Pharmaceutical Quality for the 21stst Pharmaceutical by tpr17675


									Pharmaceutical Quality for the 21st

         Moheb M. Nasr, Ph.D.
             CDER, FDA

             CAMP Annual Meeting
              Gaithersburg, MD
              February 2, 2005

Pharmaceutical Quality for the 21st
 GMP Final Report (September 29, 2004)
   Specific Objectives
   Key Accomplishments
   Plan for Meeting the Needs of Tomorrow (CPQ)
 ONDC’s New Quality Assessment System (ONDC
 White paper)

           Specific Objectives
To encourage the early adoption of new technological advances
by the pharmaceutical industry
To facilitate industry application of modern quality management
To encourage implementation of risk-based approaches that
focus both industry and Agency attention on critical areas
To ensure that regulatory review and inspection policies are
based on state-of-the-art pharmaceutical science
To enhance the consistency and coordination of FDA’s drug
quality regulatory programs especially review and inspection

         Guiding Principles

Risk-based orientation
Science-based policies and standards
Integrated quality systems orientation
International cooperation
Strong public health protection

       Key Accomplishments
Adoption of a Quality Systems Model for Agency
Development of a Quality Systems Guidance for
CGMP Regulation
Implementation of Risk-Based Management Plan
Development of a new risk-based pharmaceutical
quality assessment system to replace the current CMC
review system in the Office of New Drug Chemistry
within CDER

       Key Accomplishments
Development of several science-based policies (e.g.,
Guidance on PAT and Aseptic Processing) and training
programs to support risk-based regulatory decisions
and continuous improvement in pharmaceutical
Establishment of a Council on Pharmaceutical Quality
   Policy development,
   Coordination and implementation

   Science Based Regulations of
         Product Quality
The Agency must ensure that science-based policies
and standards form the foundation upon which product
quality regulation is based
This is illustrated by our shift from the current CMC
review system to a new risk-based pharmaceutical
quality assessment system within CDER’s ONDC.
  This new system will encourage the implementation of new
  technologies, such as process analytical technology (PAT),
  and facilitate continuous manufacturing improvements via
  implementation of an effective quality system.

   Science Based Regulations of
         Product Quality
PAT team and Manufacturing Science Working Group
  Final PAT guidance
  PAT team has completed its training and certification
  Significant support structure (International collaboration, ASTM’s
  committee on Pharmaceutical Applications of Process Analytical
  technology, etc.)
International Collaborations
  ICH Activities (ICH Q 8, Q 9 and Q 10)
  Bilateral and multilateral agreements
  the FDA is seeking membership in the Pharmaceutical
  Inspection Cooperation Scheme (PIC/S)

   Plan for Meeting the Needs of
   Under the leadership of the Council on Pharmaceutical

Develop additional guidance on quality systems for
pharmaceutical manufacturing so that the Agency’s goal to
enhance and modernize the regulation of pharmaceutical
manufacturing and product quality is met
Continue development of the risk-based pharmaceutical quality
assessment system that will replace the current CMC review
system to remove hurdles to continuous improvement following
drug approval
Revise the 1987 industry guideline on Process Validation to
include 21st century concepts, including risk management and a
life-cycle approach

   Plan for Meeting the Needs of
Continue to explore and formalize risk-based tools to enhance
FDA's regulatory oversight
Refine the CGMPs and meet our harmonization (internal and
international) goals
Continue timely communication of our current thinking on
various quality issues to the public to facilitate compliance with
FDA requirements
Further enhance FDA’s own quality systems (including more
mechanisms to facilitate communication within the Agency)
Continue and expand on opportunities to integrate science-based
policy and standards into our product quality regulatory

ONDC’s New Quality Assessment

ONDC’s Organization and workload
Current CMC Review Practices
New Risk-based Quality Assessment System
Restructuring ONDC

                                                                Office of New Drug Chemistry
                                                                Moheb M. Nasr, Office Director

                                                                    Chi-Wan Chen, Deputy Director
                                                                     Guirag Poochikian, Associate
                                                                      David Morley, Senior Program Analyst
                                                                       Michael Folkendt, Special Assistant

  Division of New Drug Chemistry I                            Division of New Drug Chemistry II                     Division of New Drug Chemistry III
                   (HFD-810)                                                      (HFD-820)                                        (HFD-830)
  John Simmons, Division Director                                  Eric Duffy, Division Director                      Chi-Wan Chen, Acting Division
       Hasmukh Patel, Deputy Director                                 Blair Fraser, Deputy Director                              Director
                594-2570                                                        827-6420
                                                                                                                    Norman Schmuff, Acting Deputy Director
              FAX 827-4590                                                    FAX 827-0878
                                                                                                                                  FAX 827-2103

                                        Metabolic and
   Cardio-Renal                           (HFD-510)         Medical Imaging/                  Metabolic and      Anti-Infective                  Dermatologic
     (HFD-110)                          Mamta Gautam-     Radiopharmaceutical                   Endocrine          (HFD-520)                      and Dental
Kasturi Srinivasachar                       Basak              (HFD-160)                        (HFD-510)                                         (HFD-540)
                                                                                                                  James Vidra
      594-5376                             827-6430         Eldon Leutzinger                  Stephen Moore         827-2174                        Vacant
   Fax 594-5494                                                 827-7510                         827-6430        FAX 827-2325                      827-2041
                                                             FAX 480-6036                     FAX 443-9282                                       FAX 827-2075
   Neurology                     (HFD-120)
    (HFD-120)                                             Anesthetic, Critical                Pulmonary and        Anti-Viral                    Special Pathogen
                               Thomas Oliver
                                                          Care, and Addiction                      Allergy         (HFD-530)                     and Immunologic
 Maryla Guzewska                  594-2850
                               FAX 594-2859                    (HFD-170)                         (HFD-570)                                          (HFD-590)
     594-5571                                                                                                    Stephen Miller
  FAX 594-2859                                             Ravi Harapanhalli                    Rick Lostritto      827-2392                       Mark Seggel
                                                                827-7443                          827-1050       FAX 827-2510                         (acting)
                                Oncology II                  FAX 443-7068                      FAX 827-1271                                          827-2425
    Oncology I                   (HFD-150)
    (HFD-150)                  Rebecca Wood
   Nallaperumal                   594-2473                Gastro-Intestinal and              Reproductive and    Ophthalmics                     Anti-Inflammatory/
   Chidambaram                 FAX 594-0499                   Coagulation                       Urologic I        (HFD-550)                         Analgesics
     594-5763                                                  (HFD-180)                        (HFD-580)          Linda Ng                          (HFD-550)
   FAX 594 0498                                                Liang Zhou                     Moo-Jhong Rhee       827-2511                          John Smith
                                        Reproductive            827-7310                                         FAX 827-2531                         827-2529
                                        and Urologic II      FAX 443-9285                                                                          FAX 827-2531
                                                                                               FAX 827-4267
                                        FAX 827-4267                                                                                                     12
          ONDC Workload

Completed CMC Reviews in FY 2004

185 NDAs (119 original and 66 resubmitted)
411 commercial INDs
468 research INDs
1738 CMC supplements (728 PAS), not
including efficacy and labeling
2422 annual reports

       Current Practices
Quality of application varies widely
Many applications lack adequate pharmaceutical
development information - prevents full utilization
of risk-based assessment in CMC review
Insufficient scientific dialogue between CMC
reviewers and applicants
Evaluation of all CMC data in submissions –
resource intensive
Evaluation of entire CMC section by a single
chemistry reviewer regardless of experience and
      Current Practices
Valuable review resources are used to generate a
comprehensive application summary
Strict adherence to FDA and ICH guidances
No in-depth review of manufacturing process
information – possibly 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 Practices
Late and voluminous CMC amendments often lead
to delayed CMC review or first-cycle non-approval
(internal and external causes)
Guidances established to provide regulatory relief
to industry often result in an increased number of
CMC supplements

Pharmaceutical Quality

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 manufacturing process
     No clear emphasis on critical CMC issues
     No peer-review process

Chemistry Review vs. Quality Assessment
  Quality Assessment
    Focus on critical quality attributes and their relevance to
    safety and efficacy (chemistry, formulations, stability,
    manufacturing processes, bioavailability, product
    performance, etc.)
    Assessment conducted by interdisciplinary scientists
    (chemists, pharmacists, engineers, and others as needed)
    Ability to predict quality and performance
    Reliance on knowledge provided by applicants, including
    Pharmaceutical Development Reports and QOS
    Reduction in submission requirements (e.g., MV)
    Risk-based assessment
    Question-based review
    Utilization of peer-review process

     New Quality Assessment Paradigm-
             Major Features
Better Utilization of Resources
CMC Advisory Board
Integration of relevant Biopharm and Micro functions into CMC
Integration of Review and Inspection
New Organization Structure
Establish a Post-marketing Evaluation Division
Establish a Manufacturing Science Branch
Implementation of RPMs
Gradual but timely implementation
Recruiting, Training and Professional Development
Culture Change (ONDC is a Scientific and learning organization)

Quality Overall Summary (QOS)

Under development
  To facilitate the development of “Big Picture” assessment
  To create an NDA summary thus eliminating the need to
  use valuable resources to generate an NDA summary as
  part of NDA review
  To faciliate the establishment of a database to track CMC
  review, identify critical CMC issues and review outcome
  (pre and post marketing)

Better Utilization of Resources
Initial assessment of NDA, starting with QOS,
by a Pharmaceutical Assessment Lead (PAL)
equipped with appropriate knowledge and
skills relevant to specific clinical indication
Initial assessment will identify critical
pharmaceutical quality areas, develop an
evaluation protocol and time line to complete
the review

Establish a CMC Advisory Board

CMC Advisory board to consist of scientists with appropriate
academic, industrial and/or regulatory experience
Possibly as a WG under ACPS
Additional FDA experts will participate in meetings as needed
(Clinicians, PharmTox, Biostatistics, Compliance, etc.)
Critical CMC issues and findings will come before the CMC
Scientific Advisory Board (NME, Non-approval, For cause,
Meetings to be held on regular basis
The Advisory Board will help establish an appropriate training
program and a seminar series

Integration of Relevant Biopharm and
  Micro functions into CMC Review

Integration of all quality review functions of
new drugs
Allows for the incorporation of manufacturing
science into all aspects of CMC review
Optimization of setting drug
release/dissolution specification
Sterility Assurance (micro review) is a critical
manufacturing process attribute
Integration of Review and Inspection
  To be further developed with compliance and ORA
  Establish criteria for participation in routine GMP inspection
  Develop criteria and strategies for participation in pre-
  approval inspection:
     For cause
     Clear identification of critical manufacturing and product
     Pre inspection meeting/discussion
     Incorporation of inspection findings into CMC review
     Resolution of scientific/technical issues at facilities

Pharmaceutical Quality Standards
  CMC specifications to be based on:
    Risk-based assessment
    Clinical relevance (performance and safety
    Process knowledge and understanding - not only process
    capability and analytical method limitations
    Knowledge gained from Pharmaceutical Development
    Reports (PDR)
    Better utilization of modern statistical methodologies
    These issues will be addressed at PQRI Workshop in
    March 2005

       Restructuring ONDC
Establishing the Office of New Drug Quality
Assessment (ONDQA)

Our Vision: ONDQA is a strong scientific
organization that serves CDER, FDA, and the
public through leadership in innovation and
international collaboration

Our Mission: ONDQA assesses the critical quality
attributes and manufacturing processes of new
drugs, establishes quality standards to assure safety
and efficacy, and facilitates new drug development

          Restructuring ONDC
Dedicated premarketing and postmarketing divisions
Pharmaceutical Assessment Leads (PALs) in the premarketing
divisions, serving as a dedicated scientific liaison to a respective
clinical division, will develop a “Big-Picture” assessment
protocol and timeline for completing the review
The PAL in the postmarketing division will perform an initial
assessment of each CMC supplement to determine the need for
further evaluation and to develop assessment protocols to
address major CMC changes prior to work assignments

Establish a Post-marketing Evaluation Division
  To streamline and improve the supplement review
  process, develop meaningful strategies to reduce and
  eliminate the need for certain types of supplements,
  and to provide scientific input into the evaluation of
  critical pharmaceutical manufacturing issues (pre and
  post approval)
  Increase efficiency by separating post-approval
  supplement review from NDA review (CMC
  supplements should not be considered or handled as
  a resubmitted NDA)

Establish a Manufacturing Science Branch

 Establish a Manufacturing Science Branch to address
 critical manufacturing issues in NDAs and post-
 marketing supplements
 Team will be made of:
    ONDC existing resources (Industrial pharmacy,
    PAC/PAT, others)
    Pharmaceutical and Chemical engineers with
    extensive industry experience


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