1. The ACPS’s Process Analytical Technology Subcommittee
Ajaz S. Hussain, Ph.D.
Deputy Director
Office of Pharmaceutical Science
CDER, FDA
ACPS Meeting November 28, 2001

2. Objectives of PAT Discussion
To delineate the goals and objectives of the ACPS’s Subcommittee on PAT
Enumerate expectations of the ACPS
reporting and timeline

3. Outline Overview (Ajaz Hussain) ACPS discussion and recommendations
Background Information
July 19, 2001 ACPS Discussion
November 16, 2001 FDA Science Board Discussion
A Vision for PAT in Pharmaceutical Manufacturing
Proposed responsibilities and timelines
October 25, 2001 FR Notice on PAT Subcommittee
ACPS discussion and recommendations

4. July 19, 2001 ACPS Discussion on Optimal Applications of PAT
Initiate public discussion on application of process analytical chemistry tools in pharmaceutical manufacturing
Strong ACPS support to move forward
Recommendation to form a PAT Subcommittee
Related discussion on “Rapid Microbial Testing”
No further development to report at this time

5. FDA Science Board Discussion Nov. 16, 2001
Speakers
Janet Woodcock
CDER, FDA
Doug Dean and Frances Bruttin
PricewaterhouseCoopers
G. K. Raju
MIT
Norman Winskills and Steve Hammond
Pfizer
Ajaz Hussain
OPS, CDER, FDA

6. Science Board’s Response
Strong unanimous endorsement of the proposal
Would like to support this initiative
talks, seminars,…
Would like to receive updates on progress
Questions from ACPS?

7. Current Status US Drug products are of high quality, BUT
Dr. Woodcock’s presentation summary
Current Status
US Drug products are of high quality, BUT
Increasing trend toward manufacturing-related problems
Low manufacturing and QA process efficiency--cost implications
Innovation, modernization and adoption of new technologies slowed
Introduction of new technologies in facilities not for US market
High burden on FDA resources

8. Dr. Woodcock’s presentation summary
How Did We Get Here?
System evolved beginning years ago--when sectors of industry lacked rigorous SOPs
Science/technology base did not evolve as quickly as in other sectors
Empirical GMP standards necessitates stringent scrutiny
International conference on Harmonization--consensus based standards (1990’s)
Industry--regulatory risk averse

9. Dr. Woodcock’s presentation summary
Challenges for FDA
How to encourage innovation while ensuring high quality
Successful adoption of new technologies will IMPROVE overall quality
How to successfully shift from empirical to science based standards for manufacturing process quality
How to decrease reliance on pre-approval review and physical evaluation
How to recruit and train a scientific workforce proficient in application of new technologies

10. Questions for the Science Board
Dr. Woodcock’s presentation summary
Questions for the Science Board
Are you able to support the approach?
What resources do you suggest FDA draw on?
Are there additional aspects to regulation of pharmaceutic quality that we should focus on?

11. Measurement Shows Potential for Improvement
100%
Cost reduction
Time Compression 0%
35 days
3days
Best Practice: VA Ratio 50%

12. Benefits - Increased Effectiveness of Compliance Infrastructure0%
100%
Level of Compliance
Cost 5 2
Compliance Gain
Direct Cost Recovery

13. PROCESS D WITH QC TESTS: Cycle Times including BULK ACTIVE
20 DAYS
15 DAYS
BLEND 2:
PRE-BLEND
FILM
COATING
BOTTLE
PACKAGING
GRANULATION
STEP
CHEMICAL
WEIGHING
BLEND 1:
FINAL
BLEND
COMPRESS
PROCESSING
10 DAYS
15 DAYS
QC1
QC3
QC2
21-90 DAYS
60 DAYS
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

14. ON-LINE TECHNOLOGY IMPACTS DOMINANT CYCLE TIMES
On-line LIF, NIR, Data Analysis, etc.
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

15. LOOKING BEYOND THE “AVERAGE”
Lots with Exceptions
Lots without Exceptions
OVERALL CYCLE TIMES
100
200
300
400
500
600
700
800
LOT NUMBER
NEED FOR FUNDAMENTAL TECHNOLOGY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

16. Impact of Exceptions PERFORMANCE MEASURE VALUE
(Detailed Analysis of 2 Products)
PERFORMANCE MEASURE
VALUE
Average Cycle time days
Std dev(Cycle time) > 100 days
Exceptions increase cycle time by > 50 %
Exceptions increase variability by > 100%
Capacity Utilization of “System” LOW
NEED FOR FUNDAMENTAL TECHNOLOGY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

17. PAT Applications at DP Sites
RM Testing (warehouse based)
Packaging Components
Blending (at-line or on-line)
Drying
Tableting (potency and CU)
Encapsulation (potency and CU)
Tablet Coating (coating thickness)
Packaged product
Equipment cleaning (on line monitoring of CIP)
Equipment cleaning (surface monitoring)
Note - Less than 15% of applications at US sites

18. The “Don’t Use” Scenario
What:
Modern PAT methods not used/developed during product development so not used for routine process control
Why:
Fear of regulatory delays
Wasteful of resources to duplicate method development -“current methods work OK”
Concern of “raising the bar” unnecessarily: information generated for one process may be expected from all
Issues:
Loss of benefit of PAT - improved process information and control

19. The “Don’t Tell” Scenario
What:
PAT methods not registered but used in parallel with registered (conventional) methods to gain greater process insight and control
Why:
Concern over delays in regulatory approval
Concern that data may be interpreted inappropriately by regulators. More data will lead to more deviations from “norms” - need to be able to determine which are relevant and which are not
Issues:
Duplication, inefficiency, environment of “mistrust”

20. The “Win - Win” Scenario
What:
Modern PAT methods used to gain greater understanding of processes during development, are registered and used as in-process control (and release?) methods
PAT methods accepted as alternatives to traditional lab based methods - but not required
Why:
Methodology understood and accepted by regulators and industry alike
Issues:
This is where we should all want to get to. Making progress, but we are not there yet……….

21. How can we create a “Win-Win” Environment?
Dealing with the real or perceived regulatory hurdles:
Sponsor joint forums to promote discussion and enhance understanding of the issues and opportunities offered by PAT
Develop an effective process for the evaluation of new PATs
Develop appropriate guidelines for the development, validation and implementation of new PATs
lab based extraction/chromatography rules don’t apply
participate in “dummy run” submissions
Ensure consistent approach to PAT by Review and Inspection

22. Shift the Manufacturing Paradigm

23. Issue: Need for FDA to Facilitate Introduction of PAT
Ajaz Hussain’s presentation summary
Issue: Need for FDA to Facilitate Introduction of PAT
Industry is hesitant to introduce PAT in US
Regulatory uncertainty/risk leads to “Don’t Tell” or “Don’t Use” practice
New Technology = New Questions
Method suitability, chemometrics and validation
Old products + New technology = New Regulatory Concerns
Problems not visible under the current system
Mindset: Why change?
PAT application will add to current regulatory requirements

24. “Win-Win” Opportunities
Ajaz Hussain’s presentation summary
“Win-Win” Opportunities
Optimal application of modern process analytical technologies can
Improve quality and manufacturing efficiency
Reduce the likelihood of scrap/recalls
Improve the scientific and engineering basis of many current FDA-Industry debates

25. What Should FDA Do to Facilitate Introduction of PAT?
Ajaz Hussain’s presentation summary
What Should FDA Do to Facilitate Introduction of PAT?
Eliminate regulatory uncertainty
Official position - FDA will accept new technology that is based on “good” science
Develop standards for PAT
Method suitability and validation
Multivariate statistical/computer pattern recognition
Critical process control points and specifications
Changes
OOS….

26. What Should FDA do to Facilitate Introduction of PAT?
Ajaz Hussain’s presentation summary
What Should FDA do to Facilitate Introduction of PAT?
Define a clear science based regulatory process
Current system “adequate for intended use”
Introduction of PAT not a requirement
Define conditions under which PAT may replace current “regulatory release testing”
Process for addressing existing “invisible” problems in marketed products
Review and inspection practices
International harmonization

27. How Should FDA Facilitate PAT?
Ajaz Hussain’s presentation summary
How Should FDA Facilitate PAT?
Limited institutional knowledge and experience at FDA
Seek input and collaboration
Advisory Committee for Pharmaceutical Science - Subcommittee on PAT
Industry (individual companies?)
Academic Pharmaceutical Engineering and Process Analytical Chemistry programs
PQRI

28. 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
“Real time” review and inspection from Rockville, White Oak, NJDO,...

29. Key Elements of the Emerging Program on PAT (Draft)
A “general principles” guidance on PAT
Articulate an FDA position on PAT
Definitions and terminology
Outline a regulatory process for introducing PAT
Pre- and post approval phases
Addressing existing but invisible problems
“Team” approach for review and inspection
Types of experimental evidence and justification
“Alternate” and “Primary” control/test
“Direct” and “Correlation-based” control/test
Appropriate level of redundancy or backup systems
On/In/At-line release testing (parametric release)

30. Types of Tests/Controls
“Alternate” control/test
A PAT tool validated by comparison to a traditional in-process test using development data and/or data from routine production for a period of time. Traditional in-process test discontinued after sufficient data collected to support validation.
On-line blend uniformity using NIR validated by comparison to data obtained on blend samples collected using a “thief”
“Primary” control/test
A PAT tool is developed and validated on its own merits
Accuracy, precision, specificity,…….

31. Types of Tests/Controls (Contd.)
Correlation-based controls/tests
Use of chemometrics or pattern recognition methods to identify and develop a correlation between a measurement and product attribute
E.g., Prediction of tablet hardness, dissolution rate from NIR spectral fingerprints
Validation based on predictive performance only
Validation based on predictive performance plus mechanistic justification (causal links)

33. Parametric Release & Release Tests
What is “parametric release”
When "data derived from the manufacturing process sterility assurance validation studies and from in-process controls are judged to provide greater assurance that the lot meets the required low probability of containing a contaminated unit (compared to sterility testing results from finished units drawn from the lot), any sterility test procedure adopted may be minimal, or dispensed with on a routine basis.” (USP)
Need to redefine this term

34. EMEA's Note for Guidance on Parametric Release (effective since 9/01)
Defines Parametric Release as:
" a system of release that gives assurance that the product is of the intended quality based on the information collected during the manufacturing process and on the compliance with specific GMP requirements related to parametric release."
In addition, this note extends the Parametric Release concept to other dosage forms.

35. Parametric Release: Dissolution?
Provide a greater assurance (compared to the current dissolution test method)
Lot will meet established specification
Lot will meet established BA/BE
Data derived from
Process that utilizes in-process controls that can measure and control all critical variables that effect dissolution
Appropriately designed manufacturing process validation studies
Validation based on predictive performance plus mechanistic justification (causal links)

36. Non-homogeneous distribution of magnesium stearate

37. ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION
What specific test conditions and acceptance criteria are appropriate? [IR]
YES
dissolution significantly affect BA?
Develop test conditions and acceptance
distinguish batches with unacceptable BA NO
Do changes in formulation or manufacturing variables affect dissolution?
YES
Are these changes controlled by another procedure
and acceptance criterion?
YES NO NO
Adopt appropriate test conditions and acceptance criteria without
regard to discriminating power, to
pass clinically acceptable batches.
Adopt test conditions and acceptance
criteria which can distinguish
these changes. Generally, single point
acceptance criteria are acceptable.
aaps Annual Meeting

38. PAT FR Notice Oct. 25, 2001 Request names of qualified individuals
Process analytical chemistry, pharmaceutics, industrial pharmacy, chemical engineering, pharmaceutical analysis, chemometrics, pattern recognition, expert systems, IT, and statistics
Report on scientific issues related to application and validation of on-line process technologies (e.g., NIR).
Both drug substance and drug product manufacture
Feasibility of “parametric” release concept
Potential benefits and risks
Applications should be received by 11/30/01

39. Subcommittee should report on (?)
Current status and future trends: PAT in pharmaceutical development and manufacturing
Available technologies, capabilities,...
Application in US Vs. Non-US plants
Perceived and/or real regulatory hurdles
General principles for regulatory application
Principles of method validation, specifications, OOS
Appropriate use and validation of chemometric tools
Feasibility of “parametric release” concept (also, redefine)
Case study: vibrational spectroscopy (NIR)?
Research and training needs (FDA and industry)