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