Manufacturing subcommittee of the advisory committee for pharmaceutical science july 20 21 2004
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Manufacturing Subcommittee of the Advisory Committee for Pharmaceutical Science July 20-21, 2004 Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA PAT Initiative July 2001 CGMP for 21 st Century Initiative “Desired State” Medical Innovation Critical Path

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Manufacturing Subcommitteeof the Advisory Committee for Pharmaceutical ScienceJuly 20-21, 2004

Ajaz S. Hussain, Ph.D.

Deputy Director

Office of Pharmaceutical Science

CDER, FDA


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PAT Initiative

July 2001

CGMP for 21st

Century Initiative

“Desired State”

Medical Innovation

Critical Path

Initiative


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Strong

Public Health

Protection

Time

International

cooperation

Integrated quality

systems orientation

Science-based

policies and standards

Risk-based orientation

Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21st Century

FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices

http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html (August 21, 2002 )


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Directional Vectors

  • Ensure regulatory review and inspection policies are based on state-of-the-art pharmaceutical science

  • Encourage new technological advances

  • Encourage risk-based approaches that focus both industry and Agency attention on critical areas

  • Facilitate modern quality management techniques, including implementation of quality systems

  • Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency's business processes and regulatory policies concerning review and inspection activities

Second Progress Report and Implementation Plan.

http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)


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Covering the Space Defined by the Directional Vectors

Preapproval Inspection Compliance Program

Dispute Resolution Process

Risk

Pharmaceutical Inspectorate

Product Specialists on Inspection Process

Systems/Integration

Guidance on CFR Part 11

Aseptic Processing

Comparability Protocol

ICH P2, QbD, & Risk

PAT

Science


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The Scientific Opportunity

  • Pharmaceutical (development and) manufacturing is evolving from an art form to one that is now science and engineering based.

  • Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes.

http://www.fda.gov/cder/gmp/21stcenturysummary.htm


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The Risk Mitigation and Communication Opportunity

  • Intuitive/Subjective to Quantitative

    • HCCP

    • FMEA

    • Quality by Design

      • “Reliability is a design engineering discipline which applies scientific knowledge to assure a product will perform its intended function for the required duration within a given environment. This includes designing in the ability to maintain, test, and support the product throughout its total life cycle. Reliability is best described as product performance over time.”

http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html


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cGMPs

The Quality Systems Opportunity A Historical Note on Quality: Milestones in Quality Journey or Lurching from Fad to Fad?

  • Sampling Plans (‘50s)

  • Zero-Defect Movement (‘60s)

  • ISO-9000 (‘80s)

  • QS-9000

  • Malcolm Baldrige Award

  • European Quality Award

  • Total Quality Management

  • Six Sigma

    • The Ultimate Six Sigma - “The Big Q”

Pharmaceutical

Quality

System

for the 21st

Century

K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427


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A Two Year Journey? What is the Destination?

  • “Vision 2020 - I can see clearly now”

  • The “Desired State”

http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt


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http://www.fda.gov/cder/gmp/21stcenturysummary.htm

Desired State

  • Product quality and performance achieved and assured by design of effective and efficient manufacturing processes

  • Product specifications based on mechanisticunderstanding of how formulation and process factors impact product performance

  • Continuous "real time" assurance of quality


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http://www.fda.gov/cder/gmp/21stcenturysummary.htm

Desired State

  • Regulatory policies tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability

  • Risk based regulatory scrutiny relate to the:

    • level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance, and

    • the capability of process control strategies to prevent or mitigate risk of producing a poor quality product


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Meeting Objectives

  • Seek input and advise on charting the most efficient path towards the “desired state”

    • Review assessment of Chemistry, Manufacturing, and Controls (CMC) sections of submissions

    • Risk based cGMP Inspections: Selection of Manufacturing sites for inspections


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What do we wish to accomplish with ICH Q8

  • Ensure Q8 facilitates movement towards the “desired state” we have articulated

  • This will

    • Help us better understand the proposed product and process design and its relation to the intended use

      • improve process of establishing regulatory specifications

    • Improve our ability to identify and understand critical product and process factors

      • improve our understanding and confidence in risk mitigation strategies

    • Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement

    • Improve communication and systems thinking

      • More efficient review and inspection process

    • Be a “win win win” for public health, regulators and industry


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Intended Use

Route of administration

Patient population

…..

Product Design

Design Specifications

(Customer requirements)

Regulatory

Specs.

Manufacturing Process

and its Control

ICH Q8: Integrating QbD and Risk Mitigation Dimensions

Illustrative Examples of points to consider

Development Objectives

Risks to Quality

Risk of incorrect identity

Poor product & process

Changes in clinical trial product

(Bridging studies)

Inadequate Design Specifications

(e.g., TDS adhesive attribute)

Critical to quality and performance?

Risk of unqualified impurities

Risk of poor bioavailability

Risk of incorrect expiry date

Risk of inadequate controls

Risks After Approval

[Risk of SUPAC,..]

[Risk of unrepresentative test samples]

[Risk of Inadequate Facility and QS]

Tests & Controls -Risk Mitigation

ICH Q9


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Continuous Improvement – Emerging ICH Q8 “Design Space” Concept

  • Multi-dimensional space defined by critical vectors of product quality and performance

    • Examples of critical vectors

      • Robust manufacturing process – consistent, reproducible delivery of product meeting its specifications

        • Manufacturing options

      • Stability (shelf-life) and

      • Bioavailability


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Current CMC Submissions Space” Concept

raw material properties

process

conditions

environmental

Data based decisions: No Generalization


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Knowledge based decisions: Improved Ability to Generalize Space” Concept

Pharmaceutical Development Knowledge

raw material properties

process

conditions

environmental

Robust process

Stable and Bioavailable product


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cGMP Space” Concept

regulatory

oversight

ICH Q8

Company’s

Quality system

Risk

Post

approval

change

Process

Understanding

CMC

regulatory

oversight

ICH Q8&9


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Process Space” Concept

Understanding

Process

Understanding

Process

Understanding

CMC

regulatory

oversight

CMC

regulatory

oversight

CMC

regulatory

oversight

cGMP

regulatory

oversight

cGMP

regulatory

oversight

cGMP

regulatory

oversight

Company’s

Quality system

Company’s

Quality system

Company’s

Quality system

Post

approval

change

Continuous

Improvement

PAC to

Continuous

Improvement

Risk

(P/R)

Risk

Risk

ICH Q8 + Q9

Proposed

ICH Q 10


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Moving towards the “Desired State” Space” ConceptDay 1

  • Update on Current Efforts

    • ICH Q8, Q9 and proposed Q10

    • ASTM

  • Awareness topic: Filling the gaps – Research planning

    • Bayesian approaches in CMC?

    • Critical Path Initiative

  • Implementing the concepts developed in ONDC and OGD

    • Manufacturing Science

    • Quality by Design


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Moving towards the “Desired State” Space” ConceptDay 2

  • Risk based CGMP Inspections

    • Update on research study on pharmaceutical industry practices

    • Pilot model for prioritizing selection of manufacturing sites for inspections

    • CGMPs for the Production of Phase I INDs

  • Efforts on facilitating continuous improvement through reduction in the need for “Prior Approval Supplements”

    • PAT Example

    • Comparability protocol concept


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