FDA
FDA CGMP
CGMP
China
China
Training
Training Program
Program
December
December 55-7,
-7, 2005
2005
Ying
Ying Jie
Jie Convention
Convention Center
Center
Beijing
Beijing University
University Beijing
Beijing
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
An Outline
Outline
• Legal bases for CGMP
• CGMP legal principles
• CGMP Implementation Tools
• CGMP Resources
• Overview of CGMP Requirements
• Integrity of Records and Data
FD&C
FD&C Act;
Act; 501(a)(2)(B)
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
FD&C Act;
Act; 501(a)(2)(B)
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
CGMP legal
legal principles
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
CGMP legal
legal principles
principles
• Non-compliance = eventual problems
– Superpotency/subpotency
– Contamination
– Misbranding
– Bioavailability
– Safety and efficacy
CGMP
CGMP Legal
Legal Principles
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
CGMP legal
legal principles
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
CGMP Legal
Legal Principles
Principles
• Current = dynamic
– Standards evolve over time
• Good practices
– Minimal standards
– Not “best practices”
» Unless “best” is, in fact, current minimal
CGMP
CGMP Legal
Legal Principles
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
The CGMP
CGMP Regulation
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
The CGMP
CGMP Regulation
Regulation
• CGMP for Finished Pharmaceuticals
21 CFR 210, 211
– Substantive
» Force and effect of law
– Constitute major part of (not
entire) CGMP
more...
The
The CGMP
CGMP Regulation
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
CGMP Implementation
Implementation
Tools
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
CGMP Implementation
Implementation
Tools
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
CGMP Implementation
Implementation
Tools
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
CGMP Implementation
Implementation
Tools
Tools
• CGMP Guidance Documents
– Investigating Out of Specification
Test Results for Pharmaceutical
Production
– Manufacturing, Processing or
Holding of Active Pharmaceutical
Ingredients
CGMP
CGMP Implementation
Implementation
Tools
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
CGMP Implementation
Implementation
Tools
Tools
• CGMP Guides to Inspection of….
– Help field investigators apply
CGMP
»Uncover need for CGMP changes
»Specific to topics (e.g., cleaning
validation)
CGMP
CGMP Resources
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
Overview of
of CGMP
CGMP
requirements
requirements inin the
the
regulation
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
Overview of
of CGMP
CGMP
requirements
requirements inin the
the
regulation
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
Overview of
of CGMP
CGMP
requirements
requirements inin the
the
regulation
regulation
• CGMP Regulations
– 21 CFR 211
»Subpart A General Provisions
• this is minimum CGMP
Overview
Overview of
of CGMP
CGMP
requirements
requirements inin the
the
regulation
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
requirements
• CGMP Regulations
– 21 CFR 211
»Subpart H Holding and Distribution
• quarantine before release
• store under appropriate conditions
Overview
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Overview of
of CGMP
CGMP
requirements
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
Data and
and records
records that
that
are
are not
not acceptable
acceptable or
or
are
are misleading
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
Records Must
Must be
be True
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
ÎAny 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)
ÎAn untrue statement of material fact is a false statement,
a misstatement or an omission of a fact that is important
in the review process.
ÎSystem-wide incompetence is also a wrongful act
ÎWhen 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
ÎPattern- More than one instance of errors or acts
involving the subject matter important to the
evaluation of an application
ÎPractice- An act or process of doing something
affecting subject matter important to the evaluation
of an application
ÎA 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
ÎThe 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.
ΓSubmitted” is an understandable term and includes
documents received by the review branch.
ÎWrongful 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
ÎDocumentation 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???
ÎCooperation with investigators
ÎIdentification of involved individuals
ÎCredible internal review & actions
ÎProblem analysis/identify all instances of wrongful acts
ÎUse of impartial auditor/Outside consultant
ÎAudit Plan, audits, audit reports
ÎOther measures as FDA deems appropriate
Restore FDA’s Confidence in
Data
ÎCorrective Action Operating Plan:
ÎAnalysis of audit findings
ÎImplementation of auditor recommendations
ÎActions taken to correct fraud/wrongful acts, e.g.
ÎWithdraw applications & recall products
ÎTimetable
ÎIdentification of persons assigned to complete and
verify corrective actions
ÎComprehensive ethics program
ÎProcedures for monitoring effectiveness of the plan
ÎTraining in the requirements of the Act and 18 USC
1001
Corrective Actions Plan
Evaluation
Monitor applicant’s actions/inquiries during
internal review
ÎInspection to assess actions taken by
applicant to determine if
ÎInternal Review performed adequately
ÎCorrective Action Operating Plan
implemented adequately
ÎSubmit recommendation to CDER to remove
site from the policy
ÎExpect a long time to pass before restoration
Overview
Overview of
of CGMP
CGMP
requirements
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
Input for
for CGMP
CGMP Changes
Changes
• Establishment inspections
– Industry changes/problems
• Defect reports/complaints/recalls
• Litigation
• Agency application reviews
• Trade/scientific literature
• Citizen petitions
Management
Management ofof CGMP
CGMP
Regulatory
Regulatory Program
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
We Have
Have Discussed
Discussed
• 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:
[email protected] Montrose Metro Centre II Room 438
11919 Rockville Pike
Rockville, MD 20852
