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FDA cGMP
Training Program
cGMP in the USANicholas Buhay
Deputy Director
Division of Manufacturing & Product Quality
Office of Compliance, CDER, FDA
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Introduction to
Drug
Current Good ManufacturingPracticeOf US FDA
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An Outline
Legal bases for CGMP CGMP legal principles CGMP Implementation Tools CGMP Resources
Overview of CGMP Requirements Integrity of Records and Data
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FD&C Act; 501(a)(2)(B)
A d ru g shall be deemed adulterated if:... the meth o d s used in, or the faci l i t ies
or con t ro l s used for, its manufac tu re ,process ing , pack ing , or ho ld ing do notconform to or are not operated or
administered in conformity with cur ren tgo od m anu fac tu r ing p rac t ice ...
more...
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FD&C Act; 501(a)(2)(B)
to assure that such drug meets therequirements of this Act as to safety and has the ident i ty and s t rength , andmeets the qual i ty and pur i ty characteristics, which it p u rp o r t s or is
represented to possess .
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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 notbe shown) Firm and its management are
responsible
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CGMP legal principles
Non-compliance = eventual problems Superpotency/subpotency
Contamination Misbranding Bioavailability
Safety and efficacy
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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)
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CGMP legal principles
Excluded from the CGMPrequirement Positron emission tomography, per
FDAMA (own CGMP to be developed) Drug products compounded per Section
503 Pharmacy Compounding (FDAMA)
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CGMP Legal Principles
Current = dynamic Standards evolve over time
Good practices Minimal standards Not best practices
Unless best is, in fact, current minimal
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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
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The CGMP Regulation
CGMP for Finished Pharmaceuticals21 CFR 210, 211
Substantive Force and effect of law
Constitute major part of (not entire)CGMP
more...
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The CGMP Regulation
CGMP for Finished Pharmaceuticals21 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
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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
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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
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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 Productsmore...
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CGMP Implementation Tools
CGMP Guidance Documents Investigating Out of Specification Test
Results for Pharmaceutical Production Manufacturing, Processing or Holding
of Active Pharmaceutical Ingredients
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CGMP Implementation Tools
CGMP Compliance Programs Instructions to FDA inspectors
Drug Manufacturing InspectionsProgram Systems-based assessment of site
Preapproval Inspection Program Points to inspect Laboratory support Regulatory approaches
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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.
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Overview of CGMPrequirements 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
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Overview of CGMPrequirements 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...
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Overview of CGMPrequirements 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
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Overview of CGMPrequirements
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 systemsfor .operations as are necessary to preventcontamination or mix- ups. (see list, includesaseptic processing)
separate facilities for penicillin building.shall be.clean and sanitary
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Overview of CGMPrequirements
CGMP Regulations 21 CFR 211
Subpart D Equipment surfaces .shall not be reactive, additive, or
absorptive Equipment.shall be cleaned, maintained and
sanitized.
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Overview of CGMPrequirements
CGMP Regulations 21 CFR 211
Subpart E Control of Components,Containers and Closures
containers and closures .handled in a manner toprevent 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
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Overview of CGMPrequirements
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
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Overview of CGMPrequirements
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
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Overview of CGMPrequirements
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
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Overview of CGMPrequirements
CGMP Regulations 21 CFR 211
Subpart H Holding and Distribution quarantine before release store under appropriate conditions
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Overview of CGMPrequirements
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....
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Overview of CGMPrequirements
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
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Overview of CGMPrequirements
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....
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Overview of CGMPrequirements
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....
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Overview of CGMPrequirements
CGMP Regulations 21 CFR 211
Subpart J Records and Reports distribution records, with lot numbers(except medical
gases) complaint files
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Problem
Drug Regulatory Program depends heavily on thereliability (i.e. truthfulness, completeness andaccuracy) of data & information in records
Applications for approval [AIP] Manufacturing Controls documentation [non-AIP]
Historical experience with broad scaleunreliability of data in records or in conductrelated to records
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Data and records that are notacceptable or are misleading
What are some characteristics of data thatlack 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 reviewprocess. Data that is not submitted, but shouldhave been
Inaccurate (e.g. First data failed specs, retest datapasses specs, no lab investigation, but retest datais submitted to the application.)
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Records Must be True
All data and information in recordssubmitted to FDA & supportingdocuments in the possession of the
applicant are accurate & truerepresentations of - Actual tests performed & the test results Actual manufacturing & quality control steps &
procedures associated with the development andmanufacture of the submission batch (clinical/pilotor biobatch)
any other actions and conditions associated with theapplication
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Wrongful Acts
Any act or conduct that subverts the integrityof 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 anomission of a fact)
submitting unreliable data which results fromsystem-wide or firm-wide behavior
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Wrongful Acts (continued)
An untrue statement of material fact is a falsestatement, a misstatement or an omission of a factthat is important in the review process.System-wide incompetence is also a wrongful actWhen an untrue statement of material fact or
system-wide incompetence is found, several stepsare required to the invoke the AIP including:
Documentation of a pattern or practice of wrongfulacts.
Ensuring that the untrue statements are materialfacts.
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Pattern or Practice
Pattern- More than one instance of errors oracts involving the subject matter important tothe evaluation of an application
Practice- An act or process of doingsomething affecting subject matter importantto the evaluation of an application
A practice can be one or more acts or processes. A pattern or practice can occur in one or moreapplications.
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If submitted to an Application
The AIP procedures broadly define the term,application to include, but not be limited to,any application, amendment, supplement orother submission made by an applicant.
Submitted is an understandable term andincludes 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
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Food, Drug, and Cosmetic ActSection 505(e) (excerpt below)
Numbered Part 5
The Secretary shall, after due notice and
opportunity for hearing to the applicant,withdrawapproval of an application with respect to any drugunder this section, if the Secretary finds.
(5) that the application contains any untruestatement of a material fact
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TO INVOKE AIP
Documentation of a pattern or practice ofwrongful conduct that raises significant
questions about the reliability of datasubmitted to an application
- wrongful acts- pattern or practice
- unreliable data
R t FDA C fid
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Restore FDAs Confidencein Data???
Cooperation with investigatorsIdentification of involved individuals
Credible internal review & actionsProblem analysis/identify all instances ofwrongful actsUse of impartial auditor/Outside
consultantAudit Plan, audits, audit reportsOther measures as FDA deems
appropriate
Restore FDAs Confidence in
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Restore FDA s Confidence inData
Corrective Action Operating Plan:Analysis of audit findingsImplementation of auditor recommendationsActions taken to correct fraud/wrongful acts, e.g.
Withdraw applications & recall productsTimetableIdentification of persons assigned to complete and verify
corrective actionsComprehensive ethics programProcedures for monitoring effectiveness of the planTraining in the requirements of the Act and 18 USC 1001
C ti A ti Pl
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Corrective Actions PlanEvaluation
Monitor applicants actions/inquiries during internalreview
Inspection to assess actions taken by applicant todetermine ifInternal Review performed adequatelyCorrective Action Operating Plan implemented
adequatelySubmit recommendation to CDER to remove site
from the policyExpect a long time to pass before restoration
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Overview of CGMPrequirements
CGMP Regulations 21 CFR 211
Subpart K Returned and Salvaged DrugProducts
if conditions cast doubt returned product shall bedestroyed unless proved ok by test, examination,investigation
salvage only if evidence from tests and inspectionshow all standards met
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Input for CGMP Changes
Establishment inspections Industry changes/problems
Defect reports/complaints/recalls Litigation Agency application reviews
Trade/scientific literature Citizen petitions
f
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Management of CGMPRegulatory Program
FDA/CDER OC/Divis ion o f Manu factu r ing and
Prod uc t Quali ty maintenance of the regulation definitive interpretation manage guidance development develop, operate, evaluate programs train FDA/outreach to industry
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We Have Discussed
Legal bases for CGMP CGMP legal principles CGMP Implementation Tools CGMP Resources Overview of CGMP requirements Integrity of Records and Data
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Montrose Metro Centre II Room 43811919 Rockville Pike
Rockville, MD 20852
Nicholas BuhayDeputy Director
Division of Manufacturing
and Product Quality, HFD-320Center for Drug Evaluation and Research
Phone: 301-827-8940 Fax: 301-827-8907
E-mail: [email protected]
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