Transcript Risk-Based CMC Review Paradigm Moheb M. Nasr, Ph.D.

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
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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
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To assure the identity, purity, quality, and
strength/potency, as related to the safety
and efficacy of new drugs throughout their
life cycle
IND
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NDA
Post
approval
ANDA
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 I
Division of New Drug Chemistry II
(HFD-810)
(HFD-820)
(HFD-830)
John Simmons, Division Director
Eric Duffy, Division Director
Hasmukh Patel, Deputy Director
594-2570
FAX 827-4590
Blair Fraser, Deputy Director
827-6420
FAX 827-0878
David Lin, Acting Division Director
Norman Schmuff, Acting Deputy Director
Cardio-Renal
(HFD-110)
Kasturi Srinivasachar
594-5376
Fax 594-5494
Neurology
(HFD-120)
Maryla Guzewska
594-5571
FAX 594-2859
Oncology I
(HFD-150)
Nallaperumal
Chidambaram
594-5763
FAX 594-0498
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Metabolic and
Endocrine
(HFD-510)
Mamta GautamBasak
827-6430
Psychological
(HFD-120)
Thomas Oliver
594-2850
FAX 594-2859
Oncology II
(HFD-150)
Rebecca Wood
594-2473
FAX 594-0499
Reproductive
and Urologic II
(HFD-580)
Vacant
827-4237
FAX 827-4267
Division of New Drug Chemistry III
827-2030
FAX 827-2103
Medical Imaging/
Radiopharmaceutical
(HFD-160)
Eldon Leutzinger
827-7510
FAX 480-6036
Metabolic and
Endocrine
(HFD-510)
Stephen Moore
827-6430
FAX 443-9282
Anti-Infective
(HFD-520)
James Vidra
827-2174
FAX 827-2325
Dermatologic
and Dental
(HFD-540)
Vacant
827-2041
FAX 827-2075
Anesthetic, Critical
Care, and Addiction
(HFD-170)
Ravi Harapanhalli
827-7443
FAX 443-7068
Pulmonary and
Allergy
(HFD-570)
Rick Lostritto
827-1050
FAX 827-1271
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
Gastro-Intestinal and
Coagulation
(HFD-180)
Liang Zhou
827-7310
FAX 443-9285
Reproductive and
Urologic I
(HFD-580)
Moo-Jhong Rhee
827-4237
FAX 827-4267
Ophthalmics
(HFD-550)
Linda Ng
827-2511
FAX 827-2531
Anti-Inflammatory/
Analgesics
(HFD-550)
John Smith
827-2529
FAX 827-2531
ONDC Workload
Completed CMC Reviews in FY 2003
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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
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Applications
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Quality of application varies widely
Applicants do not always:
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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
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Reviews
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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-thanoptimal use of resources
Adherence to FDA and ICH guidances – applicants
reluctant to take different approaches
No in-depth review of process information due to CDERORA 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
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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
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For FDA:
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For industry:
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Continuous improvement discouraged
Regulatory burden, not value added
Consequences of out-of-specification
For public:
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Resource intensive
Dealing with recalls and drug shortages
High cost of drugs
Delay in drug approval
Challenges and Opportunities
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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
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Risk-Based CMC Initiative 2000-2002
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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
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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
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FDA
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Increased availability
Faster approval of new products
Continue to receive quality products
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
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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
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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
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ONDC Vision:
ONDC is a strong scientific organization that serves
CDER, FDA, and the public through leadership in
innovation and international collaboration
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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
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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
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CMC specifications to be based on:
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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
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Regulatory relief post-approval based on:
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Pharmaceutical Development Reports may
facilitate:
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Process understanding and control (Pharmaceutical
Development Reports)
Quality systems throughout manufacturing processes
Continuous improvement
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Meeting first cycle approval goal
Science-based specifications
Risk-based GMP inspection
Regulatory relief post-approval
New Quality Assessment Paradigm
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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:
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Provide scientific consultation when needed
Oversee ONDC regulatory research program
Restructure and modernize ONDC training program
Develop a seminar series
New Quality Assessment Paradigm
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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
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ONDC to reengineer the CMC review
process to:
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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
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Chemistry Review
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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
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Quality Assessment
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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
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Role of comparability protocol in the new paradigm
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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
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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 postmarketing product improvement and to provide
more resources for new NDA review
Pilot Study to Streamline CMC
Review of Resubmissions
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A senior CMC reviewer performs initial assessment
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Primary reviewer performs in-depth assessment
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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
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
Less regulatory
oversight for postapproval changes
Streamlined
CMC review of
resubmissions
More
resources
for new
NDA review
QbD and PDR
by applicant
Risk-based
quality
assessment
Comprehensive
28 QOS by applicant
Less review
time
More incentive for
continuous product
improvement
First cycle
approval of
new drugs
Better and less
expensive
drugs to
patients sooner
Effective
communication
between FDA
and applicant
Acknowledgments
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Janet Woodcock (CDER) and the GMP
Steering Committee
Helen Winkle (OPS)
Ajaz Hussain (OPS)
Chi-Wan Chen (ONDC)
Guirag Poochikian (ONDC)