Upload
logan-morrison
View
233
Download
2
Tags:
Embed Size (px)
Citation preview
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
2
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
3
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
4
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
5
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
6
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
7
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
8
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
9
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
10
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
11
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
12
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
13
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.
14
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.
15
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)
16
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
17
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(?))
18
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
19
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
20
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
21
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
22
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
23
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
24
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
25
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
26
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
27
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
28
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
29
Acknowledgments
Janet Woodcock (CDER) and the GMP Steering Committee
Helen Winkle (OPS) Ajaz Hussain (OPS) Chi-Wan Chen (ONDC) Guirag Poochikian (ONDC)