Challenges and Opportunities in Enhancement of the CMC Section of NDAs: Quality by Design

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Challenges and Opportunities in Enhancement of
the CMC Section of NDAs Quality by - Design

• Ajaz S. Hussain, Ph.D.
• Deputy Director
• Office of Pharmaceutical Science
• CDER, FDA

DIA Annual Meeting, Washington D.C., June 2004
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Background Yesterday at DIA

• Risk Based CMC Review - Moheb Nasr
• The 21st Century Initiative and the new paradigm
  for Pharmaceutical Quality
• The Desired State
• New Quality Assessment Paradigm at ONDC (under
  construction)
• Assessment conducted by interdisciplinary
  scientists (chemists, pharmacists, engineers and
  others as needed)
• Focus on critical quality attributes and their
  relevance to safety and efficacy (chemistry,
  formulations, manufacturing processes, dosage
  forms, product performance, etc.)
• Reliance on knowledge provided by firms
• Utilization of Risk-based analysis

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Opportunity

• Over the last two decades we have improved our
  ability to solve complex multi-factorial problems
• A systems approach to development
  pre-formulation, formulation development, and
  clinical relevance
• Multivariate empirical methods (e.g., Response
  Surface Methods)
• New measurement and information technologies
• Measurements that can predict performance
• Such information is often filtered out of
  regulatory submissions
• fear or regulatory uncertinty
• ICH Q8 can open the door for sharing and
  utilizing this information

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Opportunity

• For companies that acquire extensive
  understanding about their product and
  manufacturing process and share this with the
  regulators
• Enhanced science and risk-based regulatory
  quality assessment will be possible
• Setting specifications
• Reduction in the volume of data to be submitted
  replaced by more knowledge based submissions
• Flexible post approval continuous improvement

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Janet Woodcock, M.D. May 19, 2004
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Desired State
http//www.fda.gov/cder/gmp/21stcenturysummary.htm

• Product quality and performance achieved and
  assured by design of effective and efficient
  manufacturing processes
• Product specifications based on mechanistic
  understanding of how formulation and process
  factors impact product performance
• Continuous "real time" assurance of quality

ICH Q8 agreed Desired State
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What do we wish to accomplish with ICH Q8

• Ensure Q8 facilitates movement towards the
  desired state we have articulated
• This will
• Help us better understand the proposed product
  and process design and its relation to the
  intended use
• improve process of establishing regulatory
  specifications
• Improve our ability to identify and understand
  critical product and process factors
• improve our understanding and confidence in risk
  mitigation strategies
• Allow us to utilize risk based approaches and
  recognize good science and facilitate continuous
  improvement
• Improve communication and systems thinking
• More efficient review and inspection process
• Be a win win win for public health, regulators
  and industry

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ICH Q8 Integrating QbD and Risk Mitigation
Dimensions
Illustrative Examples of points to consider
Development Objectives
Risks to Quality Risk of incorrect identity Poor
product process Changes in clinical trial
product (Bridging studies) Inadequate Design
Specifications (e.g., TDS adhesive
attribute) Critical to quality and
performance? Risk of unqualified impurities Risk
of poor bioavailability Risk of incorrect expiry
date Risk of inadequate controls Risks After
Approval Risk of SUPAC,.. Risk of
unrepresentative test samples Risk of
Inadequate Facility and QS
Tests Controls -Risk Mitigation
ICH Q9
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CTD-P2 Sec. QbD and Risk
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Continuous Improvement Emerging ICH Q8 Design
Space Concept

• Multi-dimensional space defined by critical
  vectors of product quality and performance
• Examples of critical vectors
• Robust manufacturing process consistent,
  reproducible delivery of product meeting its
  specifications
• Manufacturing options
• Stability (shelf-life) and
• Bioavailability

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What could/should be the ICH Q8 Design Space
Concept?

• Within this space, available knowledge (derived
  from established scientific literature, in-house
  experiments from previous and current projects)
  provides a basis for reliable (degree of
  reliability can be linked to risk based
  decisions) estimation and/or prediction of
• manufacturing process capability,
• stability and
• bioavailability

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More on the Design Space Concept

• This knowledge (preferably quantitative e.g.,
  a valid multivariate mathematical model) is
  utilized to identify and define formulation and
  manufacturing factors ranges that provide
  acceptable product quality and performance
• Regulatory assessment and utility for
  establishing specifications and controls (wider
  range than the current approach)
• Manufacturing options (e.g., process, equipment
  scale, etc.), parameters within this space should
  not require prior review/approval and should be
  addressed within a companies quality system and
  subject to CGMP inspections
• Change the change to Continuous Improvement

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Data based decisions No Generalization
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Knowledge based decisions Improved Ability to
Generalize
Pharmaceutical Development Knowledge
raw material properties
process conditions
environmental
Robust process Stable and Bioavailable product
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cGMP regulatory oversight
ICH Q8
Companys Quality system
Risk
Process Understanding
Post approval change
CMC regulatory oversight
ICH Q89
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ICH Q8 Q9
Proposed ICH Q 10
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To illustrate the current state A Case Study
Dissolution Attribute The case study attempts
to connect many dots
Dissolution
Desired State
1
Current State
ICH Q6A
4
ICH Q8
2
BCS
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3
BA/BE
Desired State
Testing to Document Quality
SUPAC
Quality By Design
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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
How?
What?
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
Why?
YES
Why?
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.
Why?
How do we currently establish dissolution
specifications
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Without adequate product and process development
and/or knowledge sharing

• Without design consideration, high level of
  uncertainty with respect to critical attributes,
  representative test sample, and adequacy of
  risk coverage (e.g., compendail tests) to assure
  batch quality Regulatory Concern/Risk
• Reduce concern/risk by covering all apparent
  attributes with acceptance criteria based on
  capability of test methods and/or manufacturing
  process plus very inflexible SOPs Current
  Regulatory Risk Mitigation Strategy

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Without adequate product development and/or
knowledge sharing we debate frequently
And then, have CGMP problems?
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A Warning Letter
This can be catastrophic for the business and
availability of Important drugs
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OOS or Exceptions Further Increase Cycle Times
(Source G. K. Raju, M.I.T.FDA Science Board
Meeting, November 16, 2001)
Dissolution
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Testing to Document Quality Requires Less
Variable Test Methods

• The current USP 10-mg Prednisone Calibrator
  Tablets exhibit slower dissolution over time
• If the acceptable test equipment calibration
  limit is 28-54 what can we say about use of f2
  criteria (mean profile difference of 10) as a
  way to document unchanged quality (e.g., SUPAC)?

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Dissolution Experience at the FDA Division of
Pharmaceutical Analysis

• Dissolution testing with USP Apparatus 1 and 2
  requires diligent attention to details
  mechanical and chemical
• Dosage forms can respond differently to small
  variations in apparatus set up or degassing
• Large differences in dissolution results are
  possible unless all parameters are carefully
  controlled
• The experience at DPA indicates that differences
  in reproducibility can often be traced to
  improper mechanical calibration and/or degassing

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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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Do we need a dissolution specification of every
solid oral drug product? No ICH Q6A Decision
Tree 7 (1)
Establish drug release acceptance criteria ER
Multiple time point MR Two stage, parallel or
sequential
Modified release?
Yes
No
High solubility?
No
Yes
Rapid dissolution?
Generally single-point dissolution acceptance
criteria with a lower limit
No
How? Test Test Comparison?
No
Yes
Relationship between Disintegration - Dissolution?
Generally disintegration acceptance criteria
with an upper limit
Yes
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Disintegration - Dissolution Relationship
10 screen
Fraction dissolved
Note Disintegration and dissolution process in a
dissolution apparatus may differ from that in a
disintegration apparatus (different hydrodynamics
and other conditions)
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Testing to Document Quality

• The phrase has many dimensions
• In-process and end-product release and stability
  testing
• Reliability of specifications (attribute, test
  method, and acceptance criteria)
• Managing post approval changes/continuous
  improvement (e.g., reduce variability, improve
  efficiency,..)
• Product and process knowledge acquisition and
  generalization

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How can pharmaceutical development knowledge help?

• Demonstrate quality was designed in?
• Specifications based on mechanistic
  understanding?
• Continuous "real time" assurance of quality?
• Flexible continuous improvement?

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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
Clin. Pharm. What?
Product Design (Postulate - Confirmed Based on
mechanism and/or empirically)
YES
Develop test conditions and acceptance
distinguish batches with unacceptable BA
dissolution significantlyaffect BA?
Design of Manufacturing and Controls How
(reliable)?
NO
Do changes informulation ormanufacturing
variables affect dissolution?
Are these changes controlledby another procedure
and acceptancecriterion?
YES
So what?
Overall Risk-based CMC Why?
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.
Overall CMC Systems approach (e.g., link to
morphic form, particle size, stability failure
mechanisms) CMC Why? Then How?
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Based on Quality of Pharmaceutical Development
Knowledge can we not evaluate

• Overall CMC Systems approach (e.g., link to
  morphic form, particle size, stability failure
  mechanisms) and address concerns and risks
• Is a dissolution specification needed?
• Instead of wet dissolution test, can we use
  disintegration test?
• Real time release and stability based on process
  controls, and NIR test for capsules?

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Not all information mandatory

• We are okay with this
• But we wish to avoid confusion and the potential
  vocabulary that may evolve from this two
  different systems
• Instead we see this as one system with different
  levels of QbD
• we will use the process understanding
  predictive ability vocabulary as a means to
  create a continuous framework and avoid two
  different systems

March 2004 ICH Q8 Meeting FDAs Goals
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Challenges we face

• Common approach to, and more clear articulation
  of
• Not all information mandatory
• Improved process understanding and control
  technologies may be afforded reductions in
  regulatory requirements
• An inverse relation is expected between the
  effectiveness of the Quality by Design and the
  risk to a patient being exposed to product that
  is not fit for use
• Ensuring continuous improvement and a process for
  continuous learning and updating of the knowledge
  base

March 2004 ICH Q8 Meeting FDAs Goals