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Ajaz S. Hussain, Ph.D.

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Traditional Dosage form Immediate release Direct compression Wet granulation Dry granulation Buccal tablets Sub-lingual tablets Capsules Hard gelatin Soft gelatin ... – PowerPoint PPT presentation

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Title: 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

2
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?

3
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.
4
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.)

5
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.

6
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.

7
Achieving Quality by Design?
Christopher Sinko, Ph.D. Pfizer Global Research
Development
Design
8
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

9
Christopher Sinko, Ph.D. Pfizer Global Research
Development
10
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)

11
August 2000 FDA Guidance
12
BCS Applications
13
Dissolution Test Bioequivalence Risk Assessment
14
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)).
15
Appropriate Specification or Over-discrimination
All Bioequivalent to RLD
16
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
30
USP Specification
20
Log(AUC) CI 89.1 - 130.0
10
0
0
10
20
30
40
50
Cmax CI 105.3 - 164.2
Time in Minutes
17
Failure to Discriminate Between Bio-in-equivalent
Products Inappropriate Test Method?
18
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.

19
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

20
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.
21
Average of BE Studies At a Major
Pharmaceutical Company
22
In Vivo BE for Justifying Changes During
Development
23


                               Tablet Formulation
24
Is Dissolution Rate Limiting?
25
Metoprolol IR TabletsIn Vitro - In Vivo
Relationship
FDA-UMAB (931011)
26
Metoprolol IR Tablets Experimental Simulation
Data
27
(No Transcript)
28
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
29
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

30
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)

31
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

32
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

33
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?

34
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
35
Quality Risk Priority
Quality by design Systems approach
Probability of Detection
Low
Medium
High
High
3
Medium
Risk Classification
2
Low
1
36
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

37
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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