1. PAT Initiative: Next Steps
Ajaz S. Hussain, Ph.D.
Deputy Director
Office of Pharmaceutical Science, CDER, FDA

2. PAT Initiative FDA Science Board Meetings (11/01, 4/02)
Emerging Science Issues in Pharmaceutical Manufacturing
Current state of Pharmaceutical Manufacturing
G. K. Raju (M.I.T) and Doug Dean (PriceWaterHouseCoopers)
Opportunities for improvements
Norman Winskill and Steve Hammond (Pfizer)
New Technology - “Don’t Use” or “Don’t Tell” approach
Ray Scherzer (CAMP/GlaxoSmithKline)
Challenge to Phrama Industry - Quality By Design
Science Board support for FDA’s proposal to facilitate innovation

3. PAT Progress
Advisory Committee for Pharmaceutical Science (PAT Subcommittee) deliberations
Definitions, benefits, and scope
Perceive/real regulatory “hurdles”
Internal (with-in company) “hurdles”
Need for across discipline communication
Pharmacy+Chemistry+Engineering = Pharmaceutical Engineering
Approaches for removing these “hurdles”
Case studies
General approaches for validation
PAT Training curriculum for FDA staff

4. PAT Teams: 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 (ORA/SJN-DO)
Erin McCaffery (ORA/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
(Ali Afnan, OPS/CDER)
PAT Training Coordinators
John Simmons, Karen Bernard
and Kathy Jordan

5. Why Process Analytical Technologies?
PAT provides an opportunity to move from the current “testing to document quality” paradigm to a “Continuous Quality Assurance” paradigm that can improve our ability to ensure quality was “built-in” or was “by design” - ultimate realization of the true spirit of cGMP!
Greater insight and understating of processes
At/On/In-line measurement of “performance” attributes
Real-time or rapid feedback controls (focus on prevention)
Potential for significant reduction in production and development cycle time
Minimize risks of poor process quality and reduce (regulatory) concerns

6. PAT Conceptual Framework for Regulatory Policy Development
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

7. 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

8. Regulatory Framework PAT tools not a requirement Research exemption
Continuous improvement without the fear of being considered non-compliant
Regulatory support and flexibility during development & implementation
Eliminate the fear of delayed approval
Dispute avoidance/resolution
Science & Risk based regulatory approach
Low risk categorization based on a higher level of process understanding

9. Strategy for Moving Forward
Scientific Workshops
Several FDA co-sponsored and other workshops conducted (US and Europe)
Scientific discussion and debate
across disciplines (pharmacy, chemistry, chemical engineering)
organizational units (development, manufacturing, quality control, and regulatory departments)
General guidance on PAT to be released
Training workshop
Bring together different Associations (disciplines)

10. Strategy for Moving Forward
Champions to drive this initiative towards a “shared vision” or “desired state”
Industry: Pfizer, GSK, BMS, Aventis, Lilly, Novartis,...
Academia: MIT, Purdue, Washington, Tennessee, Michigan, Rutgers, Maryland, Minnesota, Connecticut, Puerto Rico, Duquesne.., London, Bradford, Basel,… (planned - Gifu and other universities in Japan)
PAT introduced in Pharmaceutical Engineering programs at Purdue, Michigan and Rutgers
(Instrument vendors - moving towards an association to address common issues)

11. Strategy: Moving forward
Improving the FDA knowledge base for technical policy development
Several experts recruited
Intramural research refocused to address technical needs and for in-house training
Significant increase in peer reviewed contributions
Learn from other industries (e.g., link with ASTM)
CRADA with Pfizer developed, awaiting final FDA approval (focus on chemical imaging)
Collaborate with NSF (Center for Pharmaceutical Processing Research)

12. Strategy: Moving forward
PAT Initiative a part of the broader cGMP Initiative for the 21st Century (announced 12 August 2002)
An example of science and risk-based systems approach to product quality regulations

13. Strategy for Moving Forward
Post approval implementation of PAT
PAT-Comparability protocols proposed by several companies
systems thinking, process understanding, risk mitigation strategies - Manufacturing Science
PAT Review & Inspection team
training and certification
science and risk based review and inspection
Product Specialist on inspection concept
Expertise: Industrial pharmacists, chemical engineers, chemometric, process analytical chemistry

14. Move from “testing to document quality” to “quality by design”
What does this mean?
Effective methods for managing/controlling (particle size) variability to provide consistent performance
Establishing causal links between material attribute (particle size) variability and performance
Reduce reliance on lab-based test methods
Improve focus on process understanding as compared to “test” to “test” comparisons

15. Risk = ? Minimal potential -AR Change = Risk(?)
Section 116 of the Modernization Act section 506A (21 U.S.C. 356a) the Food, Drug, and Cosmetic Act (the Act)
…….potential to have an adverse effect on the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product (506A(c)(2)).
Substantial Potential - PAS
Moderate potential - CBE-30 Days or CBE
Minimal potential -AR

16. Risk Based Review
Review - minimizes intolerable risk to patient safety
Process
Identify risk scenarios
Assess likelihood of fault condition
Assess severity of impact
Assign risk grade
Assess probability of detecting fault condition
Determine mitigation strategy

17. Quality Risk Scenarios
Risk of unacceptable quality (examples)
Releasing a unacceptable quality product
Inadequate controls/specifications
“New” impurities
Bio-in-equivalence
Inadequate process validation
sampling not “representative”
Stability failure
Poor Process quality
Others

18. Risk of Bio-in-equivalence
Risk factors
Manufacturing changes pre/post approval
minor - moderate - major changes
Poor process capability
high between and within batch variability
Reliance on in vitro dissolution tests
single point specification - sampling - predictability
Other factors
deficiencies in BE study design - Type II error
Bioequivalence - one of the critical links between quality and S&E

19. BCS a tool for risk management
Assessment of risk
What is the risk of bio-in-equivalence between two pharmaceutical equivalent products when in vitro dissolution test comparisons are used for regulatory decisions?
Likelihood of occurrence and the severity of the consequences?
Regulatory Decision
whether or not the risks are such that the project can be persued with or without additional arrangements to mitigate the risk
Acceptability of the Decision
is the decision acceptable to society?

20. 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

21. 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

22. A Perspective on PAT: One piece of the puzzle
“Vision I can see clearly now”
Quality & performance by design + Continuous “real time” monitoring of quality
Specifications based on mechanistic understanding of how formulation and process factors impact product performance
High efficiency and capacity utilization
Science based regulatory decisions focused on product and process quality

23. PAT = Process Understanding
Intended Use
1st Principles
Modeling
Optimization
Continuous
Improvement
(including CAPA)
Risk based Regulatory Assessment
Arden House 2004