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2025-04-10 15:55本頁面
【正文】 risk of failing to achieve the desired clinical attributes. 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 bination 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, 2023 A Systems Approach 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。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。 Capable? Unstable Corrective Actions Eliminate “Special Cause” Reduce “Common Cause” Variability Frequent, Major OOS Minor, Occasional OOS Stable Capable On the Continuous Improvement Path State of Control Improving Uncertainty Management ? Demand management ? Specified and procrustean standards ? ., 90% CI 80125%, inprocess blend uniformity tests, ….. SOP’s,….. ? Pa
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