Defining Quality of a Pharmaceutical Product

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Defining Quality of a Pharmaceutical Product

• Janet Woodcock, M.D.
• September 17, 2003

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Common Definition of Quality

• A product or service that meets/exceeds
  customers needs

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Regulatory Context Pharmaceutical Quality

• Customer/market cant 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 dont just let
  market sort it out

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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

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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

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Regulators 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

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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

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• Another regulatory quality attribute made in
  compliance with cGMPs

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From the point of view of the customers

• An important quality metric for a pharmaceutical
  is availability

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• Issue How does surrogate fit for use relate
  to ultimate metric clinical performance?

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Relationship has several dimensions

• Qualitative
• Quantitative
• Probabilistic

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Qualitative

• What quality attributes are selected as critical
  to performance?
• How is this decided?
• Determines usefulness of surrogate

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Quantitative

• Per attribute, what is the relationship between
  values of the attribute and safety or
  effectiveness?
• Usually nonlinear, often unknown

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Graph A
Minimal Acceptable Level
Improved Safety Or Effectiveness
Content uniformity
How to set minimum acceptable level per attribute?
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Graph B
No improvement in performance
Safety Or Effectiveness
Increased rigor of attribute
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GRAPH C
Level qualified by toxicology studies
IMPROVED SAFETY
unknown
Increasing impurity level
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Graph D
NOT OK
Drug Safety
OK
Determined by Convention
Contamination by inactive metabolite
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Graph E
Safety Or Effectiveness
Other Color Ink (readable)
Right Color Ink
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• Probabilistic relationship between measurements
  or surrogate markers for attribute and medical
  performance
• a. Testing
• b. GMP Compliance

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Probabilistic Relationship Testing

• Ordinarily, dont evaluate attribute for each
  unit. Take sample and extrapolate from sample
• What is the probability that X test result will
  predict Y outcome?

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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?

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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

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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