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OFFICE OF REGULATORY AFFAIRS

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OFFICE OF REGULATORY AFFAIRS FIELD OPERATIONS CDR Thomas R. Berry, RPh, PharmD FDA, Senior Regulatory Review Officer DEN-DO / SWR / ORA FDA For FY 2010 FDA s budget ... – PowerPoint PPT presentation

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Title: OFFICE OF REGULATORY AFFAIRS


1
OFFICE OF REGULATORY AFFAIRS FIELD
OPERATIONS CDR Thomas R. Berry, RPh, PharmD FDA,
Senior Regulatory Review Officer DEN-DO / SWR /
ORA
2
Information Disclaimer The information provided
is only intended to be general summary
information. It is not intended to take the place
of either the written law or regulations. Opinion
Disclaimer The comments and opinions expressed
are those solely of the presenter. They are not
intended to take the place of either the written
law or regulations
3
FDA
  • Center for Drug Evaluation and Research (CDER)
  • Center for Biological Evaluation and Research
    (CBER)
  • Center for Devices and Radiological Health (CDRH)
  • Center for Food Safety and Applied Nutrition
    (CFSAN)
  • Center for Veterinary Medicine (CVM)
  • National Center for Toxicological Research (NCTR)
  • Office of Regulatory Affairs (ORA)
  • Center for Tobacco Products (CTP)

4
FDA Leadership
Commissioner Margaret A. Hamburg,
MD Principle Deputy Commissioner Joshua
Sharfstein, MD Associate Commissioner for
Regulatory Affairs Dara Corrigan, Esquire
5
Commissioners Initial Steps Toward Effective
Enforcement and Public Health
  • Set post-inspection deadlines
  • Streamline the warning letter process
  • Work more closely with our regulatory partners
  • Prioritize follow-up on warning letters and other
    enforcement actions
  • Be prepared to take immediate action in response
    to public health risks
  • Develop and implement a formal warning letter
    close-out process

6
FDA Resources
  • For FY 2010 FDAs budget was 3.2 billion which
    represented a 19 increase over 2009.
  • President Obamas FY 2011 budget request for FDA
    is nearly 4 billion which represents a 6
    increase to 2.51 billion. (Percentage
    discrepancy due to anticipated collection of user
    fees from the food, tobacco and drug industries.
  • This budget would increase the agency FTE ceiling
    by approximately 1,250, bringing the workforce
    total to 13,586.

7
Dara Corrigan, Esq., ACRA
  • DHHS - Associate Deputy Assistant Secretary for
    Health Policy in the Office of the Assistant
    Secretary for Planning and Evaluation. Managed
    thirty economists and public health experts to
    provide leadership and address policy concerns
    about Medicare, Medicaid, childrens health, the
    uninsured, and public health.
  • Arnold Porter (DC-based international law firm) -
    Partner, FDA and Health Care Policy Group
  • DHHS - Acting Inspector General and Principal
    Deputy Inspector General in Office of the
    Inspector General.
  • Assistant U.S. Attorney at the Department of
    Justice
  • Deputy Chief Counsel for CMS in the Office of
    General Counsel at HHS
  • Director of Program integrity at the Centers for
    Medicare and Medicaid Services.
  • Dara earned her JD at the University of Virginia
    School of Law, and her bachelors degree at
    Baylor University in Texas.

8
ORA
  • Regulating almost 124,000 business
    establishments that annually produce, warehouse,
    import and transport 1 trillion worth of
    consumer goods is no small task. The FDA devotes
    to this crucial task, which is directed by the
    Office of Regulatory Affairs (ORA), about
    one-third of the agency's personnel. Stationed in
    more than 160 offices, resident posts and
    laboratories from coast to coast and in Puerto
    Rico, ORA's highly trained staff provides the
    eyes, ears and the long arm of the agency that
    ensures the implementation of the FDA's high
    public health standards.

9
Southwest Region

10
DEN-DO Organizational Chart
District Director
Director Denver Laboratory
11

12
National Domestic and Import Investigator
Experience Levels
13
Denver District Investigator Experience Levels
14
The Changing Face of the Denver District Office
15
  • FDA Science Initiative
  • Significant increase in sample analysis using
    high throughput methodology

16
Consumer Safety Officer
  • What is fieldwork?

17
Compliance Officer
  • Reviews and evaluates evidence and findings
    indicating a possible lack of compliance with
    Agency enforced laws and regulations.
  • Analyzes data samples and documented information
    gathered during inspections and investigations
  • Determines whether an investigation is complete
    or what additional work may be required
  • Recommends legal action to Headquarters, the
    Office of Chief Counsel, the responsible U.S.
    Attorney
  • Maintains working liaison with the U.S.
    Attorneys Office and U.S. Marshals Service in
    implementing approved actions
  • Ensures that non-compliant establishments make
    necessary changes to meet the regulations.
    Enforcement includes official correspondence as
    well as legal actions taken in a court of law

18
Consumer Safety Officers
  • Credentialed Federal Officers
  • Food, Drug and Cosmetic Act (FDC)This Act,
    passed in 1938, remains FDAs main legal basis.
    It greatly enlarged the agencys mission and
    authority by
  • requiring that new drugs be shown to be safe
    before marketing.
  • extending FDAs control to cosmetics and
    therapeutic devices.
  • authorizing factory inspections and standards of
    identity for food staples.
  • eliminating a requirement to prove intent to
    defraud in drug misbranding cases.
  • adding court injunctions to the previous
    penalties of seizures and prosecutions.

19
Major Inspection Programs
  • Imports
  • Food
  • Drug
  • Biomedical Monitoring
  • Biologics
  • Medical Device
  • Training Location
  • International

20
  • Food Safety Enhancement Act of 2009
  • Approved by the House
  • FDA Food Safety Modernization Act
  • Under review in the Senate

21
Drug
  • The term drug means (A) articles recognized in
    the official USP, official Homeopathic
    Pharmacopeia of the United States, or official
    National Formulary, or any supplement to any of
    them and (B) articles intended for use in the
    diagnosis, cure, mitigation, treatment, or
    prevention of disease in man or other animals
    and (C) articles (other than food) intended for
    use as a component of any articles specified in
    clause (A), (B), or (C).

22
Dietary Supplement
  • A statement for a dietary supplement may be made
    if the statement claims a benefit related to a
    classical nutrient deficiency disease and
    discloses the prevalence of such disease in the
    United States, describes the role of a nutrient
    or dietary ingredient intended to affect the
    structure or function in humans, characterizes
    the documented mechanism by which a nutrient or
    dietary ingredient acts to maintain such
    structure or function, or describes general well
    being from consumption of a nutrient or dietary
    ingredient.

23
  • 21st Century Reality
  • Our borders are boundaries to our jurisdiction.
  • Borders are not barriers to
  • Disease
  • Information Flow
  • Product Acquisition
  • Challenges of Globalization
  • . . . borders CAN NOT be barriers to FDAs realm
    of activities

24
Importation of FDA Regulated Products
  • 2006
  • 14.98M Lines
  • 2007
  • 16M Lines
  • 2008
  • 17.9M Lines

150 countries exporting FDA
products to US -130,000
US importers of record
-300,000 foreign manufacturers
25
(No Transcript)
26
FDAs International Presence
27
Foreign Inspection Workplan
28
Foreign Inspection/ Import Workplan
29
Domestic Inspection Workplan
30
Drug Inspection Cadre
  • Pre-Approval Inspections
  • Surveillance GMP Inspections
  • Compliance GMP Inspections
  • PADE Inspections (Phase IV)
  • PDMA Inspections
  • MedWatch Investigations
  • DQRS Investigations
  • FAR Investigations
  • Consumer / Trade Complaints
  • Pharmacy Compounding

31
Pharmacy Compounding
  • Food and Drug Administration Modernization Act of
    1997 (FDAMA)
  • November 1997, Section 127 added Section 503A to
    the FDC Act
  • Congress through Section 503A provided conditions
    under which compounded drugs could be exempt from
    the adulteration, misbranding, and new drug
    provisions of the FDC Act provided certain
    requirements were met.

32
FDA 483 Disclaimer
  • This document lists observations made by the FDA
    representative(s) during the inspection of your
    facility. They are inspectional observations, and
    do not represent a final Agency determination
    regarding your compliance. If you have an
    objection regarding an observation, or have
    implemented, or plan to implement, corrective
    action in response to an observation, you may
    discuss the objection or action with the FDA
    representative(s) during the inspection or submit
    this information to FDA at the address above. If
    you have any questions, please contact the FDA at
    the phone number and address listed above.

33
Significant Issue
1 - 21 CFR 211.165(f) - Drug products failing to
meet established standards, specifications, and
quality control criteria are not rejected. If
your active ingredient has not arrived and you
receive an immediate order for a product
containing that active ingredient, FDA still
expects you to wait for the active ingredient to
arrive from the supplier and put it in the
product.
34
Example Observations
  • The event description for complaint XXXXX states
    Baby started choking and screaming. Couldnt
    catch his breath, was crying, applied cold water
    to his mouth and threw up. She then gave him 2
    pumps of his inhaler. Heart racing very very
    fast no documentation of the result of the
    event
  • Formulation room XXX had a 2.5 diameter uncapped
    port behind formulation tank XXX exposing the
    Grade C area of formulation room XXX to the
    uncontrolled XXX room XXX.
  • There is no evidence that the firm has evaluated
    the safety and determined the acceptability of
    the introduction of this new clinical product
    and/or its excipients into the manufacturing
    facility and subsequent use on commercial
    equipment.
  • Small cryogenic vessels (home units) are filled
    from a large (XL-50) dewar located at the stand
    tank. This process was used when the van with the
    bulk unit is not available. This supply dewar had
    an industrial oxygen label with another companys
    name affixed.

35
Turbo EIR
  • Provides more consistency between inspections and
    investigators
  • Provides specific citations and examples of
    violations
  • Provides information for statistical analysis and
    identifies potential investigator / FDA /
    industry trends

36
Inspection Outcomes
  • NAI No Action Indicated
  • VAI Voluntary Action Indicated
  • OAI Official Action Indicated
  • Withhold Application
  • Regulatory Meeting
  • Untitled Letter
  • Warning Letter
  • Seizure
  • Injunction
  • Prosecution

37
Top Drug Citations (2006 2009)
38
Drug Recalls
2009 1742
  • 2008
  • 426

39
Investigators Top Ten
  • 21 CFR 211.192 Investigations of discrepancies,
    failures / CAPA
  • 21 CFR 211.22 (1) - Quality Control Unit
    Responsibilities and Procedures
  • 21 CFR 211.100 Written production and process
    control procedure deviations
  • 21 CFR 211.160 Scientific Sound Laboratory
    Controls
  • 21 CFR 211.67 Written Procedures Not Followed
    for Cleaning Maintenance of Equipment

40
Investigators Top Ten
  • 21 CFR 211.80 Written Procedures Not Followed
    for the Receipt and Testing of Components and
    Drug Product Containers
  • 21 CFR 211.84 - Certificates of Testing
    (Containers, Closures)
  • 21 CFR 211.180 Annual Product Reviews
  • 21 CFR 211.166 Stability Program does not
    support expiration dates
  • 21 CFR 211.188 Batch Production Control
    Records


41
Investigators Significant Issues
  • Allowing a new product and/or chemical entity
    into a facility to include the active
    pharmaceutical ingredient and all excipients
    before documented review and approval by Quality.
  • Process Validation/Process Capability
    Understanding and Review

Quality, Production, Materials Systems
42
Top Device Citations (2006 2009)
43
Device Recalls 2006 - 2009
44
Device Recalls 2006 - 2009
45
Concerns
  • Adequate testing programs for incoming materials
  • (audits of suppliers, acceptance of
    supplier COA)
  • Management review of complex statistical analysis
  • (Cp/Cpk, multivariate analysis, etc.)
  • - Statistics vs Biostatistics
  • - Limitations of programs
  • Laboratory staff
  • - Education/Qualifications
  • - Workload
  • - Oversight

46
Statistical Review
USL
Target
LSL
47
Statistical Review
48
Statistical Review
  • Compliance with application specifications
  • Process capability and control
  • Adherence to standard operating procedures
  • Investigation initiation and subsequent
    Corrective/Preventative Actions
  • Applicability to other batches
  • Regulatory compliance (Field Alert Reports)
  • Correct Understanding of Statistics Results

49
Statistical Review Example 1
USL
Target
LCL
LSL
50
Statistical Review Example 2
USL
Target
LCL
LSL
51
Statistical Applications
  • Provide an Educated Guess
  • Allow prediction of an outcome
  • Analysis of results to determine capabilities
  • Analysis of results to identify root causes of
    events
  • Useful in many regulatory areas to include Annual
    Product Reviews, Validations, Complaints,
    Deviations, Investigations, etc.
  • Process Analytical Technology

Must always ensure compliance with specifications
52
GMP Practice ViolationsPaxil CR Avandamet
53
Cosmetic Augmentation of the Buttocks
54
Contaminated SyringesSerratia marcesens
55
ORA / Drug Investigator
  • Questions ???
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