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Defining Quality of a Pharmaceutical Product. Janet Woodcock, M.D. September 17, 2003. Common Definition of Quality. A product or service that meets/exceeds customer’s needs. Regulatory Context: Pharmaceutical Quality.
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Defining Quality of a Pharmaceutical Product Janet Woodcock, M.D. September 17, 2003
Common Definition of Quality A product or service that meets/exceeds customer’s needs
Regulatory Context: Pharmaceutical 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: Pharmaceutical 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) • Secondary = overall, public has a stake health professionals who prescribe and dispense medicine
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, including • 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”
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 has several dimensions: • Qualitative • Quantitative • Probabilistic
Qualitative • What quality attributes are selected as critical to performance? • How is this decided? • Determines usefulness of surrogate
Quantitative • Per attribute, what is the relationship between values of the attribute and safety or effectiveness? • Usually nonlinear, often unknown
Graph A Minimal Acceptable Level Improved Safety Or Effectiveness Content uniformity How to set minimum acceptable level per attribute?
Graph B No improvement in performance Safety Or Effectiveness Increased rigor of attribute
GRAPH C Level qualified by toxicology studies IMPROVED SAFETY unknown Increasing impurity level
Graph D NOT OK Drug Safety OK Determined by Convention % Contamination by inactive metabolite
Graph E Safety Or Effectiveness Other Color Ink (readable) Right Color Ink
Probabilistic relationship between measurements or surrogate markers for attribute and medical performance a. Testing b. GMP Compliance
Probabilistic Relationship: Testing • Ordinarily, don’t evaluate attribute for each unit. Take sample and extrapolate from sample • What is the probability that X test result will predict Y outcome?
Probabilistic Relationship: cGMP Compliance • Inspection leads to set of observations about quality practices of organization • How does set of facts [x] about cGMP compliance relate to probability of [y] outcome on safety or efficacy?
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