The Science of Quality By Design

Janet Woodcock, M.D.May 19, 2004

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

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

Critical Path: Industrialization Dimension

Process Design Reliability Robustness Amenable to feedback control Human Factors [Experts will discuss!]

Quality by Design

Stipulate (postulate) key performance parameters early in development process

Design product & process to be robust for these parameters

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

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

Goal: Consistent High Quality

But if you want to design quality in – how do you define quality?

Need consensus definition – regulators and manufacturers

A Common Definition of Quality:

A product or service that meets/exceeds customer’s

needs

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

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

Who are the Customers? Primary = people who take medicine (and

their parents, caregivers, relatives, etc) or use medical devices

Secondary = overall, public has a stakehealth professionals who prescribe and dispense medicine or medical

devices

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

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

Another regulatory quality attribute: “made in compliance with cGMPs”

- Therefore -cGMP requirements should support

achieving the consensus definition of quality

From the point of view of the customers:

An important quality metric for a pharmaceutical is availability

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

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

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

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

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