1. Regulatory Assessment of Quality by Design A CGMP Perspective September 17, 2003 Joseph C. Famulare Director, Division of Manufacturing and Product Quality Office of Compliance, CDER

2. Quality System “This system assures overall compliance with CGMPs and internal procedures and specifications. The system includes the quality control unit and all of its review and approval duties (e.g., change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.). It includes all product defect evaluations and evaluation of returned and salvaged drug products. See the CGMP regulation, 21 CFR 211 Subparts B, E, F, G, I, J, and K.” Compliance Program 7356.002

3. Quality Systems In other words… J. Woodcock, M.D. State of CDER September 10, 2003 • Say what you do • Do what you say • Prove it • Improve it

4. Quality By Design • What does “Building quality in” mean? • Developing a product that meets the patient’s needs • Identifying and developing appropriate specifications • Developing a process that can reliably reproduce a product meeting these specifications • Mechanism for translating process knowledge to maintain/improve state of control

5. What is a “State of Control?” • Processes are well-characterized and understood • Process checks are essentially confirmatory (ideally, rather than controlling) • Feedback loops • Feed-forward warning indicators and failure alarms • Instructions and procedures • Verification of critical operations/documentation • Immune system (detection; root cause determination; implement corrections) • Consistency Madsen, R., “Real Compliance,” PDA Journal, 2000

6. Product / Process Design • Product design • Product specifications reflect formulation, safety & efficacy knowledge • Process design • Operating parameters evolve from process development knowledge • Action limits reflect process capability knowledge • Suitable equipment & measurement tools

7. Current Drug CGMP requirements for Product / Process Design • 211.42 Design of facility • 211.63 Design of equipment • 211.100 Design of production and control procedures • 211.160 Design of laboratory controls “scientifically sound specs”

8. CGMP Quality System Materials Facilities & Equipment Production Quality Packaging & Labeling Laboratory

9. CGMP Quality System • Focus on: • Patient safety • Product quality through sound science and technology • A Quality System Approach • Management ultimately responsible for quality • Applied to design, execution, review and inspection of product and processes • The Regulatory Process • Encourages new technology to improve product quality and process control

10. CGMP Quality System • Ultimate Goal: Integrated Quality System • Integrated systems approach across design, execution, review and inspection • Increase ability to control quality within your system • Focus on critical process parameters, measurements and product performance • Documentation focuses on critical product and process parameters • Efficient, science-based inspections resulting in increased consistency

11. CGMPs for the 21st Century • Science-Based • Risk-Based • Encourage Use of Modern Technology • Modern Quality Management Techniques • Clearer Guidance • ICH Discussions • Risk Based Group • Common Technical Document (CTD) Group

12. CGMPs Quality Systems for the 21st Century:A Risk Based Approach • In the future, pharmaceutical manufacturing will need to employ…the best principles of quality management to respond to the challenges of new discoveries and ways of doing business such as individualized therapies or genetically tailored treatments.