Ajaz S. Hussain, Ph.D.

1
Quality by Design Next Steps to Realize
Opportunities?

• Ajaz S. Hussain, Ph.D.
• Office of Pharmaceutical Sciences
• CDER, FDA
• 17 September 2003

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Outline

• Quality by Design (QbD)
• What is QbD from a pharmaceutical science
  perspective?
• How is/should QbD be achieved?
• When is/should QbD achieved?
• How is/should level of QbD be evaluate and
  measured?
• How should QbD communicated?
• What is the relationship between QbD and Risk?
• What are/should be the regulatory benefits of
  QbD?
• What steps should FDA take to realize the
  benefits of QbD?

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What is QbD from a pharmaceutical science
perspective?

• Traditional
• Dosage form
• Immediate release
• Direct compression
• Wet granulation
• Dry granulation
• Buccal tablets
• Sub-lingual tablets
• Capsules
• Hard gelatin
• Soft gelatin

Product Design Process Design
Design features of these conventional products
and processes have essentially been defined over
the last several decades and toady we often do
not consider these as a design issue. Thinking
or rethinking in terms of Quality by Design
offers significant opportunities.
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Dosage form Design

• A rational approach to dosage form design
  requires a complete understanding of the
  physicochemical and biopharmaceutical properties
  of the drug substance.
• DOSAGE FORM DESIGN A PHYSICOCHEMICAL APPROACH.
  Michael B. Maurin (DuPont Pharmaceuticals
  Company, Wilmington, Delaware, U.S.A.), Anwar A.
  Hussain and Lewis W. Dittert (University of
  Kentucky, Lexington, Kentucky, U.S.A.)

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MODERN TABLET FORMULATION DESIGN AND
MANUFACTURE Larry L. Augsburger and Mark J.
Zellhofer

• Tablet dosage forms have to satisfy a unique
  design compromise. The desired properties of
  rapid or controlled disintegration and
  dissolution of the primary constituent particles
  must be balanced with the manufacturability and
  esthetics of a solid compact resistant to
  mechanical attrition.
• The objective of preformulation studies is to
  develop a portfolio of information about the drug
  substance to serve as a set of parameters against
  which detailed formulation design can be carried
  out. Preformulation investigations are designed
  to identify those physicochemical properties of
  drug substances and excipients that may influence
  the formulation design, method of manufacture,
  and pharmacokinetic-biopharmaceutical properties
  of the resulting product.

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Design Features TABLET FORMULATIONLarry L.
Augsburger and Mark J. Zellhofer

• Optimal drug dissolution and, hence, availability
  from the dosage form for absorption consistent
  with intended use (i.e., immediate or extended
  release).
• Accuracy and uniformity of drug content.
• Stability, including the stability of the drug
  substance, the overall tablet formulation,
  disintegration, and the rate and extent of drug
  dissolution from the tablet for an extended
  period.
• Patient acceptability. As much as possible, the
  finished product should have an attractive
  appearance, including color, size, taste, etc.,
  as applicable, in order to maximize patent
  acceptability and encourage compliance with the
  prescribed dosing regimen.
• Manufacturability. The formulation design should
  allow for the efficient, cost-effective,
  practical production of the required batches.

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Achieving Quality by Design?
Christopher Sinko, Ph.D. Pfizer Global Research
Development
Design
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Example Attribute Bioavailability

• Objective Maximize reproducible
• Absorption mechanism (passive, active, site
  specific)
• Physico-chemical attributes (solubility,
  dissolution rate, salt selection, particle size,
  morphic form, stability of drug substance .)
• Formulation design (disintegrating agent, wetting
  agent, solubilizer, pH modifiers, absorption
  enhancers,..)
• Process design (wet/dry granulation, lubrication,
  compaction,.)
• Specifications and controls on all critical
  variables

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Christopher Sinko, Ph.D. Pfizer Global Research
Development
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Formulation Process Design

• Starting at small scale pilot clinical/prod.
• Need tools to screen/evaluate various design
  prototypes
• In Vitro Dissolution Test
• bio-studies to ensure relevance of in vitro
  dissolution test
• Relevance based on physico-chemical aspects of
  the drug and formulation
• Observations (personal)
• Often a dissolution test is used to
  screen/evaluate experimental formulations without
  sufficient considerations or verification of its
  in vivo predictability (relevance)

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August 2000 FDA Guidance
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BCS Applications
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Dissolution Test Bioequivalence Risk Assessment
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False Positives and False Negatives!!!
Test/Ref. Mean
I. J. MacGilvery. Bioequivalence A Canadian
Regulatory Perspective. In, Pharmaceutical
Bioequivalence . Eds. Welling, Tse, and Dighe.
Marcel Dekker, Inc., New York, (1992)).
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Appropriate Specification or Over-discrimination
All Bioequivalent to RLD
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Failure to Discriminate Between Bio-in-equivalent
Products Inappropriate Acceptance Criteria
Product B
110
Product B was not bioequivalent to Product A
100
90
Product A
80
70
60
Drug Dissolved
50
40
Log(AUCinf) CI 94.6 - 123.6
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USP Specification
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Log(AUC) CI 89.1 - 130.0
10
0
0
10
20
30
40
50
Cmax CI 105.3 - 164.2
Time in Minutes
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Failure to Discriminate Between Bio-in-equivalent
Products Inappropriate Test Method?
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NDA X Bioequivalent?

• Drug X (100 mg dose, volume required to dissolve
  the dose at pH 8, lowest solubility, is 230 ml,
  extent of absorption from a solution is 95)
• Weak base exhibits a sharp decline in solubility
  with increasing pH above 3
• Clinical-trial formulation Wet granulation, drug
  particle size (D50) 80 microns, lactose MCC,
  starch, Mg-stearte, silicon dioxide. Tablet
  weight 250 mg. Dissolution in 0.1 N HCl 65 in 15
  min and 100 in 20 minutes. Disintegration time
  10 minutes.

• The company wants to manufacture the product
  using direct compression.
• To-Be-Marketed formulation Direct compression,
  drug particle size (D50) 300 microns, dicalcium
  phosphate, MCC, Mg-stearate, silicon dioxide.
  Tablet weight 500 mg. Dissolution in 0.1 N HCl -
  85 in 15 min., and 95 in 20 min. Disintegration
  1 min.
• Clincal product exhibits poor dissolution in pH
  7.4 media (about 30 in 60 minutes). Data for
  T-b-M not available.

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Failure of Dissolution Tests to Signal
Bio-in-equivalence

• Inappropriate acceptance criteria
• One point specification
• Set too late
• Inappropriate test method
• media composition (pH,..)
• media volume
• hydrodynamics
• Excipients affect drug absorption
• Other reasons

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ICH Q6A DECISION TREES 7 SETTING ACCEPTANCE
CRITERIA FOR DRUG PRODUCT DISSOLUTION
What specific test conditions and acceptance
criteria are appropriate? IR
YES
Develop test conditions and acceptance
distinguish batches with unacceptable BA
dissolution significantlyaffect BA?
NO
Do changes informulation ormanufacturing
variables affect dissolution?
Are these changes controlledby another procedure
and acceptancecriterion?
YES
YES
NO
NO
Adopt appropriate test conditionsand acceptance
criteria without regard to discriminating power,
to pass clinically acceptable batches.
Adopt test conditions and acceptance criteria
which can distinguish these changes. Generally,
single point acceptance criteria are
acceptable.
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Average of BE Studies At a Major
Pharmaceutical Company
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In Vivo BE for Justifying Changes During
Development
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                               Tablet Formulation
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Is Dissolution Rate Limiting?
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Metoprolol IR TabletsIn Vitro - In Vivo
Relationship
FDA-UMAB (931011)
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Metoprolol IR Tablets Experimental Simulation
Data
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(No Transcript)
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An hypothetical case study Critical Formulation
variables?
Dissolution predominantly effected by
disintegrant level and by interaction terms
involving disintegant and dilutent and dilutent
and mg stearate.
Unpublished Data from DPQR/CDER/FDA
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What is QbD?

• Design decisions based on through formulation and
  process understanding as these relate to the
  intended use
• What is the relationship between QbD and Risk?
• Within a given quality system and for a product
  inverse relationship between level of QbD and
  Risk

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QbD Questions (Contd.)

• How is/should QbD be achieved?
• In a structured manner guided by scientific
  information/knowledge gathered during
  pre-formulation, development, scale-up, and in
  production
• When is/should QbD achieved?
• Ideally for clinical trial material (all
  major/critical aspects), fine-tune over the
  life-cycle
• How is/should level of QbD be evaluate and
  measured?
• Established relationships (preferably
  quantitative /mathematical) between product
  process variables and quality attributes (as in
  draft PAT Guidance)
• How should QbD communicated?
• As part of the original submission (e.g., CTD-Q
  P2 Pharmaceutical Development) and/or
• Post-approval (supplement or comparability
  protocol)

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QbD Questions (Contd.)

• What are/should be the regulatory benefits of
  QbD?
• Product and process specifications are based on a
  mechanistic understanding of how formulation and
  process factors affect product performance
• Risk-based regulatory approaches recognize
• the level of scientific understanding of how
  formulation and manufacturing process factors
  affect product quality and performance and
• the capability of process control strategies to
  prevent or mitigate the risk of producing a poor
  quality product
• Example Customized SUPAC SUPAC C

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What steps (is) should FDA (taking) take to
realize the benefits of QbD?

• Start to build elements of Pharmaceutical
  Development in all relevant guidance documents
  (e.g., Draft Drug Product Guidance)
• Support development of ICH guideline on
  Pharmaceutical Development
• Train FDA staff on how to evaluate the knowledge
  content of Pharmaceutical Development Reports

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What steps (is) should FDA (taking) take to
realize the benefits of QbD?

• While the ICH process on Pharmaceutical
  Development is ongoing
• Focus on SUPAC-C concept
• Work with/within the draft Comparability Protocol
  Guidance
• Is this format too restrictive?
• In addition to Comparability Protocol concept
  develop additional guidance on SUPAC-C
• Appendix to Comparability Protocol?
• Planned revisions of current SUPAC guidance?
• Independent SUPAC-C guidance?

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SUPAC-C Quality Risk Classification (based on
SUPAC and GAMP-4)
Quality by design Systems approach
Risk Likelihood
Level 3
Level 2
Impact on Quality
Level 1
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Quality Risk Priority
Quality by design Systems approach
Probability of Detection
Low
Medium
High
High
3
Medium
Risk Classification
2
Low
1
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Level of QbD Metrics

• Achievement of pre-determined product and process
  performance characteristics that are adequate for
  the intended on every batch and in an established
  cycle time
• Performance characteristics are selected or
  developed through scientific studies
• to identify target characteristics
• of all relevant sources of variability in the
  target characteristics
• to evaluate the effectiveness of testing/controls
  strategies to mitigate the risk of variability
• Metrics
• Right-first-time
• Process Time/Cycle time
• Ability to reliably predict impact of changes

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Quality by Design (QbD)

• What is QbD from a pharmaceutical science
  perspective?
• How is/should QbD be achieved?
• When is/should QbD achieved?
• How is/should level of QbD be evaluate and
  measured?
• How should QbD communicated?
• What is the relationship between QbD and Risk?
• What are/should be the regulatory benefits of
  QbD?
• What steps should FDA take to realize the
  benefits of QbD?