Process Analytical Technologies An Introduction

1. Process Analytical TechnologiesAn Introduction Sheila G. Magil BioProcess Technology Consultants, Inc. Presented at Interphex New York, New York March 19, 2009

2. PAT is: • A system for designing, analyzing, and controlling manufacturing through timely measurements …of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality • A mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of critical process parameters (CPP) which affect product quality attributes (CQA) • The real-time testing and adjustment based on the complete understanding of how the components and related processes  affect the final product • Nothing less than a shift in process control philosophy – replacing end of unit operation testing with continuous, or nearly so, on-line monitoring of product quality

3. QbD 21st Century GMPs PAT Goal: Well Controlled Product PAT is One Part ICH Q8, Q9, Q10, Q11 ASTM E55 Standards

4. Process Understanding Product Knowledge Product Quality Attributes Process Controls Process Parameters Product Specifications Product Design Unit operations, control strategy, etc. Process Design Desired Product Performance Dosage form, stability, formulation, etc. Process Performance Cpk, robustness, etc. Product Understanding Continuous Improvement Quality by Design PAT Process Understanding Moheb Nasr PAT and QbD • QbD means that product and process performance characteristics are scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches Utilization of increasingly sophisticated instruments and measurements • PAT provides: • Increased information on the process • Continuous learning • Identification of sources of variability • Increased understanding of which process variables effect critical product parameters

5. PAT is Process Engineering Regulatory Reform PAT Process Analytical Chemistry Manufacturing Science

6. PAT IS NOT NEW • PAT has been used by the chemical industry since WWII • Core concepts in use for decades in chemical, semi-conductor, petroleum and other manufacturing industries • Formalized with founding of CPAC in 1984 • Goal of PAC (process analytical chemistry) – supply quantitative and qualitative information about a chemical process • Initiated by the FDA as part of the 21st Century GMP initiative in 2001 with the goal of increasing productivity • Analytical in PAT includes chemical, physical microbiological, and/or mathematical analyses

7. PAT IS ALSO NOT • A fix-all • One of many tools in the process improvement toolbox • FDA requirement • Only implementable with new processes • PAT can be implemented throughout the product life-cycle • A one-way street • Research data does not need to be shared with the FDA • Can try and reject

8. Example of Historical Use of PAT • Mid 80s • Use near IR(NIR) to control fermentations • Early 90’s • Use of NIR with libraries for API • Beginning use for Drug Product manufacture • Late 90s • New technologies emerging such as Raman, acoustic, etc. • Increasingly used with Drug Product, monitoring blending or disposition of drug in tablets. • Currently • Real time monitoring of vial filing, replacing weight checks • On-line purification control

9. Specifics • Eli Lilly presented results in 2003

10. Control of feed concentration to a centrifuge for harvest Increased yield and reproducibility of unit operation Column cycle time reduction Achieved 50% reduction in cycle time Control of enzymatic reaction step Increased yield Close coupling of an ion exchange chromatography step Reduced process variability Increased throughput 10x Some Usages of PAT Reported by Lilly

11. THANK YOU! For more information, contact • Sheila G. Magil, Ph.D. • BioProcess Technology Consultants, Inc. • 289 Great Road, Suite 303 • Acton, MA 01720 • 978-266-9110 • 978-266-9152 (fax) • smagil@bioprocessconsultants.com • www.bioprocessconsultants.com