【正文】 Subject to CGMP Inspections (nochange or variation) Maintain “State of Control” “Fisher” “Shewart” “Deming” Theory of experimental design Statistical Process Control Theory of Variation By Improving Uncertainty Management we have began a process of engineering a proactive decisions system for pharmaceutical quality ? Reactive (examples) ? Testing to document quality ? Repeating deviation and out of specification investigations ? Waiting for FDA guidance to submit ANDA demonstrating therapeutic equivalence of generic products ? Potential for multiple NDA CMC review cycles ? Waiting for FDA to approve a prior approval supplement for process optimization and continuous improvement efforts ? Fear, apprehension ? Proactive (examples) ? Quality by design and real time process controls to achieve real time release‖ ? Right First Time ? Innovative approaches for demonstrating therapeutic equivalence of generics ? Single NDA CMC review cycle ? Process optimization and continuous improvement efforts within a facilities quality system ? Ability to utilize prior knowledge ? Empowerment, recognition 。 Continuous Improvement Options Manufacturing amp。 use of advanced technologies, and the role of conformance batches in the product lifecycle. ? A focus on three fullscale production batches would fail to recognize the plete story on validation. Draft Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations Traditional goals Nontraditional goals (risk based, flexibility, robustness, scalability, continuous improvement, innovation, efficiency,….) Characteristics Complexity, uncertainty Relationships (between goals amp。 Play‖ ―Time to Market‖ + ―Production Efficiency‖ Science of Design ? Often design and development activities are carried out based on experiential knowledge, intuition and rough guidelines – difficult to municate to individuals from different backgrounds (the ―art‖ argument) ? To learn how to represent designs at a much higher level than the current descriptive ―recipe‖ format (., executed batch records, SOP’s) while rigorously documenting key constrains A Validated System ? We have begun updating our current thinking on validation ? Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to PreMarket Approval (CPG , Sec ). ? Rational experimental design and ongoing evaluation of data ? Achieving and maintaining a state of control for a process begins at the process development phase and continues throughout the mercial phase of a product39。 Tech. Integration – Continuous Learning amp。 Mode of Response Uncertainty Management System Modification QbD Flexibility Operational Root cause investigation, Efficiency, etc. – Learning to Ramp。 Yet difficult to generalize because of multi factorial aspects + lot of subjectivity Limited information in NDA/ANDA Prior knowledge within a pany and a move towards mechanistic Understanding (ICH Q8 is intended to fill this gap) G