Implementation of Quality-by-Design: OGD Initiatives

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Implementationof Quality-by-DesignOGD
Initiatives

• Lawrence Yu, PhD
• Director for Science
• Office of Generic Drugs
• Food and Drug Administration

Advisory Committee for Pharmaceutical Science
October 5, 2006
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What is Quality by Design?

• Pharmaceutical Quality by Design (QbD)
• QbD means designing and developing formulations
  and manufacturing processes to ensure predefined
  product quality
• Understanding and controlling formulation and
  manufacturing process variables affecting the
  quality of a drug product

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Question-based Review

• Question-based Review (QbR) is a general
  framework for a science and risk-based assessment
  of product quality
• QbR contains the important scientific and
  regulatory review questions to
• Comprehensively assess critical formulation and
  manufacturing process variables
• Set regulatory specifications relevant to quality
• Determine the level of risk associated with the
  manufacture and design of the product

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Questions Come First Say What You Do and Do What
You Say

• Questions guide reviewers
• Prepare a consistent and comprehensive evaluation
  of the ANDA
• Assess critical formulation manufacturing
  variables
• Questions guide industry
• Recognize issues OGD generally considers critical
  
• Direct industry toward QbD
• Questions inform readers of the review
• How QbD was used in the ANDA
• Provide the basis for a risk assessment

5
FDAs Pharmaceutical cGMP for the 21st
Century QbD Initiative
Generic Sponsor Implementing QbD in
development and manufacturing
FDA OGD Developed a Question- based Review
System that assesses sponsors QbD ANDAs
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QbR Questions Embodies QbD
What attributes should the drug product possess?
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QbR Questions Embodies QbD
How was the product designed to have these
attributes? Were alternative formulations or
mechanisms investigated? How were the excipients
selected? How was the final formulation
optimized?
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QbR Questions Embodies QbD
Unit operations, control strategy, etc.
Quality by Design
What are the unit operations in the drug product
manufacturing process? Why was the manufacturing
process selected? How are the unit operations
related to the drug product quality?
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QbR Questions Embodies QbD
How were the critical process parameters
identified, monitored, and controlled? In the
proposed scale up plan what operating parameters
will be adjusted to ensure the product meets all
in-process and final product specifications? What
evidence supports the plan to scale up the
process to commercial scale?
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Why is QbD for Generic Drugs Unique?
Biopharmaceutical properties of drugs already
known such as polymorphism, absorption, and
pharmacokinetics information
Target product quality profile well defined such
as dissolution, purity, uniformity, and stability
Extensive formulation and manufacturing
experience for many generic manufacturers
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Quality by End Product Testing
?
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Quality by Design
Clinical Relevance
Drug Substance
Unit Operations Mixing Compression Coating
Always Meet Spec
PAT
Assay Uniformity Purity Diss
Excipients
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QbD More Information to Review
Quality By Testing
Quality by Design
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Quality Assessment under Old CMC Review?

• Reviewers prepare a summary of the application
• Write deficiency letters in response to missing
  information or insufficient specifications
• No pharmaceutical development information in ANDAs

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Quality Assessment under QbR

• The QbR quality review includes
• Comprehensively evaluate sponsors Quality by
  Design
• Set regulatory specifications relevant to quality
• Determine the level of risk associated with the
  manufacture and design of the product
• Explain the reason for each deficiency

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Old CMC Review to QbR Assessment
Old
QbR
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Diagram of the ICH Common Technical Document
QOS Summary of Critical CMC Elements
Body of Data CMC Submission Package
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OGD Model QOS

• Model QOS for ER Product (1/2006)
• http //www.fda.gov/cder/ogd/
• OGD_Model_Quality_Overall_Summary.pdf
• Model QOS for IR Product (3/2006)
• http //www.fda.gov/cder/ogd/
• OGD_Model_QOS_IR_Product.pdf

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QbR Where Are We Today?

• Generic Drug Industry On Board
• GPhA Technical Committee QbR WG
• Over 35 QbR ANDAs
• Over 20 Generic Companies
• First QbR Approval
• CMC Review Time 4 months, 1 cycle
• Total Review Time 8 months

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Experience with Assessment of QbR ANDAs
Technical Advantages

• Enhanced product and review assessment
• Critical formulation and manufacturing process
  variables identified and controlled in QbR-QOS
• Insight into sponsors development plans
• Product Process Design, and Development
• Directly address the OGDs questions
• Better understanding of sponsors' rationale for
  decisions and therefore, less misunderstandings

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Experience with Assessment of QbR ANDAs
Documentation Advantages

• Primary reviewer saves time (20)
• Summary of application
• Facts finding
• Tables charts
• Chemical structures
• Specifications etc
• No transcriptional errors

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Question-based Review Progress/Communication
2004 1/2005 2/2005 6/2005 6/2005 8/2005 10/2005 1
0/2005 1/2006 1/2006 2/2006 5/2006 7/2006 9/2006 9
/2006 1/2007
FDAs cGMP Initiative and Initiation of QbR QbR
Questions drafted GPhA Technical Advisory
Committee Meeting OGD GPhA Technical Advisory
Committee Joint Meeting GPhA Technical Advisory
Committee Meeting OGD QbR White Paper OGD GPhA
Technical Advisory Committee Joint Meeting GPhA
Fall Technical Workshop ANDA Submission
Checklist Example Quality Overall Summary GPhA
Technical Advisory Committee Meeting GPhA QbR
Webcast GPhA Teleconference on Quality of QOS OGD
QbR Retreat First QbR ANDA Approval Full
implementation of QbR
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Challenges

• Quality of QOS prepared by sponsors
• Too long
• Non-critical data Multiple tables same data
• Analytical Validation USP methods
• Leaving out questions
• Inconsistencies between QOS and body of data
• OGDs Actions
• Communication
• Training first October 20, 2006

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Challenges

• Knowledge of formulation and manufacturing
  science
• Chemists
• OGDs Actions
• Recruiting
• Formulation scientists and process engineers
• Internal training
• QbR seminars and workshops
• Review papers or commentary
• External training
• Purdue NIPTE 12 review chemists attended Purdue
  NIPTE liquid and solid dosage form training

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Next Step

• Risk Assessment and Supplement Reduction
• Two opportunities for supplement reduction
• For QbR ANDAs at the time of approval
• For all ANDAs after sufficient product
  commercial manufacturing history

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Conclusions

• OGD is implementing a new pharmaceutical quality
  assessment system that
• Enhances quality of generic drugs
• Improves review quality and consistency
• Reduces review time
• Reduces supplements

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OGD QbR Initiative

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

, Brenda Arnwine, Gururaj Bykadi, James Fan,
Scott Furness, Dave Gill, Hossein Khorshidi,
Shing Hou Liu, Albert Mueller, Susan Rosencrance,
Michael Smela, Glen Smith, Ubrani Venkataram,
Naiqi Ya, Susan Zuk 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, Dominick Roselle,
Xiumei Ruan, Barbara Scott, Mouna Selvam, Aloka
Srinivasan, Guoping Sun, Neeru Takiar, Ruth
Warzala, Quan Zhang, Susan Zuk Gary Buehler,
Robert West, Rita Hassall, Helen Winkle, Keith
Webber, Mansoor Khan, Joseph Famulare, Nicholas
Buhay, Albinus D Sa, Rick Friedman, Brian
Hasselbalch