1. Office of Pharmaceutical Science, CDER, FDA
ACPS Process Analytical Technology (PAT) Subcommittee Meeting #3 Opening Remarks
Ajaz S. Hussain, Ph.D.
Deputy Director
Office of Pharmaceutical Science, CDER, FDA

2. Outline Update on FDA progress
PAT Team
Blend uniformity and its link to PAT
Manufacturing Subcommittee
What have learned from the PAT Subcommittee discussions?
PAT Conceptual framework and regulatory incentives
What information are we seeking today?

3. Progress Report PAT Review - Inspection team assembled
ORA, CDER, and CVM
Successful team-building meeting
Training curriculum developed and contracts established (Univ. Washington (CPAC), Univ. Tennessee (MCEC), and Univ. Purdue)
PAT Policy Development Team
Successful recruitment
PAT Research
Publications and presentations

4. PAT-Review & Inspection Team: ORA, CDER & CVM
PAT Steering Committee
Doug Ellsworth, ORA/FDA
Dennis Bensley, CVM/FDA
Mike Olson, ORA/FDA
Joe Famulare, CDER/FDA
Yuan-yuan Chiu, CDER/FDA
Frank Holcomb, CDER/FDA
Moheb Nasr, CDER/FDA
Ajaz Hussain Chair, CDER/FDA
PAT Review - Inspection Team
Investigators:
Robert Coleman (ORA/ATL-DO)
Rebecca Rodriguez (SJN-DO)
Erin McCaffery (NWJ-DO)
George Pyramides (PHI-DO)
Compliance Officers:
Albinus D’Sa (CDER)
Mike Gavini (CDER)
William Bargo (CVM)
Reviewers:
Norman Schmuff (CDER)
Lorenzo Rocca (CDER)
Vibhakar Shah (CDER)
Rosario D’Costa (CDER)
Raafat Fahmy (CVM)
PAT Policy Development Team
Raj Uppoor, OPS/CDER
Chris Watts, OPS/CDER
Huiquan Wu, OPS/CDER
PAT Training Coordinators
John Simmons, Karen Bernard
and Kathy Jordan

6. Lyon, et al. Near-Infrared Spectral Imaging for Quality Assurance
of Pharmaceutical Products: Analysis of Tablets to
Assess Powder Blend Homogeneity
AAPS PharmSciTech 2002; 3 (3) article 17

7. Blend Uniformity & PAT Univariate Testing to Document Quality Approach
Traditional test
methods
Current PQRI proposal
and draft Guidance
Draft Guidance may
include information on
the use of NIR methods
At-line
test methods
On- and/or At-line
test methods
for all critical
components and
processes
Proposed PAT Guidance
Incentive?
Higher efficiency
Lower “risk” leading to
lower regulatory concern
Multivariate
Quality-by
Design
Approach

8. Manufacturing Subcommittee
Provide input/advice to CDER/FDA
Science based CMC and cGMP policy development
Continued development of the PAT initiative
cGMP for the 21st Century: A Risk Based Approach

9. Manufacturing Subcommittee
Modeled after the PAT Subcommittee
Core membership based on expertise in manufacturing and quality assurance
Some members of the PAT subcommittee will be invited to participate (sunset PAT Subcommittee)
Focused working groups or fact finding groups (sunset after assignment is completed)

10. In-put from ACPS PAT-Subcommittee
Conceptual framework on PAT
Emerging regulatory incentives for PAT
Research exemption
Risk based regulatory focus, opportunity to reduce regulatory burden
PAT as a part of, and a example of, the new FDA wide initiative “cGMP for the 21st Century”

11. PAT: Conceptual Framework
Incoming
Materials.
Specifications
Relevant to
“Process-ability”
Incoming material attributes
used to predict/adjust
optimal processing parameters
within established bounds
(more flexible bounds)
PAC
PCCP LT CM IT
Direct or inferential
assessment of quality
and performance (at/on-line)
Control of process critical
control points (PCCP).
Process end point (PEPs’) range
based on “performance” attributes.
PEP’s
Chemometrics (CM)
and IT Tools
for “real time”
control and decisions
At-line
In/On-Line
Process Analytical
Chemistry Tools
Laboratory
or other
tests
Development/Optimization/Continuous Improvement
(DOE, Evolutionary optimization, Improved efficiency)
Multivariate
Systems
Approach
Risk
Classification
and
Mitigation
Strategies

12. Taking Advantage of Built-in Redundancy?
General
Quality
System
Product specific
SOP’s,...
PAT Based
Measurements
and Controls
Systems Approach
Validation
Taking Advantage of Built-in Redundancy?

13. Product and Process Quality Knowledge: Science-Risk Based cGMP’s
Quality by Design
Process Design
Yes, Limited to the
Experimental
Design Space
Maybe,
Difficult to
Assesses
GMP/CMC FOCUS
Design qualification
Focused; Critical
Process Control
Points (PAT)
Extensive;
Every
Step
(CURRENT)
DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
DECISIONS BASED ON
UNIVARIATE APPROACH
CAUSAL LINKS
PREDICT PERFORMANCE
MECHANISTIC
UNDERSTANDING
1st
Principles

14. Quality Risk Priority Probability of Detection Medium Low High 3
Quality by design +
Systems approach
Probability of Detection
Low
Medium
High
High 3
Medium
Risk Classification 2 1
Low

15. Quality Risk Classification (based on SUPAC and GAMP-4)
Quality by design +
Systems approach
Risk Likelihood
High
Medium
Low
Level 3
Level 2
Impact on Quality
Level 1

16. Appropriate labeling and risk management
PAT: Connecting-the-Dots Development - Manufacturing:: Review - Inspection
Appropriate labeling and risk management
Discovery Development Review Marketing
Pre-clinical Clinical
I, II, III Approval IV AER’s
Pre-formulation
Formulation (Clinical) (Optimization)
Optimization Scale-Up Manufac.
(For Market) Changes
Appropriate Controls & Specifications
Building Quality In ?
Safety
&
Efficacy
(“Make Your Own SUPAC”?)
(Interim Spec?)
(Final Specs.?)

17. Today we seek information on
Computer software validation
Several excellent guidance documents exists
CDRH, GAMP-4, others (?)
We plan to adopt and/or refer to some of these in the PAT guidance
What additional considerations would you recommend for PAT guidance?

18. Today we seek information on
What aspects of 21 CFR Part 11 need clarification for PAT applications?
Note that Part 11 applies to all systems generating electronic records
We wish to focus our discussion within the context of PAT

19. Data elements to be acquired and stored?
What incoming material data elements should be acquired, e.g., NIR?
What incoming material data elements should be retained, e.g., matches spectrum, full spectrum?
What in-process data elements should be acquired, e.g., image fields for homogeneity monitoring?
What in-process data elements should be retained, e.g., meets acceptance criteria, retain final pH value or all values measured?
What product release data elements should be acquired, e.g., individual tablet NIR or Raman spectra?
What product release data elements should be retained, e.g., passes, all data elements?

20. Today we seek information on
Case Studies - Regulatory challenges and solutions
“Mock” submissions
Rapid Microbial Testing
How should this be addressed in the PAT guidance?

21. Current State Product quality Process quality
Based on the small number of recalls due to product quality, we probably are already close to Six Sigma level of quality
Process quality
Ranges from poor to good
Poor process quality can have a catastrophic effect on the reputation and economic health of a company
Poor process quality can lead to drug shortages

22. It is the Right Time to Focus on Process Quality
Higher level of process quality is desirable from both public health and business perspective
Reduce risk of releasing a poor quality product
Reduce regulatory risks and costs
Reduce time-to-market
Reduce stress and frustration
Today we can be proactive

23. How?
Most pharmaceuticals are complex, multivariate, physico-chemical systems
Have to rely on iterative empirical development approach - guided by a formulators experience
Mathematical optimization would require use of Response Surface Methodologies
Subjective measures of material functionality
Many variables and long waiting periods for lab data
Not enough time and/or material available
No regulatory incentive for formulation/process optimization

24. Why Transforming Efforts Fail
Not establishing a great enough sense of urgency
Not creating a powerful enough guiding coalition
Lacking a vision
Under communicating the vision by a factor of ten
Not removing obstacles to the new vision
Not systematically planning for and creating short-term wins
Declaring victory too soon
Not anchoring changes in the corporation’s culture

25. Thank You
See you at
Arden House US
Arden House UK
IFPAC