Using Manufacturing Science and Risk Management Principles to Achieve “Quality by Design”

1. Using Manufacturing Science and Risk Management Principles to Achieve “Quality by Design” PhRMA Perspective G.P.Migliaccio FDA Manufacturing Subcommittee September 17, 2003

2. Objectives • Design quality into pharmaceutical manufacturing processes. • Encourage innovation and continuous quality improvement in pharmaceutical manufacturing. • Encourage flexibility in the associated regulatory processes.

3. Key Definitions • Risk • The probability of a manufacturing event occurring and impacting fitness-for-use, factored by the potential severity of that impact.

4. Key Definitions • Manufacturing Science • The body of knowledge available for a specific product or process, including critical quality attributes and critical process parameters, process capability, manufacturing technologies, process control technologies and the quality systems infrastructure.

6. How do we develop a quantitative measure of Manufacturing Science?

7. Manufacturing Science • API • Critical attributes (physical and chemical) • Compatibility with excipients • Excipients • Critical physiochemical and biopharmaceutical attributes

8. Manufacturing Science • Drug Product Formulation • Rationale for dosage form • Formulation development • Physiochemical attributes and relationship to product quality • Performance testing

9. Manufacturing Science • Drug Product Manufacturing Process • Critical to quality manufacturing steps • Manufacturing technologies • Critical to quality process parameters • Relationship of critical to quality parameters to quality • Process control technologies • Sterilization method (if applicable)

10. Manufacturing Science • Manufacturing Facility • Quality Systems Infrastructure • Inspectional Performance

11. Manufacturing Science API Excipients DP Formulation DP Product Quality Systems Potential Metrics Process Complexity Process Robustness Process Capability Manufacturing Science Metrics

12. Defining the Level of Risk • Complexity • Lower complexity generally means lower risk. • Robustness • Higher robustness generally means lower risk. • Process Capability • Higher CPk generally means lower risk.

13. Mitigating Risk • For higher risk products and processes, advanced manufacturing and process control technologies can be used to mitigate risk. • For inherently low risk products, advanced technologies may not provide any benefit.

14. Examples of Risk Mitigation • Process automation • Isolators and closed systems • Dedicated equipment and closed systems • PAT • Vision Systems

15. Quantitative Method • An algorithm could be development to assign a Manufacturing Science Factor to any process as a relationship of: • Process complexity • Process robustness • Process capability • Risk mitigation

17. How Do We Operationalize? • Establish Three Working Groups Within PQRI: • Manufacturing Science WG • Risk Management WG • Regulatory Process (Change Management) WG

18. Manufacturing Science WG • Propose methodology for classifying process complexity and robustness. • Propose methodology for sharing knowledge on product/process understanding, complexity, robustness and capability (knowledge required to classify risk).

19. Risk Management WG • Propose Risk Assessment Model • Agree on Risk Mitigation Strategies

20. Regulatory Process WG • Develop agreement on handling of Manufacturing Science knowledge in the review process. • Propose post-approval change management requirements.

21. Benefits of Quality by Design • Enhanced quality assurance • Encourages knowledge sharing • Promotes increased process understanding (mechanistic view) • Promotes effective use of FDA and Industry resources • Facilitates innovation and continuous improvement

22. Summary • FDA and Industry support for the establishment of PQRI Working Groups is essential to operationalize Quality by Design.