Implementation of Quality-by-Design (QbD) Principles in CMC Review of Generic Drugs

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Implementation of Quality-by-Design (QbD)
Principles in CMC Review of Generic Drugs

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

Advisory Committee for Pharmaceutical Science
October 26, 2005
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OGD Question-based Review System

• Why?
• How?
• And What?

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Receipts of ANDAs
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Receipts of Supplements
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cGMP Initiative Desired State Regulatory

• 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 OGD CMC Review

• One size fits all Risk is not systematically
  considered
• 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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Why Question-based Review?

• Workload
• Quality
• cGMP for 21st Century Quality by Design
• Continuous improvement of our review process

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OGD Question-based Review System

• Why?
• How?
• And What?

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cGMP Initiative Desired State Manufacturing

• 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
• An ability to effect continuous improvement and
  continuous "real time" assurance of quality

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Discussions Internally

• 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
• 2/2005 12/2005 Discussions with Stakeholders
  and Upper Management
• 9/2005 12/2006 Trial Period and Gradual
  Implementation
• 1/2007 Full Implementation

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Discussions Externally

• 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
• More

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Question-Based Review for CMC Evaluations of
ANDAs The Office of Generic Drugs (OGD) is
developing a question-based review (QbR) for the
Chemistry, Manufacturing, and Controls (CMC)
evaluation of an Abbreviated New Drug Application
(ANDA) that is focused on critical pharmaceutical
quality attributes. The QbR initiative began in
early 2005 with the development of a revised
review template and is approaching the early
implementation phase as we gain feedback through
wide internal and external discussions. The QbR
will transform the CMC review into a modern,
science and risk-based pharmaceutical quality
assessment that incorporates and implements the
concepts and principles of the FDAs
Pharmaceutical cGMPs for the 21st Century A
Risk-Based Approach and Process Analytical
Technology initiatives .. ..   August, 2005
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How is Question-based Review Developed?

• 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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OGD Question-based Review System

• Why?
• How?
• And What?

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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 formulation
  manufacturing process variables
• Determine the level of risk associated with the
  manufacture and design of the product

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What Does a CMC Reviewer do?

• Evaluates identity, strength, stability, purity,
  and quality
• Definition of Quality the drug product is free
  from contamination and will reproducibly deliver
  the therapeutic benefit promised in the label to
  the consumer (Janet Woodcock)
• Determines that the generic drug product
• is appropriately designed (a pharmaceutical
  equivalent to the brand name product)
• can be reproducibly manufactured

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Questions to Whom?

• CMC Reviewer
• Questions guide reviewers to provide a consistent
  and comprehensive evaluation of the application
• Industry
• Questions also alert the industry to what issues
  we generally consider critical in the evaluation
  of their applications

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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

• 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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CMC Review Under Question-based Review
(Continued)

• Three-tiered assessment of manufacturing
• Tier 1 applies to all dosage forms
• Tier 2 applies to dosage forms that are not
  solutions (equivalent to current practice)
• Tier 3 applies to dosage forms that are not
  solutions, IR tablets, or IR capsules

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CMC Review Under Question-based Review (Continued)

• Proposed Risk-based Scoring System
• ANDA drugs Risk score
• NTI Drugs
  1
• Complex dosage form 1
• Insufficient or missing PD reports 1
• Application of poor quality (gt 2 CMC cycles) 1

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CMC Review Under Question-based Review (Continued)

• Post-approval Change Recommendation
• Total risk score of 1 or less
• Many CBE-0 and CBE-30 changes shifted to annual
  report
• Possible to downgrade certain PAS changes to
  CBE/annual report
• Total risk score of gt1
• No change in supplement submission and review
• At the time of ANDA approval the review team will
  propose a risk assessment score for the
  application

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CMC Review Under Question-based Review (Continued)

• Risk-based Conclusion and Post-approval
  Supplements Reduction
• Should the application be approved?
• What post-approval waivers/commitments are
  appropriate for this product?
• Eliminate/ downgrade up to 80 of CMC
  supplements, and thus free up scarce review
  resources
• Allow sponsors freedom to execute changes in
  manufacturing processes for which they have
  demonstrated process understanding

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Generic Drug Applications Under Question-based
Review

• Common Technical Document Format
• Quality Overall Summary that will
• directly address the reviewers questions and
  guide reviewers through the application
• eliminate unnecessary copying of information such
  as composition, specification, and manufacturing
  process, etc., resulting in shorter review time

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Generic Drug Applications Under Question-based
Review (Continued)

• Product Development Report (Quality by Design)
  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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Generic Drug Applications Under Question-based
Review (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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Generic Drug Applications Under Question-based
Review (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 of Question-based Review

• Risk based reduction of supplements
• Science based specifications
• Consistency and transparency of review
• Efficient and timely review process

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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
• Quality by Design (OPS)
• Preformulation, Biopharmaceutics, Dissolution
• Process Identification, Simulation, Monitoring,
  and Control

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Expectations

• Office of Generic Drugs
• Ask the right questions
• Produce a concise, consistent, and comprehensive
  review
• Industry
• Consistent, science and risk-based assessment
• Accelerated approval of applications
• Reduced supplements

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OGD Question-based Review System

• Why?
• Workload, cGPM initiative, and current review
  process
• How?
• Quality by design, risk and science-based
  approach, and wide consultation
• What?
• A modern, science and risk-based pharmaceutical
  quality assessment system

More Information on Question-based
Review www.fda.gov/cder/ogd/QbR.htm
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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, Michael Smela, Glen Smith, Ubrani
Venkataram, Karen Bernard, Neeru Takiar, Roslyn
Powers, Mouna Selvam, Ramnarayan Randad, Shanaz
Read, Quan Zhang, Andrew Langowski, Susan
Rosencrance, Barbara Scott, Robert Iser, Guoping
Sun, Yanping Pan, Raman Murali, Aloka Srinivasan,
Ruth Warzala, Barbara Davit, Christina Bina,
Koung Lee, and Tom Hinchliffe