Implementation of Quality by Design (QbD): Status, Challenges and Next Steps

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Implementation of Quality by Design (QbD)
Status, Challenges and Next Steps

• Moheb M. Nasr, Ph.D.
• Office of New Drug Quality Assessment (ONDQA),
  OPS, CDER
• Advisory Committee for Pharmaceutical Science
  (ACPS)
• October 5, 2006

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Outline

• FDA Presentations
• Topic Introduction - Moheb Nasr, Ph.D.
• FDA Perspective
• ONDQA Initiatives Chi-Wan Chen, Ph.D.
• OGD Initiatives Lawrence Yu, Ph.D.
• OBP Initiatives Steven Kozlowski, M.D.
• GPHA Perspectives Gordon Johnston
• PhRMA Perspectives Robert Baum, Ph.D.
• Summary and Next Steps Helen Winkle
• Discussions and Recommendations

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The Desired State A Mutual Goal of Industry,
Society, and the Regulators
A maximally efficient, agile, flexible
pharmaceutical manufacturing sector that reliably
produces high-quality drug products without
extensive regulatory oversight.
Janet Woodcock, M.D. October 5, 2005
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What is Quality by Design (QbD)?

• In a Quality by Design system
• The product is designed to meet patient needs and
  performance requirements
• The process is designed to consistently meet
  product critical quality attributes
• The impact of starting raw materials and process
  parameters on product quality is understood
• The process is evaluated and updated to allow for
  consistent quality over time
• Critical sources of process variability are
  identified and controlled
• Appropriate control strategies are developed

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Quality by Design
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Approaches to Pharmaceutical Development
Aspects Current QbD
Pharmaceutical Development Empirical, Random, Focus on optimization Systematic, Multivariate experiments, Focus on control strategy and robustness
Manufacturing Process Fixed Adjustable within design space, managed by companys quality systems
Process Control Some in-process testing PAT utilized, Process operations tracked and trended
Product Specification Primary means of quality control, based on batch data Part of the overall quality control strategy, based on desired product performance
Control Strategy By testing and inspection Risk-based control strategy , real-time release possible
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Why QbD?
Current System
Submission (Lack of PD
Traditional CMC Review
Development (Empirical)
MS)
Desired State
Submission (Knowledge Rich in PD
Development (QbD)
PQAS
MS)
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Terminology

• Quality Attributes
• A physical, chemical, or microbiological property
  or characteristic of a material that directly or
  indirectly impacts quality
• Critical Quality Attributes (CQAs)
• A quality attribute that must be controlled
  within predefined limits to ensure that the
  product meets its intended safety, efficacy,
  stability and performance
• Critical Process Parameters (CPPs)
• A process parameter that must be controlled
  within predefined limits to ensure the product
  meets its pre-defined quality attributes

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Dosage Form and Manufacturing Process Development

• Start product design in early phases of
  development
• This may be an iterative/continuous process
• Base critical quality attributes on
  desired/targeted product performance requirements
  
• QbD is full understanding of product and process
  and implementation of that understanding
• QbD is more than traditional process and
  formulation optimization
• QbD is more than justification of CQAs and CPPs

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Dosage Form and Manufacturing Process Development

• Product design
• Evaluate early phase data - determination of
  optimum dose, route of administration,
  therapeutic index, PK profile, site of
  absorption, chemical stability, etc.
• Identify and justify desired quality attributes
• Prior knowledge can also be used to justify
  selection of certain quality attributes

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Dosage Form and Manufacturing Process Development

• Formulation development
• Materials
• Chemical and physical properties affect CQA e.g.,
  moisture and particle size distribution, which
  may influence downstream process parameters and
  product performance
• Need to understand variability in order to
  adjust process and/or set appropriate controls
• Selection of formulation components based on
  compatibility and performance requirements

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Dosage Form and Manufacturing Process Development

• Process Development
• For each unit operation
• Understand how process parameters affect CQA
• Conduct risk analysis/assessment to
• Identify significant process parameters and raw
  materials attributes
• Develop risk mitigation strategies
• Establish appropriate control strategy to
  minimize effects of variability on CQAs

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Dosage Form and Manufacturing Process Development
Design Space

• ICH Q8 Definition
• The multidimensional combination and interaction
  of input variables (e.g., material attributes)
  and process parameters that have been
  demonstrated to provide assurance of quality
• Design space is proposed by the applicant and is
  subject to regulatory assessment and approval
• Design space concept is applicable to new and
  legacy drug products
• Manufacturing experience and product knowledge

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Designing/Setting Specifications in the Future

• Relate specifications to critical quality
  attributes
• Provide scientific rationale to justify proposed
  acceptance criteria
• In a QbD system, certain traditional end product
  release testing may prove to be unnecessary

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Real Time Release (RTR)

• Ability to evaluate and ensure acceptable quality
  of in-process and/or final product based on
  process data, including valid combination of
• Assessment of material attributes by direct
  and/or indirect process measurements,
• Assessment of critical process parameters and
  their effect on in-process material attributes
• Process controls

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Implementation Challenges

• Different strategies/approaches to accommodate
  diversity of drug products
• Small chemicals vs. large Biologicals
• Oral solids vs. complex/novel dosage forms
• Drug vs. Combination Products
• Expectations for a QbD - based submissions while
  addressing traditional requirements
• Providing regulatory flexibility while assuring
  product quality

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Implementation Challenges

• Industry continuous apprehension in sharing
  information with FDA
• Different regulatory processes (BLA, NDA, ANDA,
  follow-on, etc.) and associated regulatory
  practices and cultures
• Integration of review and inspection
• Workload
• FDA Resources
• Cultural changes needed in industry and FDA

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FDAs Expectations

• The current system is adequate for regulatory
  submission
• Quality is assured by testing and inspection
• Considerable regulatory oversight
• Substantial efforts and considerable waste
• However, QbD is the desired approach
• QbD principles should result in a higher level of
  assurance of product quality
• Additional product and process understanding
  could lead to regulatory flexibility
• Implementation of QbD by industry could enhance
  manufacturing efficiency
• Focus remains on availability of safe, effective
  and high quality pharmaceuticals

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Questions
 
 
 
 

• Do you agree that application of QbD principles
  should result in (1) a higher level of assurance
  in product quality, (2) more flexibility for the
  applicant to make continuous improvement and (3)
  less need for FDA regulatory oversight on
  post-approval changes?
• Should FDA develop a new guidance on QbD to
  facilitate its implementation or rely only on ICH
  guidelines?
• What are the relevant scientific areas of
  disagreement among the stakeholders that the FDA
  should seek to establish consensus through
  additional efforts?

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Questions
 
 
 
 

• Are there additional mechanisms for educating
  reviewers and industry on changes being made?
• Are the ONDQA plans and efforts adequate to
  implement QbD?
• OGD Question-based Review initiative is currently
  limited to generic drug product. Should it be
  expanded to include drug substance?
• Should FDA develop a pilot program to explore
  specific QbD issues that are important for
  biotechnology products?