QA_GMP-GMP-Ref 1

8/12/2019 QA_GMP-GMP-Ref 1

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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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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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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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Current = dynamic Standards evolve over time

Good practices Minimal standards Not best practices

Unless best is, in fact, current minimal


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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 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 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 Guidance Documents Investigating Out of Specification Test

Results for Pharmaceutical Production Manufacturing, Processing or Holding

of Active Pharmaceutical Ingredients


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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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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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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


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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Subpart D Equipment surfaces .shall not be reactive, additive, or

absorptive Equipment.shall be cleaned, maintained and

sanitized.


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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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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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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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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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Subpart H Holding and Distribution quarantine before release store under appropriate conditions


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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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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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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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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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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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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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