The ACPS

1
The ACPSs 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
  ACPSs Subcommittee on PAT
• Enumerate expectations of the ACPS
• reporting and timeline

3
Outline

• Overview (Ajaz Hussain)
• 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 Boards 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
Dr. Woodcocks presentation summary

• 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
How Did We Get Here?
Dr. Woodcocks presentation summary

• System evolved beginning 30-40 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--consens
  us based standards (1990s)
• Industry--regulatory risk averse

9
Challenges for FDA
Dr. Woodcocks presentation summary

• 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

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Questions for the Science Board
Dr. Woodcocks presentation summary

• 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?

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Measurement Shows Potential for Improvement
100
Cost reduction
Time Compression
0
35 days
Best Practice VA Ratio 50
3days
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Benefits - Increased Effectiveness of Compliance
Infrastructure
13
PROCESS D WITH QC TESTSCycle Times including
BULK ACTIVE
20 DAYS
15 DAYS
BLEND 2 PRE-BLEND
GRANULATION
STEP
CHEMICAL WEIGHING
BLEND 1
COMPRESS
FINAL BLEND
PROCESSING
10 DAYS
15 DAYS
QC1
QC3
QC2
60 DAYS
21-90 DAYS
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE
(PHARMI)
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ON-LINE TECHNOLOGY IMPACTSDOMINANT 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
0
100
200
300
400
500
600
700
800
LOT NUMBER
NEED FOR FUNDAMENTAL TECHNOLOGY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE
(PHARMI)
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Impact of Exceptions
(Detailed Analysis of 2 Products)
PERFORMANCE MEASURE
VALUE

• Average Cycle time 95 days
• Std dev(Cycle time) gt 100 days
• Exceptions increase cycle time by gt 50
• Exceptions increase variability by gt 100
• Capacity Utilization of System LOW
  

NEED FOR FUNDAMENTAL TECHNOLOGY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE
(PHARMI)
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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
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The Dont 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

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The Dont 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.

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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 dont
  apply
• participate in dummy run submissions
• Ensure consistent approach to PAT by Review and
  Inspection

22
Shift the Manufacturing Paradigm
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Issue Need for FDA to Facilitate Introduction of
PAT
Ajaz Hussains presentation summary

• Industry is hesitant to introduce PAT in US
• Regulatory uncertainty/risk leads to Dont Tell
  or Dont 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

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Win-Win Opportunities
Ajaz Hussains presentation summary

• 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 Hussains presentation summary

• 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 Hussains presentation summary

• 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 Hussains presentation summary

• 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

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A Perspective on PAT One piece of the puzzle

• Vision 2020 - 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,...

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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,.

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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)

32
(No Transcript)
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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
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ICH Q6A DECISION TREES 7 SETTING ACCEPTANCE
CRITERIA FOR DRUG PRODUCT DISSOLUTION
What specific test conditions and acceptance
criteria are appropriate? IR
YES
Develop test conditions and acceptance
distinguish batches with unacceptable BA
dissolution significantlyaffect BA?
NO
Do changes informulation ormanufacturing
variables affect dissolution?
Are these changes controlledby another procedure
and acceptancecriterion?
YES
YES
NO
NO
Adopt appropriate test conditionsand 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.
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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

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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)