Process Analytical Technologies (PAT) Sub-Committee Report ACPS Meeting October 21, 2002

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Process Analytical Technologies (PAT)
Sub-Committee Report ACPS Meeting October 21,
2002

• Tom Layloff, Ph.D.

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Meetings

• February 25 and 26, 2002
• Applications Benefits
• Process Analytical Validation
• Chemometrics
• June12 and 13, 2002
• Product-Process-Development
• Process and Analytical Validation
• Proposed PAT Certification Program
• October 23, 2002

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Product and Process Development1

• RD efforts in pilot plant
• Process understanding
• Identify PATs for manufacturing
• Suitability for intended use
• Demonstrate it is validatable
• More rigorous performance requirements if
  intended to replace end product testing

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Product and Process Development2

• RD efforts in manufacturing
• Acceptable verification of suitability and
  validation
• Investigate transferability (equipment design and
  qualification, scale-up issues, safety,)
• Model refinement may be necessary (e.g., process
  signature developed in RD may be based on
  limited data)
• Submission as a protocol in original
  application or as a prior approval supplement -
  need to consider less burdensome filing mechanisms

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Product and Process Development3

• Routine manufacturing using PATs
• Body of PAT information should have equivalent or
  better informing power than the corresponding
  conventional approved end product test
• Recommend setting-up a table, showing
  relationship between PAT testing and current
  testing methodology
• Parallel PAT testing and conventional testing
  (in-process and/or release tests) should be
  performed for sufficient number of batches
• Level of redundancy - often a business decision

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Product and Process Development4

• Identify steps for resolving OOS obs.
• PATs may allow selective rejection, or partial
  batch release
• Within batch trend information should facilitate
  resolution of OOS
• Until PATs are approved for regulatory purposes,
  the approved conventional test results supersede
  the PAT results
• If OOS result is traced to instrument failure,
  then traditional approved methods can be utilized
  for batch release in lieu of PAT based results

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Product and Process Development5

• Identification of relevant critical formulation
  and process variables
• Based on product performance, adequate process
  control, and assurance of quality
• Justification for use of indirect or inferential
  measurements (e.g., process signature or
  correlation)
• Demonstrate a link (statistical causal) between
  PAT parameter and product characteristics
• Establish acceptable variability

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Process Analytical Validation1

• Definition
• Systems for the analysis and control of
  manufacturing processes based on timely
  measurement during procession of critical quality
  parameter and performance attributes of raw and
  in-process materials and processes, to assure
  acceptable end-product quality at the completion
  of the process.

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Background Process Analytical Validation2

• Existing validated measurements invariably
  correlate poorly with process performance
• Univariate measurements used to infer compliance
  of multivariate dynamic systems
• Measure what we can measure, not what needs to be
  measured
• Measurement has not been seen as process related
• Measurement needs to respond to process need over
  the product life cycle
• Need to understand the process
• Recognize that the conventional approach to
  validation might be limiting

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Background Process Analytical Validation3

• Understand the Process
• Break down into unit operations
• Assess risk potential for each unit individually
  and collectively using techniques, e.g.
  experimental design
• Design systems to manage risk
• Univariate measurement
• Multivariate systems
• Develop systems
• Establish proof of concept
• Challenge validation
• Objective - confirm processes and measurement
  validity in real time across life cycle

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Process Analytical Validation4

• Validation Protocols will be different for new
  products associated with well-designed understood
  manufacturing processes and existing products
  where PAT is applied retrospectively
• The validation plan will reflect the total system
  design concept since an Real-Time-QC/QA
  manufacturing process, statistically based,
  essentially revalidates itself on every
  manufacturing batch
• The rationale for model validation incorporating
  pass/fail criteria must be clearly defined
  thereby establishing the authenticity of
  predictions in routine manufacturing and ensuring
  compliance

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Process Analytical Validation5

• Three distinct ways of analyzing unit operations
  and releasing products
• Current operating scenario. Product is
  manufactured according to fixed process
  conditions set during development and confirmed
  during initial process and product validation.
  Release is conducted by physical and chemical
  testing subsequent to manufacture.
• Product is manufactured according to process
  conditions that have been shown during
  development and manufacturing to infer product
  performance and is confirmed during initial
  process and product validation. Relationships
  are developed and confirmed with physical and
  chemical testing subsequent to manufacturing
  runs. Release is conducted by review of process
  conditions during each batch manufacture.

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Process Analytical Validation6

• Three distinct ways of analyzing unit operations
  and releasing products
• 3. Product is manufactured according to process
  conditions that are responding to direct
  measurement of in-process product quality or unit
  dosage forms as they are being manufactured.
  Relationships are developed between process and
  product performance that are optimized and
  bounded by data obtained in development and
  manufacturing runs. Release is conducted by data
  collected from in-process product or each dosage
  form during manufacture.
• Release specification form and validation
  criteria can be defined for each condition based
  on the nature of their release.

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Process Analytical Validation7

• Recommendations for guidance
• Suitable for intended purpose
• General validation criteria
• References to existing guidance documents (ICH
  Q2 a and b Analytical Validation, Q6 a and b,
  Specifications, FDA Analytical Procedures and
  Methods Validation)
• Research exemption
• OOT/OOS
• Encourage use of PAT. FDA should have a
  mechanism to institute these new technologies and
  methods

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Training Certification1

• Proposed Process Analytical Technology
  Certification Program for FDA Investigators and
  Reviewers
• On completion of this certification program,
  participants should be able to evaluate the
  adequacy and performance of current and emerging
  PATs. This certification will require a
  demonstrated understanding of the fundamentals,
  importance, and impact of PATs

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Training Certification2

• Participants will be able to demonstrate an
  understanding of
• The distinguishing characteristics of a PAT
• The identification and use of PCCPs (process
  critical control points)
• Suitability and validity of the statistics,
  chemometric, and instrumental approaches applied
  to PAT
• Typical PAT applications and the associated
  capabilities and limitations of the methodology
• Data handling, analytical, control and
  engineering tools and vocabulary relevant to PAT

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Meeting 3 (10/23/02)

• Discuss issues related to computer software
  validation, security, electronic batch records,
  signatures,..
• Breakout session on
• Mock PAT submissions
• Rapid microbial testing
• At the end of this meeting information needed to
  develop a general guidance should be available
  to the FDA

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PAT FDA Progress Report

• Ajaz Hussain, Ph.D.

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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

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PAT 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 Review - Inspection Team Investigators Rober
t Coleman (ORA/ATL-DO) Rebecca Rodriguez
(SJN-DO) Erin McCaffery (NWJ-DO) George Pyramides
(PHI-DO) Compliance Officers Albinus DSa
(CDER) Mike Gavini (CDER) William Bargo
(CVM) Reviewers Norman Schmuff (CDER) Lorenzo
Rocca (CDER) Vibhakar Shah (CDER) Rosario
DCosta (CDER) Raafat Fahmy (CVM)
PAT Policy Development Team Raj Uppoor,
OPS/CDER Chris Watts, OPS/CDER Hiquan Wu, OPS/CDER
PAT Training Coordinators John Simmons, Karen
Bernard and Kathy Jordan
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In-put from ACPS PAT-Subcommittee

• Conceptual framework on PAT
• Developed, consensus established
• PAT as a part of, and a example of, the new FDA
  wide initiative cGMP for the 21st Century

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PAT Conceptual Framework
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Product and Process Quality Knowledge
Science-Risk Based cGMPs
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)

1st Principles
MECHANISTIC UNDERSTANDING
CAUSAL LINKS PREDICT PERFORMANCE
DECISIONS BASED ON UNIVARIATE APPROACH
DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION
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Quality Risk Classification (based on SUPAC and
GAMP-4)
Quality by design Systems approach
Risk Likelihood
Level 3
Level 2
Impact on Quality
Level 1
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Quality Risk Priority
Quality by design Systems approach
Probability of Detection
Low
Medium
High
High
3
Medium
Risk Classification
2
Low
1