Topic

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Topic 2 Quality by Design and Pharmaceutical
Equivalence
ACPS Meeting May 2005

• Ajaz S. Hussain, Ph.D.
• Office of Pharmaceutical Science
• Center for Drug Evaluation and Research
• Food and Drug Administration

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From a Reactive to a Proactive Decision
System for Pharmaceutical Quality

• Reactive (examples)
• Testing to document quality
• Repeating deviation and out of specification
  investigations
• Prior Approval Supplement for process
  optimization and continuous improvement efforts
• Multiple CMC review cycles
• Procrustean approach for demonstrating
  therapeutic equivalence of generic products

• Proactive (examples)
• Quality by design and real time release
• Right First Time
• Process optimization and continuous improvement
  efforts within a facilities quality system
• Single CMC review cycle and risk-based
  specifications
• QbD approaches for demonstrating therapeutic
  equivalence of generic products

This is a journey and not a destination!
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Therapeutic Equivalence

• Drug products are considered to be therapeutic
  equivalents only if they are pharmaceutical
  equivalents and if they can be expected to have
  the same clinical effect and safety profile when
  administered to patients under the conditions
  specified in the labeling.

The Orange Book
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Pharmaceutical Equivalent

• Drug products are considered pharmaceutical
  equivalents if they contain the same active
  ingredient(s), are of the same dosage form, route
  of administration and are identical in strength
  or concentration (e.g., chlordiazepoxide
  hydrochloride, 5mg capsules).
• Pharmaceutically equivalent drug products are
  formulated to contain the same amount of active
  ingredient in the same dosage form and to meet
  the same or compendial or other applicable
  standards (i.e., strength, quality, purity, and
  identity), but they may differ in characteristics
  such as shape, scoring configuration, release
  mechanisms, packaging, excipients (including
  colors, flavors, preservatives), expiration time,
  and, within certain limits, labeling.

The Orange Book
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FDA classifies as Therapeutically Equivalent
those products

• Approved as safe and effective
• Pharmaceutical equivalents in that they
• contain identical amounts of the same active drug
  ingredient in the same dosage form and route of
  administration, and
• meet compendial or other applicable standards of
  strength, quality, purity, and identity
• are bioequivalent in that
• they do not present a known or potential
  bioequivalence problem, and they meet an
  acceptable in vitro standard, or
• if they do present such a known or potential
  problem, they are shown to meet an appropriate
  bioequivalence standard
• are adequately labeled and
• are manufactured in compliance with Current Good
  Manufacturing Practice regulations.

The Orange Book
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Components of the Challenge

• Risk-based scientific decisions on pharmaceutical
  quality
• Risk combination of the probability of
  occurrence of harm and the severity of that harm
• Uncertainty with respect to severity of harm
  and/or probability of its occurrence and their
  modulating factors (e.g., critical quality
  attributes, variability,..)

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Confounding of Uncertainty, Variability, and Risk

• Product and process development paradigm
• Approval decision Risk/Benefit ratio
• Often intrinsic safety efficacy of an NME
  confounded with its product and manufacturing
  process
• Multi-factorial aspect of pharmaceutical products
  and manufacturing processes increasing
  complexity
• Establishing constraints based on prior
  knowledge and limited development experiments
  (time and material constraints)

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The Pharmaceutical Quality Paradox

• A need exists first to untangle or de-convolute
  uncertainty variability risk and then to
  achieve a scientific (re) integration of these
  for quality decisions (e.g., regulatory
  application approval decisions). This may appear
  to be paradoxical, and it probably is without the
  concept of quality by design (QbD).

Ajaz Hussain. Process Analytical Technology A
First Step in a Journey towards the Desired
State. The Journal for Process Analytical
Technology. January 2005.
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Risk/Benefit and Quality
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In Vivo BE for Justifying Changes During
Development
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Average of BE Studies At a Major
Pharmaceutical Company
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Design is about doing things consciously
Product Performance Design specifications relia
bly and consistently deliver the
therapeutic objectives
Capability Ability to reliably
and consistently deliver the target product
design specifications
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Points to consider..

• In the context of pre/post-approval changes,
  generic drugs, and the concept of follow-on
  protein pharmaceuticals, the primary goal of a
  scientific decision framework should be to ensure
  that an approved product is expected to have the
  same clinical effect and safety profile when
  administered to patients under the conditions
  specified in the labeling
• Furthermore identifying and elimination (or
  minimizing) unnecessary human and animal testing
  are also the goals of this decision framework

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Topic 2 Premise

• A QbD approach via pharmaceutical development
  information can potentially provide an excellent
  means to address a number of challenges
  previously discussed at ACPS meetings without
  complete or satisfactory resolution for
  example
• bioequivalence of highly variable drugs,
  bio-in-equivalence criteria, pharmaceutical and
  therapeutic equivalence of locally acting drug
  products (e.g., topical drug products).
• In addition, further elaboration and extended
  application of the Biopharmaceutics
  Classifications System (BCS)-based waiver of in
  vivo bioequivalence is essentially an extension
  of Topic 1 discussions.

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Our initial thoughts Are we on the right tract?

• How can pharmaceutical development information
  help to extend the applications of BCS-based
  waiver of in vivo studies for immediate release
  products?
• How can pharmaceutical development information be
  utilized to address the challenge of highly
  variable drugs?
• Establishing therapeutic equivalence of topical
  products?