1. Quality System for Product Quality (CMC) Review
FDA Science Board
April 9, 2003
Rockville, MD
Yuan-yuan Chiu, Ph.D.
Director, Office of New Drug Chemistry
OPS/CDER/FDA

2. Office of New Drug Chemistry (ONDC)
Three Divisions: Division of New Drug Chemistry (DNDC)
Teams: Each Division has a number of review teams co-located with a therapeutic group (e.g., Cardio-Renal)
Each team comprises a number of reviewers, including a Team Leader

4. CMC Review Staff (Chemistry, Manufacturing and Controls)
Academic Training
Advanced degree (vast majority with Ph.D.) in chemistry (organic, analytical, physical, medicinal), chemical engineering, biochemistry, molecular biology, biology, microbiology, pharmaceutical science, pharmacy
Post-graduate Experience
Academia
Research Institutes
Industry

5. CMC Review: Current Objectives
To assure the quality of investigational new drugs
Clinical trial material is safe for all phases (phase 1, 2 and 3) of the studies
Clinical trial material used ensures that the data generated from expanded studies are reliable
(Graded nature of data/information depends on the phase of study, patient population, duration of study, route of administration, and complexity and novelty of the product)

6. CMC Review: Current Objectives To assure the identity, purity, quality, and strength/potency, as related to the safety and efficacy of the marketed new drugs throughout their life cycle
IND
NDA
Post Approval

7. CMC Review: Current Objectives
To facilitate drug development and approval
Clear written guidance provided for various phases of drug development, and for NDA submission
Encourage End-of-Phase 2 Meeting

8. Product Types Drug Substances (Active Ingredients) Synthetic compounds
Fermentation products
Natural products:
animal/human-derived (except human blood)
plant derived
minerals
Semi-synthetic
Biotechnology products
1st generation: hormones, MnAb-Drug conjugates
2nd generation: amino acids, vitamins, statins, antibiotics, etc
Synthetic genes

9. Product Types Drug Products (Dosage Forms)
Oral: tablets (immediate or modified release), capsules, solutions, suspensions, etc.
Topical: lotions, creams, ointment, etc.
Transdermal: patches, suppository, etc.
Nasal: drops, spray
Ophthalmic: solutions, creams, ointments, etc.
Inhalation: metered-dose, dry-powder
Injectables: solutions, suspensions, solids for reconstitution, implants, etc.
Intrauterine and Intravaginal: IUD, rings, etc.
Otic: solutions, ointments, etc.

10. Scientific Evaluation of the Drug Substances (Active Ingredients) Data/Information Knowledge/ Value
Source material evaluation
Structural characterization
Physical, chemical, biological properties
Manufacturing and process control
Viral clearance studies
Assure identity and safety (e.g., BSE)
Proof identity
Assist formulation design and predict in-vivo performance
Assess production (process validation, demonstration/production batch analysis are GMP function)
Assure safety

11. Scientific Evaluation of the Drug Substances (Active Ingredients) Data/Information Knowledge/Value
Impurity profile analysis and qualification
Analytical methods and clinical batch results
Identity test
Assay
Purity/impurity/degra-dants
Other relevant drug-specific tests (e.g., solid state tests)
Assure safety
Establish specification* at release time and through shelf-life based on clinical batches Assure safety and efficacy
*NDA specifications usually are adopted as compendial specifications at a later time

12. Scientific Evaluation of the Drug Substance (Active Ingredient) Data/Information Knowledge/Value
Stability studies and results
Stress condition
Long term study
Accelerated condition
Establish storage condition and expiry or
re-test date
Assure safety and efficacy throughout shelf-life

13. Scientific Evaluation of the Drug Products (Dosage Forms) Data/Information Knowledge/Value
Composition and components
Excipients controls
Quality attributes
Performance attributes
Pharmaceutical development (ICH-Q)
Define final formulation, linkage to clinical formulations
Assure manufacturing and product performance
Understand formulation design, dosage form characteristics and critical components and attributes

14. Scientific Evaluation of the Drug Products (Dosage Forms) Data/Information Knowledge/Value
Assess production (process validation, demonstration/production batch analysis are GMP function)
Assure safety *
Manufacturing and process control
Impurities/degradants analysis and qualification

15. Scientific Evaluation of the Drug Products (Dosage Forms) Data/Information Knowledge/Value
Analytical methods and clinical batch results
Identity test
Appearance
Assay
Content Uniformity
Purity/impurity/degra-dants
Other relevant drug-specific tests (e.g., dissolution, drug release rate, sterility)
Establish specification* at release time and through shelf-life based on clinical batches
Assure product performance
Assure safety and efficacy
*NDA specifications usually are adopted as compendial specifications at a later time

16. Scientific Evaluation of the Drug Products (Dosage Forms) Data/Information Knowledge/Value
Container/closure system*
Material qualification
Compatibility to drug product
Functional tests
*when serves as a delivery device
Assure safety (e.g., leacheable for parenterals)
Appropriate for use

17. Scientific Evaluation of the Drug Products (Dosage Forms) Data/Information Knowledge/Value
Stability
Accelerated condition
Long term studies
Reconstituted/admixture studies
In use studies
Labels and certain sections of package insert
Establish storage condition, special handling instruction, in-use time, and expiry. Assure safety and efficacy Assure safety and efficacy throughout shelf-life
Provide clear and accurate information for patients and health care providers

18. CMC Review Challenges Lack of full manufacturing information
CMC review is separated from inspection with limited or no communication between the reviewers and investigators
Reviewers have no access to inspection results (483 - inspection observations, turbo 483, established inspection reports)
Compressed drug development time leads to optimization of manufacturing process after NDA approval

19. CMC Review Challenges
Data and information cover multiple scientific areas
Emerging new science and technology in formulation design, manufacturing process and novel dosage forms
Reviewers are expected to have broad knowledge to address all scientific and technical issues for all types of products

20. CMC Review Challenges
Increasing need to coordinate on generic products evaluation
Changes in patients involvement in medicine and patients expectation
Consolidation of CDER/CBER products

21. ONDC Initiatives ICH Common Technical Document - Quality
Implemented interim specifications at approval, and final specifications, skip lot testing and sunset testing post-approval
Limited involvement in pre-approval inspections
Expert review teams for special products (e.g., biotechnology products, meter-dosed inhalation products, botanical products)
Chemistry symposia and ONDC scientific rounds
Peer review - discussion on selected INDs/NDAs

22. ONDC Initiatives Good Review Practice
Review templates including executive summary
Good review guides for drug substances and products
Mapped the current process and begun to evaluate areas where changes need to be made
Professional development
Plant orientation program
Plant residency program
Modified QC program
CMC Coordinating Committee
Participated in 21st Century GMP Initiatives

23. Desired States
Product quality and performance achieved and assured by design of effective and efficient manufacturing processes
Product specifications based on mechanistic understanding of how formulation and process factors impact product performance
Continuous “real time” assurance of quality
Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability
Risk based regulatory scrutiny that relates to the level of scientific understanding of how formulation and manufacturing process factors effect product quality and performance and the capability of process control strategies to prevent or mitigate risk of producing a poor quality product

24. Benefit of a Quality System for CMC Review
Improved scientific underpinning in review
Question- and risk-based review
Risk assessment based on science
Decision based on critical analysis and thinking
Improved review standards
Enhanced peer review and feedback loop
Knowledge is integrated and shared
Improved service to patients, health care professional and other customers
Better performance measurements

25. Benefit of a Quality System for CMC Review
Professional recognition internally and externally
Better focused training and targeted hiring
More flexible and efficient use of resources
Incorporate best practices through entire ONDC organization
Continuous personal and organization improvement
Encourage and enhance innovation
Adoption to changes and agility for future

26. Quality System Initiative
Internal conceptual discussions on QS
OPS/ONDC Quality System Steering Committee
ONDC Quality System Working Group

27. Quality System: Next Steps
Recruit a Quality System specialist as a consultant through contract
Strategic planning and Quality System design
Identify customers
Survey customers to determine their needs
Establish metrics for accomplishment
Establish milestones: short term and long term goals
Determine implementation process
Continuous improvement program

28. Welcome Recommendations and Advice from Science Board!