Risk-Based CMC Review Paradigm 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

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 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 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 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 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 Less regulatory oversight for post-approval changes More incentive for continuous product improvement Reengineered supplement review More resources for new NDA review Streamlined CMC review of resubmissions Better and less expensive drugs to patients sooner First cycle approval of new drugs Risk-based quality assessment QbD and PDR by applicant Effective communication between FDA and applicant Comprehensive QOS by applicant Less review time

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