Using Manufacturing Science and Risk Management Principles to Achieve Quality by Design

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Using Manufacturing Science and Risk Management
Principles to Achieve Quality by Design

• PhRMA Perspective
• G.P.Migliaccio
• FDA Manufacturing Subcommittee
• September 17, 2003

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Objectives

• Design quality into pharmaceutical manufacturing
  processes.
• Encourage innovation and continuous quality
  improvement in pharmaceutical manufacturing.
• Encourage flexibility in the associated
  regulatory processes.

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Key Definitions

• Risk
• The probability of a manufacturing event
  occurring and impacting fitness-for-use, factored
  by the potential severity of that impact.

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Key Definitions

• Manufacturing Science
• The body of knowledge available for a specific
  product or process, including critical quality
  attributes and critical process parameters,
  process capability, manufacturing technologies,
  process control technologies and the quality
  systems infrastructure.

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How do we develop a quantitative measure of
Manufacturing Science?
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Manufacturing Science

• API
• Critical attributes (physical and chemical)
• Compatibility with excipients
• Excipients
• Critical physiochemical and biopharmaceutical
  attributes

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Manufacturing Science

• Drug Product Formulation
• Rationale for dosage form
• Formulation development
• Physiochemical attributes and relationship to
  product quality
• Performance testing

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Manufacturing Science

• Drug Product Manufacturing Process
• Critical to quality manufacturing steps
• Manufacturing technologies
• Critical to quality process parameters
• Relationship of critical to quality parameters to
  quality
• Process control technologies
• Sterilization method (if applicable)

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Manufacturing Science

• Manufacturing Facility
• Quality Systems Infrastructure
• Inspectional Performance

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Manufacturing Science Metrics

• Manufacturing Science
• API
• Excipients
• DP Formulation
• DP Product
• Quality Systems

• Potential Metrics
• Process Complexity
• Process Robustness
• Process Capability

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Defining the Level of Risk

• Complexity
• Lower complexity generally means lower risk.
• Robustness
• Higher robustness generally means lower risk.
• Process Capability
• Higher CPk generally means lower risk.

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Mitigating Risk

• For higher risk products and processes, advanced
  manufacturing and process control technologies
  can be used to mitigate risk.
• For inherently low risk products, advanced
  technologies may not provide any benefit.

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Examples of Risk Mitigation

• Process automation
• Isolators and closed systems
• Dedicated equipment and closed systems
• PAT
• Vision Systems

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Quantitative Method

• An algorithm could be development to assign a
  Manufacturing Science Factor to any process as a
  relationship of
• Process complexity
• Process robustness
• Process capability
• Risk mitigation

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How Do We Operationalize?

• Establish Three Working Groups Within PQRI
• Manufacturing Science WG
• Risk Management WG
• Regulatory Process (Change Management) WG

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Manufacturing Science WG

• Propose methodology for classifying process
  complexity and robustness.
• Propose methodology for sharing knowledge on
  product/process understanding, complexity,
  robustness and capability (knowledge required to
  classify risk).

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Risk Management WG

• Propose Risk Assessment Model
• Agree on Risk Mitigation Strategies

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Regulatory Process WG

• Develop agreement on handling of Manufacturing
  Science knowledge in the review process.
• Propose post-approval change management
  requirements.

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Benefits of Quality by Design

• Enhanced quality assurance
• Encourages knowledge sharing
• Promotes increased process understanding
  (mechanistic view)
• Promotes effective use of FDA and Industry
  resources
• Facilitates innovation and continuous improvement

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Summary

• FDA and Industry support for the establishment of
  PQRI Working Groups is essential to
  operationalize Quality by Design.