# Presentation: 735041

## Moheb M. Nasr, Ph.D.
  Office of New Drug Chemistry (ONDC)
 OPS, CDER, FDA

Advisory Committee for Pharmaceutical Science
Manufacturing Subcommittee
July 20-21, 2004

- Moheb M. Nasr, Ph.D.
-   Office of New Drug Chemistry (ONDC)
-  OPS, CDER, FDA
- Advisory Committee for Pharmaceutical Science
- Manufacturing Subcommittee
- July 20-21, 2004

## Outline

- Current Review Practices and Challenges
- Risk-Based CMC Initiative – an Update
- New Quality Assessment Paradigm
- Chemistry Review vs Quality Assessment
- Reengineering CMC Supplement Review
- Pilot Study to Streamline CMC Review of Resubmissions

##  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		ANDA
- 					    approval** **

## ONDC Workload

- Completed CMC Reviews in FY 2003
- 159 NDAs (103 original and 56 resubmitted)
- 342 commercial INDs
- 507 research INDs
- 1725 CMC supplements (624 PAS), not including efficacy and labeling
- 1132 annual reports

## Current CMC Review Practices

- Applications
- Quality of application varies widely
- Applicants do not always:
- seek consultation with FDA through end-of-phase-2 or pre-NDA meetings
- follow recommendations or agreements made prior to NDA submissions
- have and/or provide adequate pharmaceutical development information

## Current CMC Review Practices

- Reviews
- Evaluation of _all_ CMC information in applications sometimes without differentiation of criticality – resource intensive
- Evaluation of _all_ CMC information regardless of experience and expertise – increased training needs and less-than-optimal use of resources
- Adherence to FDA and ICH guidances – applicants reluctant to take different approaches
- No in-depth review of process information due to CDER-ORA agreement in early 90’s
- Tight specification, based on limited data, to assure consistency of manufacturing processes – resulting in recalls and drug shortages

## Current CMC Review Practices

- Late and voluminous CMC amendments often lead to delayed CMC review or first-cycle non-approval
- Regulatory decisions are 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
- Guidances established to provide regulatory relief to industry sometimes result in an increased number of CMC supplements

## Problems & Issues in Current System

- For FDA:
- Resource intensive
- Dealing with recalls and drug shortages
- For industry:
- Continuous improvement discouraged
- Regulatory burden, not value added
- Consequences of out-of-specification
- For public:
- High cost of drugs
- Delay in drug approval

## Challenges and Opportunities

- Product Quality System for 21st Century – a new paradigm for regulation of pharmaceutical quality
- First-cycle approval
- Workload
- 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 & combination drug products
- New technologies

## Risk-Based CMC Initiative – an Update

- Risk-Based CMC Initiative 2000-2002
- 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 only

## Risk-Based CMC Initiative – an Update

- Intended to provide regulatory relief by incorporating science-based risk assessment to CMC review
- Relevance in the new pharmaceutical quality paradigm?
- A new progressive and expanded initiative will focus on quality assessment and associated regulatory processes

## Risk-Based Quality Assessment

- Benefits of a Risk-Based Quality Assessment*
- 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.*

## Risk-Based Quality Assessment

- Benefits of a Risk-Based Quality Assessment*
- 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.*

## Risk-Based Quality Assessment

- 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)

## 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

## New Quality Assessment Paradigm

- 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 Q8, 9, 10(?))

## 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 (PDR)
- Better utilization of modern statistical methodologies

## New Quality Assessment Paradigm

- Regulatory relief post-approval 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
- Regulatory relief post-approval

## New Quality Assessment Paradigm

- ONDC will provide a better work environment to staff to facilitate superior performance and job satisfaction
- ONDC will structured to facilitate the implementation of the new quality assessment paradigm
- ONDC will consider establishing a CMC Scientific Advisory Board to:
- Provide scientific consultation when needed
- Oversee ONDC regulatory research program
- Restructure and modernize ONDC training program
- Develop a seminar series

## New Quality Assessment Paradigm

- ONDC developed new strategies to recruit, hire, and train pharmaceutical quality assessors with expertise in drug discovery, analytical chemistry, pharmaceutical development, formulation, and pharmaceutical engineering
- ONDC is building a strong and independent scientific organization to better serve the public and all internal (OND, Compliance, OGD) and external (industry, scientific organizations and academic institutes) stakeholders

## New Quality Assessment Paradigm

-  ONDC to reengineer the CMC review process to:
- Address problems identified by FDA, industry, and public
- Meet expectations of the new paradigm and achieve the desired state
- Establish a modern quality system with appropriate metrics to measure quality of CMC review and performance

## Chemistry Reviewvs Quality Assessment

- Chemistry Review
- Review conducted by chemists
- Extensive data analysis to generate necessary knowledge and summary report of CMC issues
- Guidance-based review
- More focus on chemistry and product specification issues (drug substance characterization, synthesis, analytical methods, and specifications setting)
- Less focus on process and manufacturing
- No clear emphasis on critical CMC issues
- No peer-review process

## Chemistry Reviewvs Quality Assessment

- Quality Assessment
- Assessment conducted by interdisciplinary scientists (chemists, pharmacists, engineers, and others as needed)
- Reliance on knowledge provided by applicants, including PDR and QOS
- Risk-based assessment
- Focus on critical quality attributes and their relevance to safety and efficacy (chemistry, formulations, manufacturing processes, dosage forms, product performance, etc.)
- Question-based review
- Utilization of peer-review process

## Reengineering CMC Supplement Review

- Role of comparability protocol in the new paradigm
- Provides an opportunity to bridge current system with the new quality assessment paradigm
- Applies Quality-by-Design (QbD) principles
- Facilitates continuous improvements
- Provides a scientific basis for expecting, understanding, managing, and addressing impact of changes
- Focuses on critical vs. non-critical changes
- Has a great potential for down-regulating CMC supplements

## Reengineering CMC Supplement Review

- ONDC is exploring ways to down-regulate or eliminate certain types of CMC supplements that have minimum potential to adversely affect the I/Q/P/S/P as they relate to safety and efficacy
- ONDC to manage CMC supplement review more efficiently to facilitate continuous post-marketing product improvement and to provide more resources for new NDA review

## Pilot Study to Streamline CMC Review of Resubmissions

- A senior CMC reviewer performs initial assessment
- Completes preliminary assessment within 14 days
- Orders referenced DMFs (not a trivial process)
- Prioritizes issues by impact to approvability
- Develops an assessment protocol
- Forwards initial assessment and protocol to primary reviewer
- Primary reviewer performs in-depth assessment
- Reviews, identifies, communicates, and resolves CMC approvability issues in a timely manner
- Streamlined resubmission review can provide more resources for original NDA review

## Benefits of New Quality Assessment Paradigm

- Reengineered supplement review

- Streamlined CMC review of resubmissions

- More resources for new NDA review

- Risk-based quality assessment

- QbD and PDR by applicant

- Comprehensive QOS by applicant

- Less review time

- Effective communication between FDA and applicant

- Less regulatory oversight for post-approval changes

- More incentive for continuous product improvement

- First cycle approval of new drugs

- Better and less expensive drugs to patients sooner

## Acknowledgments

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