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FDAs Advisory Committee for Pharmaceutical Science The Subcommittee on Process Analytical Technologi


Goals and Objectives of the PAT-Subcommittee and Working Groups ... Chemometrics (Kowalski and Wold) Multivariate data collection and analysis ... – PowerPoint PPT presentation

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Title: FDAs Advisory Committee for Pharmaceutical Science The Subcommittee on Process Analytical Technologi

FDAs Advisory Committee for Pharmaceutical
ScienceThe Subcommittee on Process Analytical
Technologies (PAT) Overview and Objectives
  • Ajaz S. Hussain, Ph.D.
  • Deputy Director
  • Office of Pharmaceutical Science, CDER, FDA
  • February 25, 2002, Gaithersburg, MD.

  • Overview of the FDAs PAT Initiative
  • What?
  • Why?
  • When?
  • How?
  • Goals and Objectives of the PAT-Subcommittee and
    Working Groups
  • What does FDA need/expect from you?

What are PAT?
  • Systems for continuous analysis and control of
    manufacturing processes based on real-time
    measurements, or rapid measurements during
    processing, of quality and performance attributes
    of raw and in-process materials and processes to
    assure acceptable end product quality at the
    completion of the process.
  • Process analytical chemistry tools information
    management tools feedback process control
    strategies product process design and
    optimization strategies

PAT for Pharmaceuticals Why?
  • Optimal applications of PAT can improve the
    capability and the efficiency of pharmaceutical
    processes while maintaining or improving product
  • improve process understanding and help to ensure
    quality was built in or by design
  • reduce the risk of scrap and recalls
  • reduce production cycle times and enhance
    capacity utilization
  • in the long run, reduce product development time

PAT for Pharmaceuticals Why?
  • Current level of product quality is generally
    adequate for the intended use
  • The process by which we achieve this level of
    quality is inefficient
  • The current manufacturing paradigm is skewed
    towards testing to document product quality and
    rejecting (or recalling) products of unacceptable

PAT for Pharmaceuticals Why?
  • Ensuring high efficiency of the US pharmaceutical
    manufacturing sector
  • Provide high quality drugs to the US public in a
    timely manner by taking advantage of the many new
    drug development opportunities offered by
    advances in biology and chemistry
  • Ensure optimal utilization of public and private
    resources to meet the growing health care needs
    of the US public
  • Minimize risks due to sub-optimal pharmaceutical
    process quality

PAT for Pharmaceuticals Why?
  • Low manufacturing efficiency, waste (time and
    resources) and a high cost of compliance
  • Need for very high level of regulatory scrutiny
    (review and inspections)
  • High proportion of FDA resources needed to ensure
    adequate product quality
  • Recurring problems that do not seem to get
  • Continued debates between FDA-industry, few
    permanent resolutions

Risks Due to Sub-optimal Pharmaceutical Process
Minimum Regulatory Sigma Level for Drugs?
Under cGMP when failures/recalls exceeds 10 -
no longer validated. The minimum regulatory
"Sigma 1.65?
Pharmaceutical OOS Batch Failures Rates
  • Scrap and rework - we plan for 5-10 (accepted
    as necessary) PWHC 11/16/01
  • It is authors experience that ... validation
    exercise precedes a trouble-free time period in
    the manufacturing area only to be followed by
    many hours (possibly days or weeks) of
    troubleshooting and experimental work after a
    batch or two of product fails to meet
    specifications. This becomes a never-ending
    task. Harwood and Molnar. Using DOE techniques
    to avoid process problems. Pharm. Dev. Tech.

Risks Due to Sub-optimal Pharmaceutical Process
  • Risk of releasing a poor quality product
  • Recalls are not effective quality control tools
  • Drug shortages
  • Delay in approval of important drug products
  • High potential for disruption in the availability
    of important drugs
  • Production of low volume essential drugs may be
    adversely effected

Risks Due to Sub-optimal Pharmaceutical Process
  • Regulatory commitments on an inefficient
    manufacturing process
  • Continued optimization activities in the post
    approval phase (or live with the validated but
    inefficient process)
  • Recurring manufacturing difficulties leading to
    very low efficiency and capacity utilization
  • Higher manufacturing and regulatory compliance
    costs locked-in

Risks Due to Sub-optimal Pharmaceutical Process
  • Increased risk of non-approval or delayed
    regulatory approval
  • Increased potential for quality problems
    confounding the clinical safety and efficacy
  • Past quality (compliance) problems can delay new
    drug approvals
  • Industry and FDA resources being spent on
    recurring problems

  • When was this initiative started?
  • 3rd quarter 1999 (building on the AOAC
    International Special Symposium Pharmaceutical
    Process Control and Quality Assessment by
    Non-Traditional Means, October 1993, St. Louis,
  • FIPs Millennium Congress, New Technology Forum
    of the Royal Pharmaceutical Society, PhRMA
    Technical Conclave, ...
  • 19 July 2001, ACPS Meeting
  • 16 November 2001, FDA Science Board Meeting
  • 28 November 2001, ACPS Meeting
  • Recommendation to form a PAT Subcommittee

  • When can companies submit PAT based applications
    or submissions to FDA?
  • Any time a company is ready to do so
  • they should contact the OPS/CDER/FDA to discuss
    their proposed PAT applications or submissions
  • There are many hurdles that seem to hold back PAT
  • It is widely perceived that FDA will not accept
    PAT based applications, this is not true

Need for FDA to Facilitate Introduction of PAT
  • 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
  • Problems not visible under the current system
  • Mindset Why change?
  • PAT application will add to current regulatory

How does FDA plan to facilitate introduction of
  • Eliminate regulatory uncertainty
  • 1. FDA will accept PAT applications that are
    based on good science
  • Develop standards for PAT
  • Method suitability and validation
  • Multivariate statistical/computer pattern
  • Critical process control points and
  • Changes, OOS.
  • 2. Current system adequate for intended use
  • 3. Introduction of PAT not a requirement

How does FDA plan to facilitate introduction of
  • Eliminate regulatory uncertainty
  • 4. Define conditions under which PAT may replace
    current end product release testing
  • 5. Process for addressing existing invisible
    problems in marketed products
  • 6. Review and inspection practices
  • 7. International harmonization

How does FDA plan to facilitate introduction of
PAT? Two Tracks
  • General Guidance on PAT
  • Information source ACPS Subcommittee on PAT and
    working groups
  • Meeting 1 2/25-26/02
  • Meeting 2 (6/02?)
  • Draft Guidance
  • Implementation
  • CDER-ORA Team
  • Invite companies to propose submissions
  • Expect to receive proposals for submissions (3
    by 4q 02)
  • Review-Inspection plans and teams for these
  • Plan for concurrent development

General (principles) Guidance on PAT
  • Proposed Goals and Objectives
  • General principles and terminology
  • Bring the community on the same page
  • Address issues related to regulatory
  • Clarify the regulatory process
  • Review and inspection
  • Other tangible benefits
  • Serve as a tool for building within-company
  • Promote research and development activities in
    the pharmaceutical PAT area

Guidance Development Process
  • PAT Steering Committee
  • CDER (OPS/OC) and ORA
  • Douglas Ellsworth, Mike Olson/Diane Obrien, Joe
    Famulare, Frank Holcomb, Moheb Nasr, Yuan Yuan
    Chiu, Ajaz Hussain (Chair)
  • Guidance writer Raj Uppoor
  • Project management Chris Cole
  • Communication tools - Web based and electronic
    tools (PAT_at_CDER.FDA.GOV)

NOT An NIR Guidance!
Options for Introducing PAT
PAT Subcommittee
  • A major source of information for the FDAs
    General Guidance on PAT
  • At the end of this meeting
  • Topics to be covered in the guidance (outline)
  • Layout general principles for setting
    specifications, validation, chemometrics
  • Consensus on benefits, definitions, terminology
  • Meeting 2?
  • More details on optimal applications,
    identification and control of critical
    formulation and process variables,
    specifications, validation, chemometrics,
    addressing OOS, .
  • Illustrative examples (for inclusion in the

PAT Subcommittee
  • Organization
  • Industry presentations to focus the discussion
  • Questions (see background packet) to stimulate
    and focus discussion
  • Four working groups
  • Benefits, technology, definitions/terminology
  • Process Analytical Validation
  • Chemometrics
  • Product/Process Development
  • Only two meetings planned

Chemometrics (Kowalski and Wold)
  • Multivariate data collection and analysis
  • DOE, PCA, PLS, non-linear PLS, neural
  • Calibration, process modeling, pattern
    recognition and classification, signal correction
    and compression
  • Statistical process control,.
  • Need information of the type of tools and general
    principles (and examples) for verification and
    validation of such analyses

  • Different perspectives, expertise, and
    affiliations - can we come on the same page by
    the end of this meeting?
  • Are two meetings sufficient to gather the
    information necessary to develop the general
  • Is the general guidance approach the most
    effective approach?
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