ppt

							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
  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
                      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
  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
 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
    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?
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
Dr. Woodcock’s presentation summary


               How Did We Get Here?
     • 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--
       consensus based standards (1990’s)
     • Industry--regulatory risk averse
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
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?
       Measurement Shows Potential for
100%
               Improvement

                        Cost reduction




                       Time Compression



 0%
                                             35 days
       3days   Best Practice: VA Ratio 50%
       Benefits - Increased Effectiveness of
           Compliance Infrastructure

                                               2


                     Direct Cost Recovery
Cost




                                               5


                         Compliance Gain


   0%              Level of Compliance      100%
        PROCESS D WITH QC TESTS:
  Cycle Times including BULK ACTIVE


                            20 DAYS                                            15 DAYS
                                          BLEND 2:
                                         PRE-BLEND
                                                         FILM
                                 STEP
                        GRANULATION                     COATING




                    CHEMICAL
                    WEIGHING          BLEND 1: FINAL COMPRESS BOTTLE
                           PROCESSING          BLEND         PACKAGING




             10 DAYS                                              15 DAYS
              QC1                              QC2                       QC3



21-90 DAYS                                         60 DAYS

                           MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
   ON-LINE TECHNOLOGY IMPACTS
      DOMINANT CYCLE TIMES




On-line LIF, NIR, Data Analysis, etc.
                                        MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
                          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)
               Impact of Exceptions
                  (Detailed Analysis of 2 Products)
      PERFORMANCE MEASURE                                   VALUE
•   Average Cycle time                                    95 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)
       PAT Applications at DP Sites
• RM Testing (warehouse           • Tablet Coating (coating
  based)                            thickness)
• Packaging Components            • Packaged product
• Blending (at-line or on-line)   • Equipment cleaning (on line
• Drying                            monitoring of CIP)
• Tableting (potency and CU)      • Equipment cleaning (surface
• Encapsulation (potency and        monitoring)
  CU)


          Note - Less than 15% of applications at US sites
            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
          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”
         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……….
 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
Shift the Manufacturing Paradigm
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
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
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….
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
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
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,...
     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)
         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,…….
   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)
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
  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.
  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)
Non-homogeneous distribution of
      magnesium stearate
ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA
FOR DRUG PRODUCT DISSOLUTION

 What specific test conditions and acceptance criteria are appropriate? [IR]



             dissolution significantly        YES         Develop test conditions and acceptance
                    affect BA?                            distinguish batches with unacceptable BA

                          NO


               Do changes in
               formulation or                 YES              Are these changes controlled
           manufacturing variables                                by another procedure
             affect dissolution?                                      and acceptance
                                                                        criterion?

                                                     YES
                          NO                                                 NO

       Adopt appropriate test conditions             Adopt test conditions and acceptance
        and acceptance criteria without                  criteria which can distinguish
       regard to discriminating power, to            these changes. Generally, single point
       pass clinically acceptable batches.             acceptance criteria are acceptable.

                                         aaps Annual Meeting                                  37
      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
   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)