Drug Release Specification: In Vivo Relevance

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Drug Release Specification In Vivo Relevance

• Ajaz S. Hussain, Ph.D.
• Deputy Director, OPS/CDER/FDA

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Outline

• The regulatory role of Bioavailability (BA) and
  Bioequivalence (BE) testing for ensuring
  therapeutic utility
• A few examples to illustrate why QbD principles
  and a quality assessment system that utilizes
  structured pharmaceutical development information
  will improve the level of quality assurance
  compared to what is achieved in current state

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The regulatory role of BA and BE

• Sec. 320.23 Basis for measuring in vivo
  bioavailability or demonstrating bioequivalence.
• Sec. 320.24 Types of evidence to measure
  bioavailability or establish bioequivalence.
• Sec. 320.22 Criteria for waiver of evidence of in
  vivo bioavailability or bioequivalence.

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Sec. 320.24 Types of evidence to measure
bioavailability or establish bioequivalence

• (a) BA may be measured or BE may be demonstrated
  by several in vivo and in vitro methods.
• FDA may require in vivo or in vitro testing, or
  both, to measure the bioavailability of a drug
  product or establish the bioequivalence of
  specific drug products.
• ..conduct BA BE testing using the most
  accurate, sensitive, and reproducible approach
  available among those set forth in paragraph (b)
  of this section.

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Sec. 320.24 (b) The following in vivo and in
vitro approaches, in descending order of
accuracy, sensitivity, and reproducibility, are
acceptable

• (1)(i) An in vivo test in humans in which the
  concentration of the active ingredient or active
  moiety, and, when appropriate, its active
  metabolite(s), in whole blood, plasma, serum, or
  other appropriate biological fluid is measured as
  a function of time or
• (ii) An in vitro test that has been correlated
  with and is predictive of human in vivo
  bioavailability data or
• (2) An in vivo test in humans in which the
  urinary excretion of the active moiety, and, ..

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Sec. 320.24..

• 3) An in vivo test in humans in which an
  appropriate acute pharmacological effect of the
  active moiety, ..measured as a function of time
  if such effect can be measured with sufficient
  accuracy, sensitivity, and reproducibility.
• .applicable to the category of dosage forms
  described in paragraph (b)(1)(i) of this section
  only when appropriate methods are not available
  for measurement of the.

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Sec. 320.24..

• (4) Well-controlled clinical trials that
  establish the safety and effectiveness of the
  drug product, for purposes of measuring
  bioavailability, or appropriately designed
  comparative clinical trials, for purposes of
  demonstrating bioequivalence.
• This approach is the least accurate, sensitive,
  and reproducible of the general approaches for
  measuring bioavailability or demonstrating
  bioequivalence.
• For dosage forms intended to deliver the active
  moiety to the bloodstream for systemic
  distribution, this approach may be considered
  acceptable only when analytical methods cannot be
  developed to permit use of one of the approaches
  outlined in paragraphs (b)(1)(i) and (b)(2) of
  this section, when the approaches described in
  paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) of
  this section are not available.

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Sec. 320.24..

• (5) A currently available in vitro test
  acceptable to FDA (usually a dissolution rate
  test) that ensures human in vivo bioavailability.
  
• (6) Any other approach deemed adequate by FDA to
  measure bioavailability or establish
  bioequivalence.
• (c) FDA may, notwithstanding prior requirements
  for measuring BA or establishing BE, require in
  vivo testing in humans of a product at any time
  if the agency has evidence that the product
• (1) May not produce therapeutic effects
  comparable to a pharmaceutical equivalent or
  alternative with which it is intended to be used
  interchangeably
• (2) May not be bioequivalent to a pharmaceutical
  equivalent or alternative with which it is
  intended to be used interchangeably or

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Quality Therapeutic Utility
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Sec. 320.22 Criteria for waiver of evidence of in
vivo BA or BE

• (b) For certain drug products, .. may be
  self-evident.
• self-evident based on other data in the
  application if the product meets one of the
  following criteria..
• (c) FDA shall waive ..of a solid oral dosage form
  (other than a delayed release or extended release
  dosage form) Drug Efficacy Study Implementation
  notice ..
• (d) ..demonstrated by evidence obtained in vitro
  in lieu of in vivo data..

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Pharmaceutical EquivalentIR Products
Food Effect Studies
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Remembering the Previous ACPS Debate (e.g., 7 May
1997)

• Individual Bioequivalence Update Mei-Ling Chen,
  Ph.D.
• Basically, the average bioequivalence approach
  focuses only on the population averages of test
  and the reference product.
• It ignores the distribution of the metric, such
  as AUC or Cmax.
• It also ignores the possible subject-by-formulatio
  n interaction.
• Another concern that the Agency has for the
  current bioequivalence criteria is that we use
  80-125 rule to all the drugs.
• The philosophy of "one size fits all" may not be
  appropriate in some of the cases, and obviously,
  it doesn't fit well for highly variable drugs or
  narrow therapeutic window drugs.
• Biopharmaceutics Classification System Update
  Ajaz Hussain, Ph.D.
• Gut feelers Vs. Blood letters ? Moving
  towards QbD mechanistic basis for regulatory
  decisions

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Bio-availability self-evident?Hussain et al.,
(AAPS 2000) Average PK-Profiles (n40)
Due to ACS restrictions on discussing specific
drugs, names of drugs available in open
literature have been blocked.
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SubjectFormulation Interaction?
Hussain et al., (AAPS 2000). Due to ACS
restrictions on discussing specific drugs, names
of drugs available in open literature have been
blocked.
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Oral Solutions Impact of excipients on absorption
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Dissolution specification without pharmaceutical
development information
Mean Dissolution Profiles (n6) Pivotal clinical
lots
Test 1
Test 2
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Discriminating test
FDA
Applicant
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An Illustrative Example A degree of uncertainty
in the overall control status

• For IR solid oral dosage forms 0.1 N HCl is a
  popular dissolution media in the US
• because the gastric fluid is acidic due to HCl
  secretion (and pH is generally assumed to be
  1-2)
• Many currently approved products of drugs that
  are weak bases (exhibit rapid dissolution in
  acidic media)
• Bioequivalence studies are conducted in normal
  health subjects (avoid any other medication while
  enrolled in the study)

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An Illustrative Example A degree of uncertainty
in the overall control status

• Under these conditions (previous slide) it is
  suggested that conformance to dissolution
  specification may not provide the high degree of
  certainty in product quality and performance we
  expect and demand of our selves
• It is the controls on critical variables (e.g.,
  drug particle size..), established appropriately,
  that may be more important in assuring quality

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Gastric pH Bioavailability
Due to ACS restrictions on discussing specific
drugs, names of drugs available in open
literature have been blocked.
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Differences between US Japan?
Due to ACS restrictions on discussing specific
drugs, names of drugs available in open
literature have been erased.
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• of achlorhydric subjects aged 50 years in
  1995-1999 was about 40, lower than that (60) in
  1984.
• bioavailability and bioequivalence studies
  should be performed
• taking into consideration the effects of gastric
  acidity on the in vivo performance of drug
  products

Is this relevant for US population? YES
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?
Quality by Design
BE?
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QbD an opportunity to better understand in vivo
relevance of product design

• To ensure an optimal and systematic control of
  critical product and process variables
• Improve regulatory assurance of product quality
• Improve available product designs?

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An Example Improve available product designs?

• DP is an antiplatelet agent that shows decreased
  oral bioavailability with increased gastric pH
  that occurs with commonly prescribed antacids.
• An ER formulation of DP that employs tartaric
  acid to improve bioavailability in the presence
  of elevated gastric pH was developed as a
  combination antiplatelet product with
  immediate-release ASP
• DP relative bioavailability was reduced 53 with
  conventional tablets compared to the composite
  buffered ER capsule in reduced gastric acid
  conditions.
• Peak DP plasma concentrations were 57 lower with
  immediate-release tablets compared to the
  composite formulation with high stomach pH.
• Substituting generic DP plus low-dose ASP may be
  less effective than the buffered DP composite
  product in patients with concomitant antacid
  therapies.

Derendorf et al .J Clin Pharmacol. 2005
Jul45(7)845-50.
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Without the benefit of pharmaceutical development
information

• Regulatory assessment and decisions focus
  primarily on dissolution test data
• Trial-n-error, historical opinions, lack of
  understanding of critical variables and sources
  of variability
• Different scientific disciplines have their own
  preference for certain test methods
• Specifications established late in the approval
  process based on limited test data
• A degree of uncertainty in the overall control
  status

Immediate release does not mean the release
profile can not be (or is not) designed and
controlled!
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A Systems Approach for ensuring BA/BE Elements
of QbD (Example)