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The impact and future of physiological based PK in biopharmaceutics modeling
(PBBM) in support of drug product quality.
UMB CERSI/OPQ/SBIA Conference: Current State and Future Expectations of Translational Modeling Strategies to Support
Drug Product Development, Manufacturing Changes and Controls
September 23, 2019
Paul Seo, Ph.D.Division Director
OPQ/ONDP/Division of Biopharmaceutics
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A quality product of any kind consistently meets the expectations of the user.
Pharmaceutical Quality
www.fda.gov
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A quality product of any kind consistently meets the expectations of the user.
Pharmaceutical Quality
Drugs are no different.
www.fda.gov
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Patients expect safe and effective medicine with every dose they take.
www.fda.gov
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Pharmaceutical quality is
assuring every dose is safe and effective, free of contamination and defects.
www.fda.gov
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It is what gives patients confidence in their next dose of medicine.
www.fda.gov
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Outline• Past
– Why are we here– What have we done
• Present– What are we seeing– What are we asking– How are we doing it
• Future– Expectations– Future operational state
www.fda.gov
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Past: Why are we here today?
• Purpose of this workshop:• Follow on/continuation of UMB CERSI/FDA Conference: Dissolution and
Translational Modeling Strategies Enabling Patient-Centric Product Development, May 16, 2017
• Hope to discuss in various formats the potential pitfalls, benefits, lessons learned, and future opportunities in a safe environment as scientists
www.fda.gov
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Past: Why are we here today?• Hypothetical development situation:• Drug Discovery• Screening• Pre-Clinical Testing• IND Application• Phase I Clinical Trials• Phase II Clinical Trials• Phase III Clinical Trials• New Drug Application (NDA) /• Phase IV
www.fda.gov
Mechanistic Modeling Can
play a role at every step!
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Past: Why are we here today?• Mechanistic modeling can:
– Reduce costs
– Guide experiments
– Guide Formulation/Process Design
– Predict Outcomes
• Mechanistic modeling and Quality of Medicines (Formulation and Process):
www.fda.gov
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PBPK Modeling
www.fda.gov
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Manufacturing/Process/Formulation
Attributes can control this step!
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Dissolution: What is it?
• Dissolution is one of the only batch release tests that
monitors the rate and extent of in vitro drug release, and this test
is
often used as a surrogate to ensure consistent in vivo
performance.
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This is dissolution This is in vivo
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Simple but Effective
DISSOLUTION TESTING
Pharmaceutical Development (clinical studies/formulation
variants/dose dumping)
Stability Studies
Biowaivers
InterchangeabiliityEvaluation
Routine QC Testing
SUPAC
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Dissolution: What is it?
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• The purpose of a QC dissolution method is to detect variations during routine product manufacturing and changes during product storage that might negatively impact product performance (e.g. bioavailabilities or safety/efficacy).
• Variations may be related to API, raw materials, or other critical attributes specific to the manufacturing process.
Present: Where are we today?Dissolution as a QC Test
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• Should be discriminatory across strengths/dose• Robust yet simple such for routine testing• Able to detect problems in manufacturing (change
in CMA/CPPs)• Route of administration and therapeutic usage
must be considered• Able to reject “non-BE” batches
Present: Where are we today?Dissolution as a QC Test: Challenges
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Present: Where are we today?Dissolution as a QC Test
Three Critical
Components:
• Evaluation of
the selected
method
• Demonstration
of discriminating
ability
• Selection of
acceptance criteria
IR Products
• Setting based on overall
data (BE & exhibit
batches).
• Collection of complete
dissolution profile data
(n=12).
• The selection of spec-time
point should be where NLT
80% (Q) of drug is
dissolved.
• For slow dissolving
products, more than one
time-point value may be
needed.
ER Products:• Setting based on overall data (BE
& exhibit batches)
• Collection of complete dissolution
profile data (n=12)
• At least 3 time-points covering the
initial, middle, and final phases of
the dissolution profile
• Dissolution acceptance criteria
range for the initial and middle time
points is based on mean target
value +10%
• NLT 80% of label amount as a limit
for the last time-point.
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Setting Acceptance Criteria cont…
ER Products:• Setting based on overall data (BE & exhibit
batches).
• Collection of complete dissolution profile data
(n=12).
• At least three spec time-points covering the initial,
middle, and final phases of the dissolution profile.
• Dissolution acceptance criteria range for the initial
and middle time points is based on mean target
value +10%.
• NLT 80% of label amount as a limit for the last time-
point.
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Simple but Effective
DISSOLUTION TESTING
Pharmaceutical Development (clinical studies/formulation
variants/dose dumping)
Stability Studies
Biowaivers
InterchangeabiliityEvaluation
Routine QC Testing
SUPAC
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• Common Themes in FDA/Industry discussions:– Industry:
– “You are being too stringent/restrictive”
– “You are making us throw away good batches”
– “Lifecycle management will be difficult”
– “Dissolution is irrelevant/insensitive for our product”
– Regulators:
– “Your method is not discriminatory”
– “Your method is not clinically relevant”
– “Your method cannot ensure batches will maintain efficacy”
– Post Marketing Commitments Usage
www.fda.gov
Present: Where are we today?
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• Common Themes in FDA/Industry discussions:– Industry:
– “You are being too stringent/restrictive”
– “You are making us throw away good batches”
– “Lifecycle management will be difficult”
– “Dissolution is irrelevant/insensitive for our product”
– Regulators:
– “Your method is not discriminatory”
– “Your method is not clinically relevant”
– “Your method cannot ensure batches will maintain efficacy”
– Post Marketing Commitments Usage
www.fda.gov
Present: Where are we today?
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– Hypothetical:• Out of Specification Report
– Keep on Market or Withdraw?
• Without some ability to link specifications to in vivo disposition or PD, challenges arise
www.fda.gov
Present: Where are we today?
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•PBPK for Biopharmaceutics Purposes:
–What are we using it for?
www.fda.gov
Present: Where are we today?
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• PBPK for Biopharmaceutics Purposes:
–What are YOU using it for?
»PURPOSE should be front and center
www.fda.gov
Present: Where are we today?
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Present: Where are we today?PBPK for “traditional” Purposes in FDA Submissions
• DDI• Pediatrics• Hepatic Impairment• Renal Impairment• Pharmacogenetics• Absorption• Pregnancy• Other
PBPK for Biopharmaceutics Purposes
• Process/Formulation Changes (SUPAC)– E.g. Particle Sizing
• Dissolution Method/AC• Formulation Variants• BCS Supportive Information• Clinically Relevant Quality
Specifications • Other
www.fda.gov
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Present: Where are we today?How are we doing it?
• Issues:
– Modeling is inherently technical
– Balancing needs of multiple programs
www.fda.gov
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Present: Where are we today?How are we doing it?• Solution:
– CDER Biopharmaceutics Policy Council (MAPP 5017.4)
– Modeling Committee
www.fda.gov
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Future: Where are we going• Proliferation of model-based/supported quality
specifications• Increasing flexibility and confidence in dissolution
product testing• Increased alignment of terminologies• Hope for public recommendations in the near
future (in the form of guidance)
www.fda.gov
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Future: Where are we goingOperational expectations
• FDA’s format guidance:– Guidance for Industry: Physiologically Based
Pharmacokinetic Analyses — Format and Content Guidance for Industry (Sept 2018)
• Model Summary should clearly state the purpose of the model and uses in the regulatory dossier.
www.fda.gov
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Acknowledgements
• Shiew-mei Huang, Ph.D.
• Sandra Suarez, Ph.D.
• Yang Zhao, Ph.D.
• Banu Zolnik, Ph.D.
• ONDP and Biopharm Colleagues
• OGD & Clin Pharm Collaborators
www.fda.gov
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Thank you &
Questions?
www.fda.gov
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