1. Office of New Drug Chemistry (ONDC)
Risk-Based CMC Review
Moheb M. Nasr, Ph.D.
Office of New Drug Chemistry (ONDC)
OPS, CDER, FDA
DIA Annual Conference 2004
Washington, D.C.
June 16, 2004

2. Risk-Based CMC Review Current Review Practices and Challenges
Risk-Based CMC Review Initiative – An Update
Pharmaceutical Quality ?
New Vision – The Desired State
A Product Quality System for the 21st Century
The New Quality Assessment Paradigm
CMC Supplement Review
Pilot on Streamlining CMC Review of Resubmitted NDAs and Supplements

4. CMC Review IND NDA Post Approval
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

5. Completed CMC Reviews in FY 2003
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

6. Current CMC Review Practices
Highest Quality Review conducted by competent and dedicated staff
Evaluation of “ALL” CMC information in submitted applications
Adherence to FDA and ICH guidances
Tight/appropriate 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

7. Challenges
Product Quality System for the 21st Century – A new Paradigm for the regulation of Pharmaceutical Quality
First Cycle Approval
Work Load
Consistency among 19 Chemistry Teams across CDER 15 clinical divisions
Guidance and policy development
Lack of expertise in some critical CMC areas
Novel dosage forms and combination drug products
New technologies

8. Risk-Based CMC Initiative – An Update
Intended to provide regulatory relief by incorporating science-based risk assessment to CMC review
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
Relevance in the new pharmaceutical quality paradigm?
A Progressive and Expanded Approach will focus on quality assessment in entirety and associated regulatory processes

9. Pharmaceutical Quality
Quality: A product that meets customer’s 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 to establish & enforce quality standards generally in the realm of clinical performance (ultimate metric!)

10. Pharmaceutical Quality The 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

11. Pharmaceutical Quality The 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 to the patient of high quality safe and effective drugs at reasonable cost

12. 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 product and process improvement
Relevant regulatory policies and procedures are tailored to reflect current level of scientific knowledge and associated risk
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

13. 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
Minor regulatory adjustments over the years:
1978 cGMP Revision
CDER-ORA agreement in early 90’s
SUPAC, BACPAC, FDAMA in late 90’s
Team Biologics

14. Problems and Issues in Current System
For FDA:
Resource intensive
Expensive and time-consuming litigation and legal actions
Dealing with recalls and drug shortages
For Industry:
Continuous improvement discouraged
Regulatory burden, not value added
Consequences of non-compliance
For Public:
High cost of drugs
Hostility, at times, towards industry and regulators

15. 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)

16. Benefits of a Risk-Based System*
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.

17. Benefits of a Risk-Based System*
Risk-Based CMC Review
Benefits of a Risk-Based System*
Industry
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.

18. Risk-Based CMC Review
This is not a single initiative to address one dimension of a multi-dimensional, often complex, quality assessment process (not just streamlining or reducing CMC supplements, etc.)
It is the new paradigm in quality assessment of new drug applications (entire pre and post marketing activities)

19. The New Quality Assessment Paradigm
Chemistry Review vs. Quality Assessment
Chemistry Review
Review conducted by chemists
Focus on chemistry issues (drug substance synthesis, analytical methods and specifications)
Data review to generate necessary knowledge to identify CMC issues
Strict adherence to FDA and ICH guidances
Quality Assessment
Assessment conducted by interdisciplinary scientists (chemists, pharmacists, engineers and others as needed)
Focus on critical quality attributes and their relevance to safety and efficacy (chemistry, formulations, manufacturing processes, dosage forms, product performance, etc.)
Knowledge Assessment
Utilization of Risk-based analysis

20. The New Quality Assessment Paradigm
ONDC Vision: ONDC is a strong scientific organization that serves CDER, FDA, and the public through leadership in innovation and international collaboration
ONDC Mission: ONDC assesses the critical quality attributes and manufacturing processes of new drugs, establishes quality standards to assure safety and efficacy, and facilitates new drug development

21. The New Quality Assessment Paradigm
CMC specifications to be based on:
Risk-based assessment
Clinical Relevance
Safety Considerations
Process Capabilities
Knowledge gained from Pharmaceutical Development Reports
Better utilization of modern statistical methodologies
Assessment starts with a comprehensive Quality Overall Summary (QOS)
Review practices based on good scientific principles (“GSP”)
Increased emphasis on manufacturing science
Peer/critical review of CMC evaluation by FDA scientists
Integration of review and inspection (ICH Q 8, 9 & 10 ?)

22. The New Quality Assessment Paradigm
Regulatory relief based on:
Process understanding and control (pharmaceutical development reports)
Quality systems throughout manufacturing processes
Continuous improvement
Pharmaceutical Development Reports may facilitate:
Meeting first cycle approval goal
Science–based specifications
Risk-based GMP inspection

23. The New Quality Assessment Paradigm
The new ONDC organization will be structured to facilitate the implementation of the new quality assessment paradigm
The new ONDC organization will provide a better work environment to staff to facilitate superior performance and job satisfaction
Consideration given to establish an FDA CMC Scientific Advisory Board
Provide scientific consultation when needed
Oversee ONDC regulatory research program
Restructure and modernize ONDC training program
Develop a seminar series

24. The New Quality Assessment Paradigm
We developed new strategies to recruit, hire and train pharmaceutical quality assessors with expertise in drug discovery, analytical chemistry, pharmaceutical development/formulation and pharmaceutical engineering (HELP??)
We will build a strong and independent scientific organization to better serve the public and all internal (New Drugs, Compliance, Generic Drugs) and external (industry, scientific organizations and academic institutes) stakeholders
We will reengineer the CMC review process at ONDC to:
Address problems identified by FDA, Public and Industry
Meet expectations of the new paradigm and to achieve the desired state
Establish a modern quality system with appropriate metrics to measure quality of CMC review and performance

25. Proposed ICH Q 10 “Life Cycle Management Systems”
Systems for monitoring processes to demonstrate control and/or identify trends
Systems for managing and rectifying undesirable occurrences
Systems to facilitate process improvements
Systems to manage change and to monitor the effect of change

26. CMC Supplement Review
Facilitate and encourage continuous improvements resulting in down-regulation and elimination of some CMC Supplements
Comparability Protocols
Provides an opportunity to bridge current system with future paradigm
Quality by Design (QbD) Principles
Continuous Improvements
Expecting, understanding and managing changes
Evaluation of impact of proposed changes and developing strategies to address impact
Critical vs. non-critical changes
A Great Potential to down-regulate CMC supplements
Future ONDC Organization to manage CMC supplement review more efficiently to facilitate continuous post-marketing product improvement

27. Pilot on Streamlining CMC Review of Resubmitted NDAs and Supplements
Initial assessment by a senior CMC reviewer
Complete preliminary assessment within 14 days
Order referenced DMFs (not a trivial process) Prioritize issues by impact to approvability
Development of an assessment protocol
Forward initial assessment and protocol to primary reviewer
Primary reviewer
Review, identify, communicate, and resolve CMC approvability issues in a timely manner
Streamlining resubmission and supplements review to provide adequate resources for new NDAs

28. CMC Review of NDAs There is no substitute for a quality
submission, including a Comprehensive
Quality Overall Summary, which
anticipates and addresses all approvability issues

29. Acknowledgments Janet Woodcock (CDER) and the GMP Steering Committee
Helen Winkle (OPS)
Ajaz Hussain (OPS)
Chi-Wan Chen (ONDC)
Guirag Poochikian (ONDC)