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FDA cGMP

Training Program


cGMP in the USA
Nicholas Buhay
Deputy Director
Division of Manufacturing & Product Quality
Office of Compliance, CDER, FDA


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

FD&C 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.
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

CGMP legal principles
Non-compliance = eventual problems
Superpotency/subpotency
Contamination
Misbranding
Bioavailability
Safety and efficacy
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)
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)
CGMP Legal Principles
Current = dynamic
Standards evolve over time
Good practices
Minimal standards
Not best practices
Unless best is, in fact, current minimal
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
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
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...
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 address
problems
e.g., Penicillin contamination control
Technology neutral
Scalable
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 Ex:USP not required for release test
Other Sub Chapters
Labeling and Repackaging
Stability/Expiration
Process Validation
Etc

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

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.
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
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...
Overview of CGMP
requirements in the regulation
CGMP Regulations
21 CFR 211
Subpart A General Provisions
this is minimum CGMP
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
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
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.
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
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
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
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
Overview of CGMP
requirements
CGMP Regulations
21 CFR 211
Subpart H Holding and Distribution
quarantine before release
store under appropriate conditions
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....
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
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....
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....
Overview of CGMP
requirements
CGMP Regulations
21 CFR 211
Subpart J Records and Reports
distribution records, with lot numbers(except medical
gases)
complaint files
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
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.)
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
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
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.


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.
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.
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
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
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

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
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


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

Input for CGMP Changes
Establishment inspections
Industry changes/problems
Defect reports/complaints/recalls
Litigation
Agency application reviews
Trade/scientific literature
Citizen petitions
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
We Have Discussed
Legal bases for CGMP
CGMP legal principles
CGMP Implementation Tools
CGMP Resources
Overview of CGMP requirements
Integrity of Records and Data
Montrose Metro Centre II Room 438
11919 Rockville Pike
Rockville, MD 20852
Nicholas Buhay
Deputy Director
Division of Manufacturing
and Product Quality, HFD-320
Center for Drug Evaluation and Research
Phone: 301-827-8940 Fax: 301-827-8907
E-mail: buhay@cder.fda.gov
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