Quality System for Product Quality (CMC) Review

1. Quality System forProduct 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 ObjectivesTo 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. 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 Scientific Evaluation ofthe Drug Substances (Active Ingredients)Data/InformationKnowledge/ Value

11. 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 Scientific Evaluation ofthe Drug Substances (Active Ingredients)Data/InformationKnowledge/Value

12. 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 Scientific Evaluation ofthe Drug Substance (Active Ingredient)Data/InformationKnowledge/Value

13. 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 Scientific Evaluation ofthe Drug Products (Dosage Forms)Data/InformationKnowledge/Value

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

15. 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 Scientific Evaluation ofthe Drug Products (Dosage Forms)Data/InformationKnowledge/Value

16. 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 Scientific Evaluation ofthe Drug Products (Dosage Forms)Data/InformationKnowledge/Value

17. 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 Scientific Evaluation ofthe Drug Products (Dosage Forms)Data/InformationKnowledge/Value

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 Systemfor 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 Systemfor 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!