1. The Science of Quality By Design Janet Woodcock, M.D. May 19, 2004

2. What Science underlies the quality of Medical Products? • Medical products must be mass produced for use in healthcare settings • Product must be designed to fulfill intended use reliably • Manufacturing process must be designed to reliably produce a consistent product • Underlying science is NOT just the medical science

3. Critical Path: Industrialization Dimension • Product Design • Material properties of components • Toxicologic properties of component • Biological properties • Feasibility of manufacture • Characterizability • Relationship of specifications to performance • Exploration of alternatives

4. Critical Path: Industrialization Dimension • Process Design • Reliability • Robustness • Amenable to feedback control • Human Factors • [Experts will discuss!]

5. Quality by Design • Stipulate (postulate) key performance parameters early in development process • Design product & process to be robust for these parameters

6. Quality by Design(cont.) • Experimentally determine sensitivity of parameters to changes in input or process or use (e.g. human factors) • Incorporate new information from clinical trials and experience

7. The Science of Quality by Design • The less you know about what is important to quality, the more factors you need to control (both regulators & manufacturers) • Scientific efforts needed to identify important factors in both product and process and then to control variability in these factors • Techniques include DOE, risk management techniques, statistical process control, FEMA, & human factors analysis

8. Goal: Consistent High Quality • But if you want to design quality in – how do you define quality? • Need consensus definition – regulators and manufacturers

9. A Common Definition of Quality: A product or service that meets/exceeds customer’s needs

10. Regulatory Context: Medical Product Quality • Customer/market can’t easily or rapidly evaluate critical attributes of performance (e.g., safety & efficacy) due to nature of products (“market failure”) • Much is at stake (life, health) so don’t just let market sort it out

11. Regulatory Context: Medical Product Quality • Therefore, by statute, FDA stands in for the customer and establishes & enforces quality standards in the realm of “clinical performance” • Clinical performance = delivery of efficacy and safety as described in the label, derived from the clinical trials • Not aesthetics, price, other consumer-defined attributes

12. Who are the Customers? • Primary = people who take medicine (and their parents, caregivers, relatives, etc) or use medical devices • Secondary = overall, public has a stake health professionals who prescribe and dispense medicine or medical devices

13. Regulator’s Definition of Quality • Outcome based – delivers clinical performance as expected • Surrogate = “fitness for use” • Regulators define “fitness for use” via standards promulgated and attributes regulated

14. A product that is “fit for use” meets its established quality attributes standards, for example • Purity • Potency/strength • Identity • Bioavailability/delivery • Labeling/packaging • Physical performance (including aspects that influence adherence and acceptability

15. Another regulatory quality attribute: “made in compliance with cGMPs” - Therefore - cGMP requirements should support achieving the consensus definition of quality

16. From the point of view of the customers: An important quality metric for a pharmaceutical is availability

17. Issue: How does surrogate “fit for use” relate to ultimate metric “clinical performance”?

18. Relationship: Fitness for use -Clinical Performance • We generally lack information except at the extremes • “Fitness-for-use” not a complete surrogate due to lack of information

19. Quality by Design: A Way Forward • Prospectively designate critical quality parameter during development (product & process) • Evaluate and refine • Create robust link between process parameter, specifications and clinical performance

20. Summary • There are key scientific disciplines relevant to the development, design and control of medical products and the processes used to manufacture them • A consensus definition of quality needs to be developed

21. Summary (cont.) • “Quality by Design” refers to making the link between the desired clinical performance parameters and the design & control parameters • The following talks give more in-depth examples of the scientific application of these principles