Question-Based Review: An Enhanced Pharmaceutical Quality Assessment System

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Question-Based Review An Enhanced
Pharmaceutical Quality Assessment System

• Lawrence X. Yu, Ph. D.
• Director for Science
• Office of Generic Drugs
• Food and Drug Administration

GPhA Fall Technical Conference, October 25, 2005
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Acknowledgement

• Andre Raw Robert Lionberger
• Radhika Rajagopalan Lai Ming Lee
• Frank Holcombe Rashmikant Patel
• Florence Fang Vilayat Sayeed
• Paul Schwartz Richard Adams
• Lawrence Yu (Chair)

Gary Buehler, Robert West, Rita Hassall, Brenda
Arnwine, Gururaj Bykadi, James Fan, Scott
Furness, Dave Gill, Shing Hou Liu, Albert
Mueller, Susan Rosencrance, Michael Smela, Glen
Smith, Ubrani Venkataram Karen Bernard, Christina
Bina, Barbara Davit, Tom Hinchliffe, Robert Iser,
Andrew Langowski, Koung Lee, MaryJane Mathews,
Yanping Pan, Susan Pittinger, Roslyn Powers,
Ramnarayan Randad, Shanaz Read, Barbara Scott,
Mouna Selvam, Aloka Srinivasan, Guoping Sun,
Neeru Takiar, Ruth Warzala, Quan Zhang, Susan
Zuk Janet Woodcock, Steven Galson, Helen Winkle,
Ajaz Hussain, Keith Webber
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Question-based Review Timetable

• 1/2005 2/2005 Question-based Review Drafted
• 3/2005 4/2005 Division Directors Discussion
• 5/2005 6/2005 Team Leaders Discussion
• 7/2005 8/2005 Reviewers Discussion
• 9/2005 1/2006 Model Pharmaceutical Development
  Report and Quality Overall Summary
• 2/2005 12/2005 Discussions with Stakeholders
  and Upper Management
• 1/2005 12/2006 Gradual Implementation
• 1/2007 Full Implementation

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Receipts of ANDAs
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Receipts of Supplements
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How to Respond?

• Need to allocate review resources
• How? According to risk!
• cGMPs for the 21st Century Initiative
• Regulatory policies and procedures are tailored
  to recognize the level of scientific knowledge
• Risk based regulatory scrutiny is associated
  with the level of scientific understanding...

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Current Review Process

• Does not adjust review to the level of scientific
  understanding
• All products (simple and complex) use the same
  approach
• All products are subject to the same
  post-approval supplements

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What is Question-based Review?

• Question-based Review is a general framework for
  a science and risk-based assessment of product
  quality
• Question-based Review contains the important
  scientific and regulatory review questions to
• Comprehensively assess critical manufacturing
  processes
• Determine the level of risk associated with the
  manufacture and design of the product

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QbR Principles

• Quality built in by design, development, and
  manufacture and confirmed by testing
• Risk-based approach to maximize economy of time,
  effort, and resources
• Preserve the best practices of current review
  system and organization
• Best available science and wide consultation to
  ensure high quality questions

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CMC Review Under QbR

• Questions guide reviewers to provide a high
  quality and comprehensive evaluation of the
  application
• Some CMC deficiencies under the current system
  are related to reviewer chemists education and
  experience
• Allow reviewers to derive bioequivalence
  inferences
• Pharmaceutical development/quality by design
  information and prior knowledge

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CMC Review Under QbR (Continued)

• The risk and science-based regulatory assessment
• Level of assessment is associated with complexity
  of drug products
• Post-approval change supplements are related to
  scientific understanding

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ANDAs Under QbR

• Common Technical Document Format
• Quality Overall Summary that will
• address the reviewers questions and guide
  reviewers through the application
• eliminate unnecessary fact finding of information
  such as composition, specification, and
  manufacturing process, etc.

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ANDAs Under QbR (Continued)

• Product Development Report that will explain
• how drug substance and formulation variables
  affect the performance of the drug product
• how the sponsor identifies the critical
  manufacturing steps, determines operating
  parameters, selects in-process tests to control
  the process, and scales up the manufacturing
  process

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ANDAs Under QbR (Continued)

• The 1999 Guidance for Industry Organization of
  an ANDA
• Does not include Quality by Design principles
• Does not provide for a QoS
• Is no longer current for the OGD Question-based
  Review

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ANDAs Under QbR (Continued)

• Future Generic Applications
• We strongly recommend that generic sponsors
  submit generic applications based on the format
  of ICH CTD, preferably, electronically
• Module 1 Administrative Information
• Module 2 Quality Overall Summary and Clinical
  Summary
• Module 3 Quality
• Pharmaceutical Development Quality by Design
• Module 4 Nonclinical
• Module 5 Clinical (Bioequivalence)

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Benefits

• Quality by design and performance-based based
  specifications assure product quality
• Risk assessment facilitates continuous
  improvement and reduces CMC supplements
• Standardized review enhances the quality of CMC
  evaluation
• QbR-based QoS assists CMC review and reduces
  review time

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Reviewer Education

• Regulatory Science Training Series
• Past training workshops
• Polymorphism, Controlled Release, Injectable Drug
  Products, Aerosols and Sprays, Impurities,
  Excipients, and Manufacturing
• Future training workshops
• Preformulation, Biopharmaceutics, Dissolution
• Process Identification, Simulation, Monitoring,
  and Control

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Communication with Stakeholders

• February 24, 2005 GPhA Technical Committee
  meeting
• June 8, 2005 GPhA Technical Steering Committee
  meeting
• June 29, 2005 GPhA Technical Meeting
• October 5, 2005 AAPS Workshop
• October 21, 2005 GPhA QbR WG Meeting
• October 25, 2005 OGD QbR Report

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Expectations

• Office of Generic Drugs
• Ask the right questions and produce a consistent,
  science and risk-based comprehensive CMC review
• Industry
• Accelerated approval of applications
• Reduced supplements
• Public
• Availability of low cost and high quality generic
  products

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OGD QbR Presentations

• Question-Based Review An Enhanced Pharmaceutical
  Quality Assessment System Lawrence Yu
• Question-Based Review Pharmaceutical
  Development Report/Quality by Design Robert
  Lionberger
• Question-Based Review Quality Overall
  Summary Andre Raw
• Question-Based Review Impact on CMC
  Post-Approval Changes Radhika Rajagopalan
• Question Answer Session Lawrence Yu and OGD
  Question-Based Review Committee

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OGD QBR (Draft)The question based
review (QBR) serves as a general framework for
the CMC assessment of ANDAs that focuses on
critical pharmaceutical attributes of product
quality. With justification, deviations or
alternate approaches to this framework can be
utilize, as necessary, to ensure the adequacy of
the assessment of product qualityFor ease of
discussion, a simple dosage form is defined as a
solution or an immediate release (IR) solid oral
dosage form.
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QBR Drug Substance

• Description and Characterization
• What are the nomenclature, molecular structure,
  molecular formula, and molecular weight?
• What are the pKa, aqueous solubility (as function
  of pH), partition coefficient, polymorphism,
  hygroscopicity, and melting points?
• Control of Drug Substance
• Appearance and Identification
• Are the specifications for appearance and
  identification appropriate?
• Assay
• Is the proposed drug substance assay limit
  acceptable?
• Is the analytical method validated and
  stability-indicating?
• Impurities and Residual Solvents
• Are all the possible impurities accounted for?
• What is the justification for the impurity
  acceptance limits?
• Are the analytical methods validated and suitable
  for their intended function?
• Additional Specifications
• Based on the review of the drug product and
  manufacturing process are specification(s)
  required on particle size, solid state form,
  moisture content, or other properties of the drug
  substance and why?
• For each additional specification What is the
  justification for the acceptance limit? Is it
  suitable for its intended function?

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QBR Drug Product

• Description and Composition
• What are the components and composition of the
  final product? What is the function of each
  excipient?
• Do any excipients exceed IIG limits in the
  context of maximum daily dose and route of
  administration?
• If product is an NTI drug or a non-simple dosage
  form
• Are there significant differences between this
  formulation and the RLD that present potential
  concerns with respect to product performance?
• Control of Excipients
• What are the specifications for the inactive
  ingredients and are they appropriate per their
  intended function?

Simple Dosage Form Either a solution or an IR
solid oral dosage form
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QBR Drug Product (Continued)

• Manufacture
• For all products
• Does the batch formula accurately reflect the
  drug product composition? If not, what are the
  differences and the justifications (e.g. potency
  adjustment, overage, excess coating solution,
  etc.)?
• If product is not a solution
• What are the key unit operations in the drug
  product manufacturing process?
• Are in-process tests identified by the sponsor
  appropriate?
• What is the difference in size between commercial
  scale and biobatch and do they use the same unit
  operations?
• If product is an NTI drug or a non-simple dosage
  form
• What are the critical steps in the manufacturing
  process?
• What are the in-process tests/controls that
  ensure each critical step is successful?
• In the proposed scale up process what operating
  conditions will be adjusted to ensure the product
  meets all in-process and final product
  specifications?
• Why do you believe the sponsor has demonstrated a
  reasonable plan to scale up the process?

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QBR Drug Product (Continued)

• Control of Drug Product
• Identity
• Is the specification for the identity of the drug
  product appropriate?
• Assay and Uniformity
• Are the proposed drug assay limits acceptable?
• Is the assay method validated and
  stability-indicating?
• How is the content uniformity evaluated? Is it
  acceptable?
• Impurities/Degradation Products
• Are the degradation products and their origins
  adequately described?
• What is the justification for the acceptance
  limits on degradation products?
• Are the analytical methods validated and suitable
  for their intended function?
• Dissolution
• What are the dissolution methods and acceptance
  criteria and how were they selected?
• What is the significant role of dissolution
  testing for this product?
• Additional Specifications
• Are there additional specifications that are
  required to ensure the product will perform as
  labeled and why?
• For each additional specification What is the
  justification for the acceptance limit? Are the
  analytical methods validated and suitable for
  their intended function?

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QBR Drug Product (Continued)

• Reference Standard
• Are there a qualification report and COA provided
  for the reference standard or is this material
  purchased from an appropriate source?
• Container/Closure System
• Has the container/closure system been used in a
  previously approved product or otherwise
  qualified for this dosage form?
• What specific container/closure attributes are
  necessary to ensure product performance?
• Drug Product Stability
• Data
• What stability data has been submitted? Has the
  sponsor provided stability data for the drug
  product packaged in the proposed
  container/closure?
• Acceptance limits
• Are all attributes that could change over time
  evaluated in the stability tests?
• What are the acceptable limits on these
  attributes?
• Shelf-life recommendation
• What is the justification of shelf life?
• Is the post-approval stability protocol
  acceptable?

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QBR Product Development Report for Complex
Dosage Forms and NTI Drugs

• Drug Substance
• Which properties or physical chemical
  characteristics of the drug substance affect drug
  product performance?
• Excipients
• Is there any evidence of incompatibility between
  the excipients and drug substance?
• Formulation
• What is the formulation intended to do?
• What mechanism does it use to accomplish this?
• Were any other formulation alternatives
  investigated and how did these perform?
• Were any formulation optimization or sensitivity
  studies carried out for variations in composition
  around the final formulation? Were these studies
  sufficient to establish a design space for
  formulation composition?
• Is the formulation design consistent with the
  dosage form classification in the label?
• Drug Product
• What are the critical quality attributes that
  ensure the product will perform as labeled?

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QBR Process Development Report

• Process Description
• Why was this manufacturing process selected for
  this drug product?
• Were alternative unit operations investigated by
  process development studies?
• Critical Steps and Scale Up
• How were the critical steps in the process
  identified?
• What are the critical process parameters for each
  critical step and how were they identified,
  monitored and/or controlled?
• Were process development studies that varied
  starting materials or operating parameters
  conducted? Were these studies sufficient to
  establish a design space for process?
• In process tests
• Why is each in process test required?
• How were the acceptance limits chosen?
• Why were the in-process tests identified as
  critical to product quality?
• What scale-up experience does the sponsor have
  with the unit operations in this process?

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QBR Risk Summary

• NTI drug
• Classified as a non-NTI drug, risk score 0
• Classified as an NTI drug, risk score 1
• Dosage Form
• Simple Dosage Form, risk score 0
• Other Dosage Forms and NTI drugs, risk score
  1
• Development Report
• If the sponsor submits a development report that
  addresses the FDAs questions Risk score 0
• Solution and IR Products Product Development
  Report
• Other Dosage Forms Product and Process
  Development Reports
• Insufficient or missing development report, risk
  score 1
• If the application is of high overall quality
• Less than or equal to 2 cycles, risk score
  0.
• Greater than 2 cycles, risk score 1

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QBR Risk-Based Conclusion

• Should the application be approved?
• What post-approval waivers/commitments are
  appropriate for this product?
• If the total risk score is less than or equal to
  1
• CBE0 and CBE30 changes may be in annual reports
• Many PAS to CBE 30
• If the total risk score is greater than 1
• All supplements should be submitted as usual