《輝瑞制藥公司fmea培訓(xùn)課程教材(英文)》(36頁)-質(zhì)量工具-文庫吧
2025-07-14 18:27 本頁面
【正文】 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 CGMP39。s Process Validation and Quality System Deviations, Out of Specifications,... ANDA Applications: Limited Information Content (., IR Capsule) ? Generally 1biobatch ? Bioequivalence goal post 80125% ? 90 % Confidence Interval for the Test/Reference ratio for Cmax and AUC in between the goal post ? Normal healthy subjects, crossover design, fasting (and fed) conditions ? Common for all oral drugs – ., procrustean ? To cover ―worst case‖ scenarios ? If mean is 100% and 90% CI is outside 80 125 say 85 ? ? Executed batch record and master batch record (., 10X) – application mitment ? Postapproval process validation and stability mitment ? Post approval changes based on SUPACIR Demonstration of ―quality by design‖? ? Analytical data + Executed batch record + biostudy + process validation ? IQ, OQ, PQ,.. ? PQ = 3 consecutive batches in conformance ? Reduced testing – ., pendial tests ? For simple, conventional product designs works fine most of the time。 quality by design is then the prior knowledge and what ever development data is generated (held at site) Uncertainty, Variability and Risk Uncertainty? Variability? Risk? Uncertainty, Variability and Risk ? Procrustean standards have to address ―worst case‖ scenarios ? Uncertainty is not risk, currently we have no choice but to force this equality ? Uncertainty is reduced by improving knowledge ? We learn what to control and the degree of control necessary to minimize risk ? For continuous quality improvement we should focus on improving uncertainty manag
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