CMC Review in the 21st Century

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CMC Review in the 21st Century

• Moheb M. Nasr, Ph.D.
• Office of New Drug Chemistry (ONDC)
• OPS, CDER, FDA
• NASRM_at_CDER.FDA.GOV
• AAPS 39th Annual Pharmaceutical Technologies
  Conference at Arden House
• January 30, 2004

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CMC Review in the 21st Century

• Office of New Drug Chemistry (ONDC) Current
  Review Practices
• Current Challenges
• Desired State
• Recent Initiatives
• Risk Based CMC Review Initiative
• Process Analytical Technology (PAT)
• Product Quality System for the 21st Century
• Continuous Marketing Application (CMA)
• Moving Forward Future Directions

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Office of New Drug Chemistry (ONDC)

• The mission of the Office of New Drug Chemistry
  (ONDC) is to evaluate the chemistry,
  manufacturing, and controls (CMC) portion of new
  drug applications (IND and NDAs), utilizing risk
  management and current scientific principles.
  The CMC review is a key element in the
  establishment of critical quality attributes,
  which are the basis of the control of drug
  quality related to drug safety and efficacy.
  ONDC initiates and participates in guidance
  development, participates in internal and
  external meetings, presents Agency policy
  regarding CMC issues to outside audiences, and
  collaborates in research, both internally and
  externally.

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CMC Review

• To assure the identity, purity, quality, and
  strength/potency, as related to the safety and
  efficacy of new drugs throughout their life
  cycle
• IND NDA Post Approval
• ,

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ONDC WORKLOAD

• Completed CMC Reviews in FY 2003
• 159 NDAs (103 original and 56 resubmitted)
• 342 Commercial INDs
• 507 Research INDs
• 1858 CMC Supplements (820 PAS), not including
  efficacy and labeling
• 1132 Annual reports

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CMC Review Practices at ONDC

• Highest Quality Review conducted by competent and
  dedicated staff
• Evaluation of ALL CMC information in submitted
  applications
• Absolute adherence to FDA and ICH guidances
• Tight specification to assure consistency of
  manufacturing processes
• Attempts made to provide regulatory relief to
  industry resulting, at times, in an increased
  workload of ONDC reviewers
• Late and voluminous CMC submissions often leading
  to delayed CMC review
• Regulatory decisions made based on submitted data
  and individuals experience with products and
  processes
• Absence of critical information on pharmaceutical
  development prevents full utilization of
  risk-based assessment in CMC review

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Current Challenges

• Product Quality System for the 21st Century A
  new Paradigm
• First Cycle Review
• Review and Inspection Boundaries and Roles
• Work Load
• Consistency among 19 Chemistry Teams across CDER
  clinical divisions
• Guidance and policy development
• Lack of expertise in some critical CMC areas
• Novel dosage forms and combination drug products
• New technologies

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Pharmaceutical Quality

• Quality A product or service that meets/exceeds
  customers needs
• Old Paradigm
• Establishment and enforcement of public/private
  standards to assure the integrity of interstate
  commerce (adulteration, counterfeit, etc.)
• Relevance to safety and efficacy?
• New Paradigm (JW, September 17, 2003)
• FDA stands in for the customer and establishes
  enforces quality standards in the realm of
  clinical performance (ultimate metric!)

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Pharmaceutical QualityThe New Paradigm (JW)

• Clinical performance delivery of efficacy and
  safety as described in the label and derived from
  the clinical trials
• Fitness for use is a surrogate for clinical
  performance
• A product that is fit for use meets established
  quality attributes (Purity, Potency/strength,
  Identity, Bioavailability/delivery,
  Labeling/packaging, Physical performance, etc.)
• Products must be made in compliance with cGMP

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Pharmaceutical QualityThe New Paradigm (JW)

• Need to examine and evaluate linkages between
• Quality attributes and clinical performance?
• Values/specifications and safety and
  effectiveness?
• cGMP compliance/inspection and safety and
  efficacy?
• Ultimate Goal The availability of high quality
  of safe and effective drugs to the patient at
  reasonable cost

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The Desired State

• Product quality and performance are ensured
  through the design of effective and efficient
  manufacturing processes
• Product and process specifications are based on a
  mechanistic understanding of how formulation and
  process factors affect product quality and
  performance
• Continuous quality assurance and process
  improvement
• Relevant regulatory policies and procedures are
  tailored to reflect current level of scientific
  knowledge
• Risk-based regulatory approaches recognize
• the level of scientific understanding of how
  formulation and manufacturing process factors
  affect product quality and performance
• the capability of process control strategies to
  prevent or mitigate the risk of producing a poor
  quality product

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Risk Based CMC Review

• Benefits of a Risk Based System
• Patients
• Increased availability
• Faster approval of new products
• Continue to receive quality products
• FDA
• More product and process knowledge shared by
  industry
• More efficient resource allocation for review and
  inspection
• Increased trust and understanding of industry
  decision making
• FDA/PQRI Workshop, April 2003, Washington, D.C.

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Risk Based CMC Review

• Benefits of a Risk Based System
• Industry
• Fewer, more efficient, science based inspections
  resulting in increased consistency
• Faster, more consistent reviews
• Potential for reduced regulatory burden
• Manage changes and nonconformance with less FDA
  oversight
• Focuses resources on critical issues
• Flexibility to focus on what should be done, not
  what can be done
• Improves communication with FDA
• FDA/PQRI Workshop, April 2003, Washington, D.C.

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Risk Based CMC Review Initiative

• Goal To provide regulatory relief by
  incorporating science based risk assessment to
  CMC review
• Current Risk-Based CMC Initiative
• Evolved over the last few years
• Multi-Tiered (establish attributes, propose and
  finalize a drug list before determining
  eligibility for regulatory relief)
• Product Specific
• Synthetic Drug Substances only!
• Characterization achieved by traditional
  analytical techniques
• IR oral solids, oral solutions, non-sterile
  topical solutions and sterile solutions of simple
  salts
• A more progressive and expanded Approach will
  focus more on Process Understanding

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Process Analytical Technology (PAT)

• PAT Initiative only a part of the broader
  Product Quality System for the 21st Century
  Initiative
• PAT is an example of science and risk-based
  system approaches to product quality assurance
• PAT provides an opportunity to move from the
  current testing to document quality paradigm to
  a Continuous Quality Assurance paradigm that
  can improve our ability to ensure quality is
  built-in or is by design - ultimate
  realization of the true spirit of cGMP!
• Greater insight and understating of manufacturing
  processes
• At/On/In-line measurement of performance
  attributes
• Real-time or rapid feedback controls (focus on
  prevention)
• Potential for significant reduction in production
  and development cycle time
• Minimize risks of poor product quality and reduce
  regulatory concerns

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PAT Guidance - An Integrated Systems Approach

• The draft PAT guidance embraces an integrated
  systems approach to CMC review and cGMP
  inspections
• Companies will also need to coordinate product
  development, manufacturing, quality assurance,
  and information/knowledge management functions in
  an integrated manner.

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Process Analytical Technology (PAT)
Regulatory Framework

• Implementation of PAT is not a requirement
• Research exemption
• Continuous improvement without the fear of being
  considered non-compliant
• Regulatory support and flexibility during
  development implementation
• Eliminate the fear of delayed approval
• Dispute avoidance/resolution
• Science Risk based regulatory approach
• Low risk categorization based on a higher level
  of process understanding

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A Product Quality System for the 21st Century

• Initiative focus on product quality and not just
  cGMP
• Major changes in pharmaceutical business over the
  years
• Greater dependence on medicine in health care
• Advances in pharmaceutical and manufacturing
  sciences
• Applications of biotechnology
• Globalization of industry
• Some regulatory adjustments over the years
• 1978 cGMP Revision
• CDER-ORA agreement in early 90s
• SUPAC, BACPAC, FDAMA in late 90s
• Team Biologics

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A Product Quality System for the 21st Century -
Fundamental Principles

• Risk Management (priorities/resource allocation
  and setting regulatory requirements)
• Science-based regulatory approaches (conduct
  scientific risk assessment and facilitate
  technological advances)
• Strong public health focus
• International cooperation
• Assessment and implementation of appropriate
  quality management systems
• Integrated product quality regulatory practice
  (review and inspection processes)

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NEW DRUG DEVELOPMENT
Discovery/ Preclinical

IND Process
NDA Review
I
HISTORICAL
II
P O S T A P P R O V A L
III


I

CURRENT
II
Dt
III
I


Dt
FUTURE GOAL
II
III
INDUSTRY TIME


FDA TIME
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Continuous Marketing Application (CMA)

• Pilot Programs to test whether providing early
  review of selected applications and additional
  feedback and advice to sponsors can further
  shorten drug development and review times
• Enhance interaction between FDA and applicants
• Only Fast Track (FT) products are eligible
• Serious or life-threatening
• Potential to address unmet medical need

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Continuous Marketing Application (CMA)

• Pilot 1 - Reviewable Units (RU) for FT under
  PDUFA
• Review a limited number of presubmitted portions
  (RU)
• Issue a Discipline Review Letter (DRL) for each
  RU within 6 months of receipt
• Implementation October 1, 2003
• CMC
• Prefer the complete technical section
• Drug substance RU may be submitted
• Rarely, drug/biologic product RU may be submitted

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Continuous Marketing Application (CMA)

• Pilot 2 - Scientific Feedback and Interaction
  During Development of FT Products under PDUFA
• More frequent scientific interaction
• Limited to no more than one FT product per review
  division
• Implementation October 6, 2003
• Pilot 2 Applicants should describe
• Past and projected milestone in drug development
• Value of frequent communication
• Potential for improvements in the efficiency of
  drug development
• Termination
• Marketing application submitted
• Applicant withdraws from the pilot
• FDA terminates

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Problems and Issues in Current Paradigm

• For FDA
• Resource intensive
• Expensive and time-consuming litigation and legal
  actions
• Dealing with recalls and drug shortages
• For Industry
• Discourage continuous improvement
• Regulatory burden, not a value added activity
• Consequences of non-compliance
• For Public
• High cost of drugs
• Hostility, at times, towards industry and
  regulators

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Moving Forward- Future Directions

• ONDC will develop new strategies to recruit,
  hire and train CMC reviewers with expertise in
  drug discovery, analytical chemistry,
  pharmaceutical development/formulation and
  pharmaceutical engineering
• We will build a strong and independent scientific
  organization to better serve the public and all
  internal (OND, OC, OGD) and external (industry,
  scientific organizations and academic institutes)
  stakeholders
• We will reengineer CMC review process at CDER
• To address problems identified by FDA, Public and
  Industry
• To meet expectations of the new paradigm and to
  achieve the desired state
• To establish a modern quality system with
  appropriate metrics to measure quality of CMC
  review and performance

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Moving Forward- Future Directions

• ONDC will provide better work environment and job
  satisfaction to CMC reviewers
• The new ONDC organization will be structured to
  facilitate the implementation of the new review
  processes
• Consider establishing an FDA CMC Scientific
  Advisory Board
• Provide consultation
• Oversee regulatory research program
• Restructure and modernize ONDC training program
• Develop a seminar series

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Moving Forward- Future Directions

• CMC specification to be based on
• Clinical Relevance
• Process capabilities
• Risk-based assessment
• Knowledge gained from Pharmaceutical Development
  Reports
• Better utilization of modern statistical
  methodologies
• Review practices based on good scientific
  principles (GSP)
• Increased emphasis on manufacturing science
• Peer/critical review of CMC evaluation by FDA
  scientists and clinicians
• Better integration of review and inspection

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Moving Forward- Future Directions

• Regulatory relief based on
• Process understanding and control (pharmaceutical
  development reports)
• Quality systems through out manufacturing
  processes
• Continuous improvement
• pharmaceutical Development Reports may
  facilitate
• Meeting first cycle review goal
• Science based specifications
• Risk-based GMP inspection

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Acknowledgments

• Janet Woodcock (CDER)
• Helen Winkle (OPS)
• Ajaz Hussain (OPS)
• Chi-Wan Chen (ONDC)
• Chuck Hoiberg (ONDC, Pfizer)