Implementation of Quality-by-Design: ONDQA Initiatives

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Implementationof Quality-by-DesignONDQA
Initiatives
Chi-wan Chen, Ph.D. Deputy Director Office of New
Drug Quality Assessment

• Advisory Committee for Pharmaceutical Science
  October 5, 2006

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Outline

• Implementation of QbD in ONDQA
• Reorganization
• Pharmaceutical Quality Assessment System
• CMC Pilot Program
• Objectives, goal/status, process, criteria,
  observation to date, benefits/challenges
• Public meetings
• Internal trainings
• Next steps

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Reorganization

• ONDC was reorganized to Office of New Drug
  Quality Assessment (ONDQA) in November 2005
• Objective To implement PQAS
• Separation of pre-marketing (INDs/NDAs) from
  post-marketing (supplements/annual reports)
  review activities to better utilize limited
  resources
• Establishment of Manufacturing Science Branch and
  recruitment of pharmaceutical scientists,
  chemical engineers, and industrial pharmacists to
  complement current review staff

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Reorganization (contd)

• Pharmaceutical Assessment Lead (PAL) in
  Pre-Marketing Division
• Serves as liaison to clinical division
• Performs an Initial Quality Assessment (IQA), a
  big-picture assessment protocol focusing on
  critical CMC issues, and a timeline for
  completing the review
• PAL in Post-Marketing Division
• Performs a risk assessment to determine the
  extent of review needed
• Where in-depth review is needed, performs an IQA
  focusing on critical CMC issues

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Pharmaceutical Quality Assessment System

• PQAS is ONDQAs new science- and risk-based
  approach to CMC review that
• Emphasizes submissions rich in scientific
  information demonstrating product knowledge and
  process understanding
• Focuses on critical pharmaceutical quality
  attributes and their relevance to safety and
  effectiveness
• Enables FDA to provide regulatory flexibility for
  specification setting and post-approval changes
• Facilitates innovation and continuous improvement
  throughout product lifecycle

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CMC Pilot Program - Objectives

• To provide participating firms an opportunity to
  submit CMC information demonstrating
• application of quality-by-design (QbD) principles
• product knowledge and process understanding
• To enable FDA to evaluate
• CQOS new concepts and approaches (e.g., QbD,
  design space, real-time release) in Q8, Q9, Q10,
  and PAT Guidance CMC Agreement team review
• To enable FDA to seek public input in developing
  a guidance on the new PQAS

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CMC Pilot Timeline/Goal/Status

• Program timeline
• FR Notice re CMC Pilot July 14, 2005
• Deadline to request for participation March 31,
  2006
• Deadline to submit NDA or supplement March 31,
  2007
• Goal 12 original NDAs and supplements
• Status
• 11 original and supplemental NDAs accepted
• 4 submitted to date
• One approved 3 under reivew
• Others are to be submitted within a year

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CMC Pilot - Submission Criteria

• An expanded Pharmaceutical Development (P.2)
• More relevant scientific information
• Demonstrating QbD, product knowledge, and process
  understanding
• Identifying critical quality attributes (CQAs)
  and how they relate to safety and effectiveness
• Linking material attributes and process
  parameters (CPPs) to quality attributes
• Identifying possible sources of variability and
  how associated risks can be mitigated
• Describing process controls and quality assurance
  strategies
• A comprehensive Quality Overall Summary (CQOS)

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CMC Pilot - Review Process

• CMC assessment performed by a team of experienced
  reviewers with
• good understanding of the new PQAS, and
• strong background in pharmaceutical and
  manufacturing sciences
• Process managed and overseen by ONDQA IO with PM
  support
• Integrated review/inspection team
• Frequent meetings with applicant before
  submission, during review, and after approval

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CMC Pilot - Expanded P.2

• All pilot NDAs to date provided more scientific
  information than typical NDAs regarding
• Formulation and product development
• Process understanding and optimization
• Most demonstrated process reproducibility, but
  not necessarily process robustness
• The more relevant scientific information is
  useful in facilitating CMC review and justifying
  proposed regulatory flexibility

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CMC Pilot - Application of QbD

• All pilot NDAs to date contained some elements of
  QbD
• Critical quality attributes (CQAs)
• Formulation development
• Risk assessment design of experiments
• Impact of DS/excipient attributes on DP
  manufacturability and/or CQAs
• Process development impact of process parameters
  on CQAs
• Design space for critical DS/excipient attributes
  and CPPs
• Other observations
• Process reproducibility, but not necessarily
  process robustness, demonstrated
• Process analyzers used to collect data in
  development, but not for commercial production

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CMC Pilot - Design Space

• Issues raised
• How were design space and control space
  established for each unit operation?
• Is the design space for each unit operation
  independent of equipment design and batch size?
• How does control space relate to design space?
• How does control space relate to operational
  ranges in the Master Batch Record?

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CMC Pilot - Regulatory Flexibility

• Examples of proposed regulatory flexibility
• In-process testing in lieu of end-product
  testing, e.g., blend uniformity in lieu of
  content uniformity
• Real-time release in lieu of end-product testing
• Annual report for post-approval changes within
  established design space
• Degree of flexibility granted would depend on
  level of knowledge and understanding demonstrated

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CMC Pilot - Regulatory Agreement(under
consideration)

• An agreement between FDA and applicant on
  critical CMC issues which could potentially
• Enable applicant to share QbD information without
  concerns about regulatory implications
• Identify CQAs and CPPs, their ranges and
  interrelationship
• Describe design space for excipient attributes
  and process parameters
• Describe control strategy
• Describe change control protocols for assessing
  post-approval changes to CQAs, CPPs, process,
  equipment, scale, etc., and associated regulatory
  mechanisms
• Describe how design space will be reassessed,
  verified, or redefined

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CMC Pilot - Benefits

• Pilot enables industry and FDA to
• Explore ways to implement Q8, Q9, PAT, and PQAS
• Pilot enables FDA to
• Better define what constitutes a QbD-based
  submission
• Better establish what constitutes a science-based
  risk assessment
• Use experience gained to develop a guidance on
  QbD and PQAS
• Good science leads to better quality product,
  fewer product rejects/recalls, and enhanced
  public health protection

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CMC Pilot - Challenges

• Level of detail in submission demonstrating
  product knowledge and process understanding
• Expectations for a QbD-based submission while
  addressing traditional requirements
• Providing regulatory flexibility while assuring
  product quality
• Industrys continuous apprehension in sharing
  information, including failed experiments, with
  FDA
• Cultural changes needed in industry and FDA
• More resources needed initially for industry FDA

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CMC Pilot - Summary

• Pilot Program got off to a good start in meeting
  its initial goal for industry participation
• Aspects of QbD were included in Pilot NDAs, and
  expanded PD is useful
• CQOS needs further development
• Scientific approaches to CQAs, CPPs, design
  space need further development
• Regulatory flexibility is being proposed
• CMC Regulatory Agreement is being explored
• Program benefits FDA in developing guidance to
  implement QbD and PQAS
• Challenges remain for industry and FDA

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Public Meetings

• CMC Workshop, October 2005
• ACPS, October 2005
• CMC-GMP Track, DIA Meeting, June 2006
• PDA-FDA Meeting, September 2006
• ACPS, October 2006
• AAPS Meeting, October 2006
• ISPE/PDA Q8/Q9 Workshop, December 2006
• FDA Quality Initiatives Workshop, February 2007

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Internal Trainings

• Hands-on training through team review
• NDA Peer Review Forum twice a month
• ONDQA Focus Groups
• Biotech Dissolution Drug Eluting Devices
• Excipients Fermentation Products
• Inhalation Products Manufacturing Science
• Oral Dosage Form Formulation Quality by Design
  Topical Products Transdermal Delivery System
• ONDQA Science Forum once a year
• ONDQA Seminar Series by outside experts
• Other subject matter trainings on an ad hoc basis

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Next Steps

• Sharing of lessons learned with each applicant
  under CMC Pilot Program
• Sharing of lessons learned from CMC Pilot Program
  within FDA and with industry
• Evaluate need for new guidances on
• PQAS
• QbD
• CQOS
• CMC Regulatory Agreement