FDA cGMP Training Program cGMP in the USA Nicholas Buhay Deputy Director Division of Manufacturing & Product Quality Office of Compliance, CDER, FDA

FDA cGMPFDA cGMP Training Program Training Program

FDA cGMPFDA cGMP Training Program Training Program

cGMP in the USANicholas Buhay

Deputy DirectorDivision of Manufacturing & Product Quality

Office of Compliance, CDER, FDA

Introduction to Drug

Current Good Manufacturing Practice

Of US FDA

An OutlineAn OutlineAn OutlineAn Outline

• 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)FD&C Act; 501(a)(2)(B)FD&C Act; 501(a)(2)(B)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)FD&C Act; 501(a)(2)(B)FD&C Act; 501(a)(2)(B)FD&C Act; 501(a)(2)(B)

“to assureassure 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 principlesCGMP legal principlesCGMP legal principlesCGMP 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 principlesCGMP legal principles CGMP legal principlesCGMP legal principles

• Non-compliance = eventual problems– Superpotency/subpotency– Contamination– Misbranding– Bioavailability– Safety and efficacy

CGMP Legal PrinciplesCGMP Legal PrinciplesCGMP Legal PrinciplesCGMP 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 principlesCGMP legal principlesCGMP legal principlesCGMP 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)


• 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 The CGMP Regulation The CGMP Regulation 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 RegulationThe CGMP RegulationThe CGMP RegulationThe 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 RegulationThe CGMP RegulationThe CGMP RegulationThe 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 ToolsCGMP Implementation ToolsCGMP Implementation ToolsCGMP 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


• 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 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...


• CGMP Guidance Documents– 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 ResourcesCGMP ResourcesCGMP ResourcesCGMP 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 Overview of CGMP requirements in the regulationrequirements 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




» 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...




» Subpart A General Provisions• this is minimum CGMP




» Subpart B Organization and Personnel• There shall be a quality control unit• quality control unit responsibility to approve/reject

Overview of CGMP Overview of CGMP requirementsrequirements



» 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




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

absorptive• Equipment….shall be cleaned, maintained and

sanitized….




» 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




» 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




» 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




» Subpart H Holding and Distribution» Subpart I Laboratory Controls» Subpart J Records and Reports» Subpart K Returned and Salvaged Drug

Products




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




» 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....




» 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




» 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....




» 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....




» 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 Data and records that are not acceptable or are misleading acceptable or are misleading Data and records that are not Data and records that are not acceptable or are misleading 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 TrueRecords Must be TrueRecords Must be TrueRecords 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 ActSection 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 investigatorsIdentification of involved individualsCredible internal review & actions

Problem analysis/identify all instances of wrongful acts

Use of impartial auditor/Outside consultant

Audit Plan, audits, audit reportsOther measures as FDA deems appropriate

Restore FDA’s Confidence in Data

Corrective Action Operating Plan:Analysis of audit findingsImplementation of auditor recommendationsActions taken to correct fraud/wrongful acts, e.g.

Withdraw applications & recall products TimetableIdentification 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

Corrective Actions Plan Evaluation

Monitor applicant’s actions/inquiries during internal review

Inspection to assess actions taken by applicant to determine ifInternal Review performed adequatelyCorrective Action Operating Plan implemented adequately

Submit recommendation to CDER to remove site from the policy

Expect a long time to pass before restoration




» 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 Input for CGMP Changes Input for CGMP Changes Input for CGMP Changes

• Establishment inspections– Industry changes/problems

• Defect reports/complaints/recalls

• Litigation

• Agency application reviews

• Trade/scientific literature

• Citizen petitions

Management of CGMP Management of CGMP Regulatory Program Regulatory Program

Management of CGMP Management of CGMP Regulatory Program 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 DiscussedWe Have DiscussedWe Have DiscussedWe Have Discussed

• Legal bases for CGMP

• CGMP legal principles

• CGMP Implementation Tools

• CGMP Resources

• Overview of CGMP requirements

• Integrity of Records and Data

Montrose Metro Centre II Room 43811919 Rockville PikeRockville, MD 20852

Nicholas BuhayDeputy Director

Division of Manufacturingand Product Quality, HFD-320

Center for Drug Evaluation and Research

Phone: 301-827-8940 Fax: 301-827-8907

E-mail: [email protected]

Return to Main Menu