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

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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

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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

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Office of New Drug Chemistry (HFD-800)

Moheb Nasr, Office Director

Chi-Wan Chen, Deputy Director Guirag Poochikian, Associate Director David Morley, Senior Program Analyst

Michael Folkendt, Special Assistant (301) 827-5918 (Office) (301) 594-0746 (Fax)

Division of New Drug Chemistry II (HFD-820)

Eric Duffy, Division Director Blair Fraser, Deputy Director

827-6420 FAX 827-0878

Division of New Drug Chemistry III (HFD-830)

David Lin, Acting Division Director Norman Schmuff, Acting Deputy Director

827-2030 FAX 827-2103

Cardio-Renal (HFD-110)

Kasturi Srinivasachar 594-5376

Fax 594-5494

Neurology (HFD-120)

Maryla Guzewska 594-5571

FAX 594-2859

Medical Imaging/ Radiopharmaceutical

(HFD-160)

Eldon Leutzinger 827-7510

FAX 480-6036 Psychological

(HFD-120)

Thomas Oliver 594-2850

FAX 594-2859

Oncology I (HFD-150)

Nallaperumal Chidambaram

594-5763 FAX 594-0498

Oncology II (HFD-150)

Rebecca Wood 594-2473

FAX 594-0499

Anesthetic, Critical Care, and Addiction

(HFD-170)

Ravi Harapanhalli 827-7443

FAX 443-7068

Gastro-Intestinal and Coagulation (HFD-180)

Liang Zhou 827-7310

FAX 443-9285

Metabolic and Endocrine (HFD-510)

Stephen Moore 827-6430

FAX 443-9282

Metabolic and Endocrine (HFD-510)

Mamta Gautam-Basak

827-6430

Pulmonary and Allergy

(HFD-570)

Rick Lostritto 827-1050

FAX 827-1271

Reproductive and Urologic I (HFD-580)

Moo-Jhong Rhee 827-4237

FAX 827-4267

Anti-Infective (HFD-520)

James Vidra 827-2174

FAX 827-2325

Anti-Viral (HFD-530)

Stephen Miller 827-2392

FAX 827-2510

Special Pathogen and Immunologic

(HFD-590)

Mark Seggel (acting)

827-2425 FAX 827-2510

Dermatologic and Dental (HFD-540)

Vacant 827-2041

FAX 827-2075

Anti-Inflammatory/ Analgesics (HFD-550)

John Smith 827-2529

FAX 827-2531

Ophthalmics (HFD-550)

Linda Ng 827-2511

FAX 827-2531

Division of New Drug Chemistry I (HFD-810)

John Simmons, Division Director Hasmukh Patel, Deputy Director

594-2570 FAX 827-4590

Reproductive and Urologic II

(HFD-580)

Vacant 827-4237

FAX 827-4267

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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.

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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)

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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

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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(?))

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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

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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

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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

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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

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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

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Chemistry Reviewvs 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

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Chemistry Reviewvs 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

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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

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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

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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

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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

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Acknowledgments

Janet Woodcock (CDER) and the GMP Steering Committee

Helen Winkle (OPS) Ajaz Hussain (OPS) Chi-Wan Chen (ONDC) Guirag Poochikian (ONDC)