Transcript Document 7291137

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
Acknowledgement
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Andre Raw
Radhika Rajagopalan
Frank Holcombe
Florence Fang
Paul Schwartz
Lawrence Yu (Chair)
Robert Lionberger
Lai Ming Lee
Rashmikant Patel
Vilayat Sayeed
Richard Adams
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
– 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
 1/2005
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Receipts of ANDAs
1000
ANDAs
Employees
800
600
400
200
0
2001
4
2002
2003
2004
2005
Receipts of Supplements
4000
3500
3000
2500
2000
2001
5
2002
2003
2004
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 postapproval 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

the reviewers’ questions and guide
reviewers through the application
 eliminate unnecessary fact finding of
information such as composition,
specification, and manufacturing process, etc.
 address
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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 Questionbased 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
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Summary
Module 3: Quality
• Pharmaceutical Development; Quality by Design
Module 4: Nonclinical
Module 5: Clinical (Bioequivalence)
Benefits
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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
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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
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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
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Question-Based Review: Pharmaceutical Development
Report/Quality by Design
Robert Lionberger
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Question-Based Review: Quality Overall Summary
Andre Raw
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Question-Based Review: Impact on CMC Post-Approval Changes
Radhika Rajagopalan
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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 quality
For 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
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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?
QBR: Drug Product
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Description and Composition
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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
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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)
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Manufacture
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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.)?
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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?
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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
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Identity
 Is the specification for the identity of the drug product appropriate?
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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?
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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?
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Dissolution
 What are the dissolution methods and acceptance criteria and how
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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?
QBR: Drug Product (Continued)
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Reference Standard
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Container/Closure System
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Are there a qualification report and COA provided for the reference standard or
is this material purchased from an appropriate source?
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
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Data
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Acceptance limits
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Are all attributes that could change over time evaluated in the stability tests?
What are the acceptable limits on these attributes?
Shelf-life recommendation
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What stability data has been submitted? Has the sponsor provided stability data for the
drug product packaged in the proposed container/closure?
What is the justification of shelf life?
Is the post-approval stability protocol acceptable?
QBR: Product Development Report for
Complex Dosage Forms and NTI Drugs
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Drug Substance
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Excipients
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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
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Is there any evidence of incompatibility between the excipients and drug
substance?
Formulation
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Which properties or physical chemical characteristics of the drug
substance affect drug product performance?
What are the critical quality attributes that ensure the product will perform
as labeled?
QBR: Process Development Report
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Process Description
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Why was this manufacturing process selected for this drug product?
Were alternative unit operations investigated by process development
studies?
Critical Steps and Scale Up
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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?

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In process tests
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Were process development studies that varied starting materials or
operating parameters conducted? Were these studies sufficient to
establish a design space for process?
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?
QBR: Risk Summary
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NTI drug
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Dosage Form
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
Classified as a non-NTI drug, risk score = + 0
Classified as an NTI drug, risk score = +1
Simple Dosage Form, risk score = + 0
Other Dosage Forms and NTI drugs, risk score = + 1
Development Report
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If the sponsor submits a development report that addresses the FDA’s
questions: Risk score = + 0
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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
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Less than or equal to 2 cycles, risk score = + 0.
Greater than 2 cycles, risk score = + 1
QBR: Risk-Based Conclusion
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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
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