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
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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
– Can’t ‘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
» Doesn’t 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
– Today’s 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
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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
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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/c’s
• test to identify each component
• tests on components for conformance with specs
• test c/c/c’s 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 FDA’s 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 FDA’s 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 applicant’s 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
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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
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Legal bases for CGMP
CGMP legal principles
CGMP Implementation Tools
CGMP Resources
Overview of CGMP requirements
Integrity of Records and Data
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
Montrose Metro Centre II Room 438
11919 Rockville Pike
Rockville, MD 20852
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