmacological&toxicological response and measurement systems further adds uncertainty,Managing Pharmaceutical Quality,Quality of a drug product,For establishing proposed therapeutic claim(label),Drug product manufactured for clinical trials,After successful demonstration of therapeutic claim(acceptable risk-to-benefit ratio),Drug product manufactured for commercial distribution,Life cycle of the product(shelf-life,exclusivity period,generic competition,post-approval changes,),Drug product manufactured at many different facilities,changes in the process,different manufactures,Uncertainty,Variability and Risk,Quality Clinical Connection,How does a product formulation and its manufacturing process impact clinical performance?,Without a clear understanding we are uncertain(lack of knowledge),In decision making there are many advantages in distinguishing between uncertainty,variability(random variation)and risk,Goals and Characteristics of a Quality Decision System:Example,Goal:,expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling,Characteristics,Uncertainty,Variability,Risk,Pharmaceutical Equivalent,Same active,identical amount,same dosage form,and route of administration.,Identity,Strength,Quality,Purity.,Compendial or other standards,Prior Knowledge(NDA),Post Approval:,Monitoring program,Such as MedWatch,Consumer Complaints,Therapeutic Inequivalence Coordinating Committee,Need for Bioequivalence Assessment,Do not present a known or potential bioequivalence problem.Acceptable,in vitro standard,Compendial Dissolution test method,Present a known or potential bio-problem.,Appropriate bioequivalence standard,90%Confidence Interval of Test/Ref ratio for rate and extent of absorption in,80-125%range,Adequately Labeled,Similarity with reference label,medication errors.,Certain differences due to changes in the manufacturer,distributor,pending exclusivity issues,or other characteristics,Manufactured in conformance to CGMPs,Process Validation and Quality System,Deviations,Out of Specifications,.,ANDA Applications:Limited Information Content(e.g.,IR Capsule),Generally 1bio-batch,Bioequivalence goal post 80-125%,90%Confidence Interval for the Test/Reference ratio for Cmax and AUC in between the goal post,Normal heal。