【正文】 CDER, FDA PQRI Workshop February 1, 2020 What is Quality? ? What is pharmaceutical quality? ? consistent delivery of the label performance and lack of contamination. ? operationalzed via a set of prespecified quality attributes (., 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. 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, 2020 A Systems Approach Science of Design Manufacturing Science Deliver Quality by Design State of Control amp。 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 management process Example of a CMC Regulatory Decision: Acceptability of a Post Approval Manufacturing Process Change ? Original NDA or ANDA = CMC Quality amp。D Control of excipients and other sources of ―mon cause‖ variability Reduce CGMP Risk Classification – Continuous Improvement of Quality System Tactical Online control [Design for Manufacturability] Critical Control Points Robust process endpoint Regulatory Specifications ―Design Space‖ Real –Time Release, Modular Validation Reg. CMC Approval Strategic Science of Design – Design to reduce ―Uncertainty‖ Sci. amp。 Quality Assurance Managed under The Company’s Quality System。s lifecycle ? Riskbased approaches inspectional scrutiny。 Control Specifications Product Design Intended Use Design Requirements Reliability To Deliver Design Requ