FDA cGMP Training Program - PowerPoint PPT Presentation

Loading...

PPT – FDA cGMP Training Program PowerPoint presentation | free to view - id: 510332-NjA1O



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

FDA cGMP Training Program

Description:

Training Program cGMP in the USA Nicholas Buhay Deputy Director Division of Manufacturing & Product Quality Office of Compliance, CDER, FDA An Outline Legal bases for ... – PowerPoint PPT presentation

Number of Views:3976
Avg rating:5.0/5.0
Slides: 56
Provided by: PaulM133
Category:
Tags: fda | cgmp | drugs | program | training

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: FDA cGMP Training Program


1
FDA cGMP Training Program
  • cGMP in the USA
  • Nicholas Buhay
  • Deputy Director
  • Division of Manufacturing Product Quality
  • Office of Compliance, CDER, FDA

2
Introduction to Drug
Current Good Manufacturing Practice Of US FDA
3
An Outline
  • Legal bases for CGMP
  • CGMP legal principles
  • CGMP Implementation Tools
  • CGMP Resources
  • Overview of CGMP Requirements
  • Integrity of Records and Data

4
FDC Act 501(a)(2)(B)
A drug shall be deemed adulterated if ... the
methods used in, or the facilities or controls
used for, its manufacture, processing, packing,
or holding do not conform to or are not operated
or administered in conformity with current good
manufacturing practice ...
more...
5
FDC Act 501(a)(2)(B)
to assure that such drug meets the requirements
of this Act as to safety and has the identity and
strength, and meets the quality and purity
characteristics, which it purports or is
represented to possess.
6
CGMP legal principles
  • Quality built into product
  • By taking care in making medicine
  • Cant test into product the quality
  • Without/Inadequate CGMP
  • Product(s) adulterated(defects need not be shown)
  • Firm and its management are responsible

7
CGMP legal principles
  • Non-compliance eventual problems
  • Superpotency/subpotency
  • Contamination
  • Misbranding
  • Bioavailability
  • Safety and efficacy

8
CGMP Legal Principles
  • Scope
  • Ingredients (APIs excipients)
  • Finished dosage forms administered to
    humans/animals
  • OTC, Rx products
  • Biologics, veterinary drugs
  • Drugs undergoing study(IND, etc)
  • Manufacturers, test laboratories,
    packagers(including pharmacies)

9
CGMP legal principles
  • Excluded from the CGMP requirement
  • Positron emission tomography, per FDAMA (own
    CGMP to be developed)
  • Drug products compounded per Section 503 Pharmacy
    Compounding (FDAMA)

10
CGMP Legal Principles
  • Current dynamic
  • Standards evolve over time
  • Good practices
  • Minimal standards
  • Not best practices
  • Unless best is, in fact, current minimal

11
CGMP Legal Principles
  • Feasible and valuable
  • No threshold for percentage in practice
  • Doesnt have to be predominant
  • Enforceable even if nobody is doing it
  • Stronger case if someone is doing it

12
The CGMP Regulation
  • CGMP for Finished Pharmaceuticals 21 CFR 210, 211
  • First issued June 1963
  • Todays version September 1978
  • Scope
  • Dosage forms for human/vet/biologics
  • OTC, Rx, IND, NDA, Medical Gases
  • Not pharmacies, ingredients, non-clinical
    research, etc

13
The CGMP Regulation
  • CGMP for Finished Pharmaceuticals 21 CFR 210, 211
  • Substantive
  • Force and effect of law
  • Constitute major part of (not entire) CGMP

more...
14
The CGMP Regulation
  • CGMP for Finished Pharmaceuticals 21 CFR 210,
    211
  • Establish what to do, not how to do
  • Minimal standards
  • Maximum flexibility
  • Specific enough to addressproblems
  • e.g., Penicillin contamination control
  • Technology neutral
  • Scalable

15
CGMP Implementation Tools
  • Compliance Policy Guides
  • Specific actions we do related to CGMP
  • Examples
  • Sub Chapter 410 Bulk Drugs
  • The regulations for finished pharmaceuticals will
    be applied as guidelines for bulk drugs
  • Sub Chapter 420 Compendial (USP)/Test
    Requirements ExUSP not required for release test
  • Other Sub Chapters
  • Labeling and Repackaging
  • Stability/Expiration
  • Process Validation
  • Etc

16
CGMP Implementation Tools
  • CGMP Guidance Documents
  • Principles
  • Not requirements
  • Agency current thinking
  • Detailed, technical
  • Expression of How to meet what to do
    (requirements)
  • Shape industry behavior
  • offers routes to efficiency in meeting CGMP
    requirement, evaluation of compliance

17
CGMP Implementation Tools
  • CGMP Guidance Documents (Examples)
  • General Principles of Process Validation
  • Compressed Medical Gases
  • Sterile Drug Products Produced by Aseptic
    Processing
  • Guideline on the Preparation of Investigational
    New Drug Products

more...
18
CGMP Implementation Tools
  • CGMP Guidance Documents
  • Investigating Out of Specification Test Results
    for Pharmaceutical Production
  • Manufacturing, Processing or Holding of Active
    Pharmaceutical Ingredients

19
CGMP Implementation Tools
  • CGMP Compliance Programs Instructions to FDA
    inspectors
  • Drug Manufacturing Inspections Program
  • Systems-based assessment of site
  • Preapproval Inspection Program
  • Points to inspect
  • Laboratory support
  • Regulatory approaches

20
CGMP Implementation Tools
  • CGMP Guides to Inspection of.
  • Help field investigators apply CGMP
  • Uncover need for CGMP changes
  • Specific to topics (e.g., cleaning validation)

21
CGMP Resources
  • Internet WWW site by DMPQ
  • http//www.fda.gov/cder/dmpq
  • CGMP regulations and ongoing changes
  • Preamble to the CGMP regulation
  • Division subject contacts
  • Medical gases
  • Active pharmaceutical ingredients
  • Human Drug CGMP Notes/Policy
  • etc.

22
Overview of CGMP requirements in the regulation
  • CGMP Regulations
  • 21 CFR 210
  • Status of the regulations
  • Applicability of the regulations
  • Definitions
  • Batch
  • Lot
  • In-process material
  • Quality control unit
  • Representative sample
  • etc

23
Overview of CGMP requirements in the regulation
  • CGMP Regulations
  • 21 CFR 211
  • Subpart A General Provisions
  • Subpart B Organization an Personnel
  • Subpart C Buildings and Facilities
  • Subpart D Equipment
  • Subpart E Control of Cmpnts/Cntr/Closures
  • Subpart F Production and Process Controls
  • Subpart G Packaging and Labeling Controls

more...
24
Overview of CGMP requirements in the regulation
  • CGMP Regulations
  • 21 CFR 211
  • Subpart A General Provisions
  • this is minimum CGMP

25
Overview of CGMP requirements in the regulation
  • CGMP Regulations
  • 21 CFR 211
  • Subpart B Organization and Personnel
  • There shall be a quality control unit
  • quality control unit responsibility to
    approve/reject

26
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart C Buildings and Facilities
  • buildings shall be.suitable
  • operations to be in specifically defined
    areas.separate. Or such other control systems
    for .operations as are necessary to prevent
    contamination or mix-ups. (see list, includes
    aseptic processing)
  • separate facilities for penicillin
  • building.shall be.clean and sanitary

27
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart D Equipment
  • surfaces .shall not be reactive, additive, or
    absorptive
  • Equipment.shall be cleaned, maintained and
    sanitized.

28
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart E Control of Components, Containers and
    Closures
  • containers and closures .handled in a manner to
    prevent contamination.
  • Testing or examination of c/c/cs
  • test to identify each component
  • tests on components for conformance with specs
  • test c/c/cs microscopically, for adulterants,
    microscopically

29
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart F Production and Process Controls
  • written procedures for production and process
    control
  • formulated not less than 100
  • portions of components identified, examined by a
    2nd person before dispensed for use in
    manufacture
  • sampling and testing of in-process materials and
    products, some specified
  • time limits
  • reprocessing allowed, but controlled

30
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart G Packaging and Labeling Controls
  • examination, approval of labels, labeling
  • strict control over labeling issue, and return to
    stock
  • written procedures, physical separation of
    labeling operations
  • examination of materials before use
  • inspection of facilities immediately before
  • tamper resistant packaging (for OTC products)
  • expiration dating

31
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart H Holding and Distribution
  • Subpart I Laboratory Controls
  • Subpart J Records and Reports
  • Subpart K Returned and Salvaged Drug Products

32
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart H Holding and Distribution
  • quarantine before release
  • store under appropriate conditions

33
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart I Laboratory Controls
  • establish specs, standards, sampling plans, test
    procedures
  • calibration, of laboratory equipment
  • test each batch of drug product
  • adequate acceptance criteria
  • validate test methods
  • conduct stability program

more....
34
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart I Laboratory Controls
  • Special tests
  • sterility and pyrogenicity
  • ophthalmic ointments for foreign/abrasive
    particles
  • controlled release products for rate of release
  • keep reserve samples
  • test non-penicillin products for penicillin when
    reasonable possibility of exposure to presence of
    penicillin

35
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart J Records and Reports
  • keep records, make available for inspection
  • conduct annual review of each drug product for
    changes to specs, control procedures
  • keep equipment cleaning and use log
  • keep component, container, closure and labeling
    records more....

36
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart J Records and Reports
  • have SOP for master production and control
    record, maintain record
  • use batch production and control records for
    manufacture, keep records
  • records to be reviewed/approved by qual control
    unit
  • complete data derived from all tests necessary to
    assure compliance

more....
37
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart J Records and Reports
  • distribution records, with lot numbers(except
    medical gases)
  • complaint files

38
  • Problem
  • Drug Regulatory Program depends heavily on the
    reliability (i.e. truthfulness, completeness and
    accuracy) of data information in records
  • Applications for approval AIP
  • Manufacturing Controls documentation non-AIP
  • Historical experience with broad scale
    unreliability of data in records or in conduct
    related to records

39
Data and records that are not acceptable or are
misleading
  • What are some characteristics of data that lack
    integrity?
  • Untrue, made up, false, no source in an event
  • Omission of significant data from the submission
    that is determined to be material to the review
    process. Data that is not submitted, but should
    have been
  • Inaccurate (e.g. First data failed specs, retest
    data passes specs, no lab investigation, but
    retest data is submitted to the application.)

40
Records Must be True
  • All data and information in records submitted to
    FDA supporting documents in the possession of
    the applicant are accurate true representations
    of -
  • Actual tests performed the test results
  • Actual manufacturing quality control steps
    procedures associated with the development and
    manufacture of the submission batch
    (clinical/pilot or biobatch)
  • any other actions and conditions associated with
    the application

41
  • Wrongful Acts
  • Any act or conduct that subverts the integrity of
    the review process, including, but not limited to
    the following
  • submitting fraudulent applications
  • offering or promising a bribe or illegal
    gratuities
  • making an untrue statement of a material fact
    (e.g. false statement, a misstatement or an
    omission of a fact)
  • submitting unreliable data which results from
    system-wide or firm-wide behavior

42
  • Wrongful Acts (continued)
  • An untrue statement of material fact is a false
    statement, a misstatement or an omission of a
    fact that is important in the review process.
  • System-wide incompetence is also a wrongful act
  • When an untrue statement of material fact or
    system-wide incompetence is found, several steps
    are required to the invoke the AIP including
  • Documentation of a pattern or practice of
    wrongful acts.
  • Ensuring that the untrue statements are material
    facts.

43
  • Pattern or Practice
  • Pattern- More than one instance of errors or acts
    involving the subject matter important to the
    evaluation of an application
  • Practice- An act or process of doing something
    affecting subject matter important to the
    evaluation of an application
  • A practice can be one or more acts or processes.
    A pattern or practice can occur in one or more
    applications.

44
  • If submitted to an Application
  • The AIP procedures broadly define the term,
    application to include, but not be limited to,
    any application, amendment, supplement or other
    submission made by an applicant.
  • Submitted is an understandable term and
    includes documents received by the review branch.
  • Wrongful acts also include omissions of data
    and/or information that should have been
    submitted to an application.

45
  • Food, Drug, and Cosmetic Act
  • Section 505(e) (excerpt below)
  • Numbered Part 5
  • The Secretary shall, after due notice and
    opportunity for hearing to the applicant,withdraw
    approval of an application with respect to any
    drug under this section, if the Secretary finds.
  • (5) that the application contains any untrue
    statement of a material fact

46
  • TO INVOKE AIP
  • Documentation of a pattern or practice of
    wrongful conduct that raises significant
    questions about the reliability of data submitted
    to an application



    - wrongful acts
    - pattern or practice
    - unreliable data

47
  • Restore FDAs Confidence in Data???
  • Cooperation with investigators
  • Identification of involved individuals
  • Credible internal review actions
  • Problem analysis/identify all instances of
    wrongful acts
  • Use of impartial auditor/Outside consultant
  • Audit Plan, audits, audit reports
  • Other measures as FDA deems appropriate

48
  • Restore FDAs Confidence in Data
  • Corrective Action Operating Plan
  • Analysis of audit findings
  • Implementation of auditor recommendations
  • Actions taken to correct fraud/wrongful acts,
    e.g.
  • Withdraw applications recall products
  • Timetable
  • Identification of persons assigned to complete
    and verify corrective actions
  • Comprehensive ethics program
  • Procedures for monitoring effectiveness of the
    plan
  • Training in the requirements of the Act and 18
    USC 1001

49
  • Corrective Actions Plan Evaluation
  • Monitor applicants actions/inquiries during
    internal review
  • Inspection to assess actions taken by applicant
    to determine if
  • Internal Review performed adequately
  • Corrective Action Operating Plan implemented
    adequately
  • Submit recommendation to CDER to remove site
    from the policy
  • Expect a long time to pass before restoration

50
Overview of CGMP requirements
  • CGMP Regulations
  • 21 CFR 211
  • Subpart K Returned and Salvaged Drug Products
  • if conditions cast doubt returned product shall
    be destroyed unless proved ok by test,
    examination, investigation
  • salvage only if evidence from tests and
    inspection show all standards met

51
Input for CGMP Changes
  • Establishment inspections
  • Industry changes/problems
  • Defect reports/complaints/recalls
  • Litigation
  • Agency application reviews
  • Trade/scientific literature
  • Citizen petitions

52
Management of CGMP Regulatory Program
  • FDA/CDER
  • OC/Division of Manufacturing and Product Quality
  • maintenance of the regulation
  • definitive interpretation
  • manage guidance development
  • develop, operate, evaluate programs
  • train FDA/outreach to industry

53
We Have Discussed
  • Legal bases for CGMP
  • CGMP legal principles
  • CGMP Implementation Tools
  • CGMP Resources
  • Overview of CGMP requirements
  • Integrity of Records and Data

54
Nicholas Buhay Deputy Director Division of
Manufacturing and Product Quality, HFD-320 Center
for Drug Evaluation and Research
E-mail buhay_at_cder.fda.gov
Montrose Metro Centre II Room 438 11919 Rockville
Pike Rockville, MD 20852
55
Return to Main Menu
About PowerShow.com