Transcript ACPS Process Analytical Technology (PAT) Subcommittee Meeting #3 Opening Remarks

ACPS Process Analytical
Technology (PAT)
Subcommittee Meeting #3
Opening Remarks
Ajaz S. Hussain, Ph.D.
Deputy Director
Office of Pharmaceutical Science, CDER, FDA
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?
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
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 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
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)
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
Blend Uniformity & PAT
Univariate
Testing to
Document
Quality
Approach
Multivariate
Quality-by
Design
Approach
Traditional test
methods
Current PQRI proposal
and draft Guidance
At-line
test methods
Draft Guidance may
include information on
the use of NIR 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
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
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)
In-put from ACPS PATSubcommittee
• 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”
PAT: Conceptual Framework
Incoming
LT Materials.
Specifications
Relevant to
“Process-ability”
Development/Optimization/Continuous Improvement
(DOE, Evolutionary optimization, Improved efficiency)
Control of process critical
control points (PCCP).
Process end point (PEPs’) range
based on “performance” attributes.
Multivariate
Systems
Approach
Risk
Classification
and
Mitigation
Strategies
PAC
PAC
PCCP
PEP’s
At-line
In/On-Line
Process Analytical
Chemistry Tools
Incoming material attributes
used to predict/adjust
optimal processing parameters
within established bounds
(more flexible bounds)
CM
IT
PAC
Laboratory
LT or other
tests
Chemometrics (CM)
and IT Tools
Direct or inferential
for “real time”
assessment of quality
control and decisions and performance (at/on-line)
Taking Advantage
of Built-in Redundancy?
General
Quality
System
PAT Based Product specific
Measurements
SOP’s,...
and Controls
Validation
Systems Approach
Product and Process Quality Knowledge:
Science-Risk Based cGMP’s
Quality by Design
Process Design
1st
Principles
GMP/CMC FOCUS
Design qualification
MECHANISTIC
UNDERSTANDING
Yes, Limited to the
Experimental
CAUSAL LINKS
Design Space
PREDICT PERFORMANCE
Maybe,
Difficult to
Assesses
DECISIONS BASED ON
UNIVARIATE APPROACH
DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
Focused; Critical
Process Control
Points (PAT)
Extensive;
Every
Step
(CURRENT)
Quality Risk Priority
Risk Classification
High
Medium
Probability of Detection
Low
Quality by design +
Systems approach
High
3
2
1
Medium
Low
Quality Risk Classification
(based on SUPAC and GAMP-4)
Impact on Quality
High
Medium
Low
Risk Likelihood
Quality by design +
Systems approach
Level 3
High
Medium
Low
Level 2
Level 1
PAT: Connecting-the-Dots
Development - Manufacturing:: Review - Inspection
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
?
Building Quality In
?
Safety
&
Efficacy
Appropriate labeling and risk management
(“Make Your Own SUPAC”?)
?
Appropriate Controls &
? Specifications
(Interim Spec?)
(Final Specs.?)
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?
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
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?
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?
Current State
• Product 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
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
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
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