2014 FDA/PQRI Conference on Evolving Product Quality
Bethesda, MD 09/17/2014
Current Practice and Leveraging
Scientific Advances to Change the
Post-Approval Paradigm
– FDA’s Perspective
Geoffrey Wu, Ph.D.
Office of Pharmaceutical Science/ CDER/FDA
Disclaimer
This presentation reflects the views of the author.
The findings and conclusions in this presentation
have not been formally disseminated by the Food
and Drug Administration, and should not be
construed to represent FDA’s views and policies.
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Outline
 Current practice in reviewing postapproval changes/management
 Scientific advances as leverage
 Possible future directions
 Summary
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Science- and Risk-Based Lifecycle
Management
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Principles
 Risk-based approach
 Product + Process Understanding
Critical Attributes
Critical Parameters
 Continuous Improvement
Fewer changes and supplements
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Outline
 Current practice in reviewing postapproval changes/management
 Scientific advances as leverage
 Possible future directions
 Summary
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Current Practice: (Generic) Industry
 Following the QbD paradigm to enhance
process/product understanding
 Small number of applicants still “file first
and develop later”
 Many post-approval changes reported
within the first few years of approval
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Current Practice: (Generic) Industry
G. Wu, et al. A survey of post-approval CMC changes to generic drugs. Pharmaceutical Technology March 2014
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Current Practice: FDA
R
I
S
K
PAS
CBE (30)
CBE (0)
Annual
Report
Approval
Notification (30 day wait)
Notification (no wait)
Notification after
implementation
Each year, the Agency receives:
 ~ 3,500 sANDAs (~ 10% PAS + 70% CBE-30 + 20%
CBE-0)
 ~ 1,500 sNDAs
G. Wu, et al. A survey of post-approval CMC changes to generic drugs. Pharmaceutical Technology March 2014
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Two-Step Supplement Review
 Step I: Risk assessment of the proposed
changes  proper filing category
determination
 Step II: In-depth review of the changes
together with the provided supporting
information/data/results  approval or
deficient
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Outline
 Current practice in reviewing postapproval changes/management
 Scientific advances as leverage
 Possible future directions
 Summary
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Scientific Advances to
Drive the Evolution of Product Quality





QbD philosophy
Risk management tools
Various emerging technologies
Evolving unit operations  uncharted areas
Exploration in continuous manufacturing of DS and
DP (or batch + continuous hybrid)
 Quality metrics/surveillance  to better gauge
performance
 Enhanced information/knowledge management tools
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Scientific Advances Potentially Lead to







Significant body of information in a short period of time
Better product and process design
Verified design space  more flexibility and agility
Enhanced process monitoring and control
Higher process capability
More consistent and predicable product quality
Identify good and bad players  individualized preand post-approval evaluations
 Less (major and moderate) post-approval changes
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Outline
• Current practice in reviewing postapproval changes/management
• Scientific advances to leverage
• Possible future directions
• Summary
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More Emphasis on the Linkage between
Pre- and Post-Approval Phases
 Risk profiling of CMAs, CPPs, and CQAs
during the pre-approval phase
 Such a risk profile guides post-approval
changes and pertaining risk analysis
 Post-approval change to a high risk A/P 
PAS
 So it is better to well define these A’s and P’s
during PD  more accountability
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Establish Post-Approval Surveillance
Based on Agreed Quality Metrics
Adapted from Theresa Mullin and Russ Wesdyk’s slides, May 2014
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Establish Post-Approval Surveillance
Based on Agreed Quality Metrics
Potential Quality Metrics
lot acceptance rate
Product quality complaint rate
OOS rate
Recall rate
Process capability
An objective measure of
the quality of:
 Products
 Site
 Quality systems
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Same Change, Different Filing
Categories
 Different process understanding and control 
different filing categories (e.g., reduce blending blend time with
BU monitored by in-line NIR vs. end-point testing)
Applicant
S
O
D
RPN
Category
A
4
2
2
16
CBE/AR
B
4
4
4
64
PAS
 Good standing in product/facility surveillance based
on quality metrics  more regulatory flexibility (e.g.,
determine when post-approval change can be reduced for specific
products, processes, or sites)
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Risk- and Science-Based Downgrading
Certain Post-Approval Changes
 AR Guidance (04/2014): downgraded lists of “CMC postapproval manufacturing changes previously submitted
under supplements that we have determined generally to
be of low risk to product quality”.  Can be more.
 Downgrade based on accumulated product/process
knowledge (e.g., PAS  CBE)
 Thought for the future: focus on high-risk areas and less
scrutiny/burden on low-risk areas (e.g., comparability
protocol for change management, pertaining data via AR)
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Enhanced Evaluation of ARs
 Standardize data submission
 Allow for data mining
 Employ automated risk analysis to facilitate
regulatory review
 Cross-talk to the quality surveillance platform
to assure data integrity and consistency
 Complement to present a more complete
picture of post-approval performance
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Outline
 Current practice in reviewing postapproval changes/management
 Scientific advances as leverage
 Possible future directions
 Summary
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Performance-Based Post-Approval
Paradigm with a Holistic Approach
Pre-Approval
Post-Approval Lifecycle Management
Emerging Technologies Better Enable QbD
QbD, Science- and Risk-Based Product/Process Design/Control, RbR
QbR
Report/Review of Post-Approval Changes
Quality Surveillance
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Acknowledgements
•
•
•
•
Dr. Susan Rosencrance
Dr. Andre Raw
Dr. Paul Schwartz
Dr. Daniel Peng
Thank you!
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