cGMP in the USA Training by CDER FDA

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.”

• 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

• 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)

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

• Current = dynamic
– Standards evolve over time

• Good practices
– Minimal standards
– Not “best practices”
» Unless “best” is, in fact, current minimal

• 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
21 CFR 210, 211
– Substantive
» Force and effect of law

– Constitute major part of (not entire)
CGMP

more...

The CGMP Regulation
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

• 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 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

(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...

– Investigating Out of Specification Test
Results for Pharmaceutical Production
– Manufacturing, Processing or Holding
of Active Pharmaceutical Ingredients

• 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 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
– 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
– 21 CFR 211
» Subpart A General Provisions
• this is minimum CGMP

Overview of CGMP
– 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
– 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
– 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
– 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
– 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
– 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
– 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
– 21 CFR 211
» Subpart H Holding and Distribution
• quarantine before release
• store under appropriate conditions

Overview of CGMP
requirements
– 21 CFR 211
• 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
– 21 CFR 211
• 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
– 21 CFR 211
• 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
– 21 CFR 211
• 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
– 21 CFR 211
• 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

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

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

practice

- wrongful acts
- pattern or
-

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
– 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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•
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Legal bases for CGMP
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

cGMP in the USA Training by CDER FDA

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