A_cGMP_Primer_rev1

A cGMP PrimerA cGMP Primer

Chet FrenchOctober 2011

A cGMP Primer Chet French Oct 2011

A cGMP PrimerAgenda

What is cGMP?What is cGMP? Basic PrinciplesBasic Principles ImplicationsImplications

Drug Regulation HistoryDrug Regulation History The FDAThe FDAInspectional MethodologyInspectional Methodology cGMP SubpartscGMP SubpartsSummary Summary


Regulations; properly applied confer benefits and protections

Nuclear Power

Airlines

Utilities

Construction

Banking

Minerals & MiningPharmaceuticals

Regulated Industries


cGMP RegulationscGMP Regulations21CFR 210 & 21121CFR 210 & 211

Proposed RegulationsProposed Regulations

FDA GuidelinesFDA Guidelines

Inspectional FindingsInspectional Findings

Best Practices – Best Practices – feasiblefeasible and and valuablevaluable

Changing Technology/TragediesChanging Technology/Tragedies

Articles and Presentations by FDA personnelArticles and Presentations by FDA personnel

ICH DocumentsICH Documents

Drug RegulationsHow Do We Know the Rules?


The cGMPs21CFR Parts 210 & 211

What are the cGMPs?What are the cGMPs?

A: General ProvisionsA: General Provisions

B: Organization & PersonnelB: Organization & Personnel

C: Buildings and FacilitiesC: Buildings and Facilities

D: EquipmentD: Equipment

E: Control of ComponentsE: Control of Components

F: Production and Process ControlsF: Production and Process Controls

G: Packaging & LabelingG: Packaging & Labeling

H: Holding & DistributionH: Holding & Distribution

I: Laboratory ControlsI: Laboratory Controls

J: Records & ReportsJ: Records & Reports

K: Returned & Salvaged Drug ProductsK: Returned & Salvaged Drug Products

Federal laws Often ambiguous Establish minimum requirements


Drug Regulation HistoryPatent Medicines 19th Century


Drug Regulation HistoryFood & Drug Act 1906

““The JungleThe Jungle”” by Upton Sinclairby Upton Sinclair

The Food and Drug Act (1906)The Food and Drug Act (1906)

Establishment of the FDAEstablishment of the FDA

Prohibited interstate commerce in misbranded Prohibited interstate commerce in misbranded and adulterated foods, drinks, and drugsand adulterated foods, drinks, and drugs


Drug Regulation HistoryFormularies 1920’s


Drug Regulation History Elixir of Sulfanilamide Tragedy 1937

Sulfa drugs were a commoditySulfa drugs were a commodity

Introduction of a liquid syrup to differentiate productIntroduction of a liquid syrup to differentiate product

Used Used diethylene glycoldiethylene glycol as solvent as solvent

240 gallons produced and sold240 gallons produced and sold

107 Deaths; 107 Deaths; Suicide Suicide of chemistof chemist


Drug Regulation History Federal Food Drug and Cosmetics Act of 1938

Must demonstrate scientific proof that new products could be Must demonstrate scientific proof that new products could be safelysafely used before putting them on the market. used before putting them on the market.

Proof of fraud Proof of fraud no longer requiredno longer required to stop false claims for to stop false claims for drugs. drugs.

Addition of poisonous substances to foods was Addition of poisonous substances to foods was prohibitedprohibited except where unavoidable in production. except where unavoidable in production.

Specific authority conferred for Specific authority conferred for conducting inspections. conducting inspections.

Federal court injunctions against Federal court injunctions against violations were added to the previous violations were added to the previous legal remedies of legal remedies of product seizuresproduct seizures and and criminal prosecutionscriminal prosecutions..


Drug Regulation History Thalidomide Tragedy 1961

Thalidomide

Severe Teratogenic Properties5,000 Pregnant women ~3,000 affected children


Drug Regulation HistoryKefauver Hearings 1960 - 1962

Regulation AmendmentsRegulation Amendments

Tightened control over Tightened control over prescription drugsprescription drugs

Safe Safe and effectiveand effective

Adverse reaction reportingAdverse reaction reporting

Benefits Benefits and risksand risks

Label changesLabel changes

Ernst KefauverErnst Kefauver

Drug Regulation HistoryTylenol Poisoning & Recall 1982

“Raising the Bar”

Tamper-proof packaging


Drug Regulation HistoryBarr Laboratories 1993

Supreme Court Decision 1993Supreme Court Decision 1993

Failure InvestigationsFailure Investigations

Process ValidationProcess Validation

Quality must be built into the product/process


Drug Regulation HistoryPDUFA 1997

Prescription Drug User Fee Act (1997)Prescription Drug User Fee Act (1997)Reduced the legal standard for new drug reviewsReduced the legal standard for new drug reviews

Reauthorized user feesReauthorized user fees

Fee for ApplicationFee for Application

Fee for EstablishmentsFee for Establishments

Renewal Fee for ProductsRenewal Fee for Products

Promotion of drugs for Promotion of drugs for ““off labeloff label”” use use


Mission: “Protect the Public”

An enforcement agency

Enforces the Federal Food Drug and Cosmetic Act of 1938

Determines the state of compliance by conducting site inspections

Annual Commerce = $1,000,000,000,000+

Under Fire for Unsafe Drug Approvals*

Inspections Behind Schedule

Resource Constraints - High Staff Turnover

*Outlook: Likely much greater safety vigilance

*Source: Institute of Medicine Report 2006

$350 BL

$102 BL

$487 BL

$39 BL

The Food & Drug AdministrationThe Food & Drug Administration


The Regulatory EnvironmentDrug Safety Under Scrutiny

VIOXX®(Acute Pain)Heart AttackStroke

MERIDIA®(Obesity)Heart FailureRenal Failure

BEXTRA®(Arthritis)Heart AttackStrokeStevens JohnsonSyndrome

AVANDIA®(Diabetes)Heart Attack

TYSABRI®(MS)PML


Drug Regulation Safety Data – Risks vs. Benefits

Safety Data Collected

?

Identified RisksIdentified Risks

Clinical Clinical ApprovalApproval

Do the Do the RisksRisks Outweigh the Outweigh the

BenefitsBenefits??

Cum

ulat

ive

Saf

ety

Pro

file


What Clinical Trials What Clinical Trials Do WellDo WellDetermine with some certainty that the product is Determine with some certainty that the product is effectiveeffective and and that thethat the common serious adverse events are identifiedcommon serious adverse events are identified

Limitations Limitations of Clinical Trialsof Clinical Trials Seldom more than 3,000 patientsSeldom more than 3,000 patients Patients with complicated medical conditions often excludedPatients with complicated medical conditions often excluded Patients receiving certain concurrent meds are often excludedPatients receiving certain concurrent meds are often excluded Pediatric and elderly populations may be excludedPediatric and elderly populations may be excluded Trials often last only weeks to months; identification of reactions due Trials often last only weeks to months; identification of reactions due

to long- term use or latent effects is difficult to long- term use or latent effects is difficult

Drug Regulation Patient Safety Takes “Center Stage”


Drug Development and Commercialization Stakeholders - Competing Interests

AccessibleAccessible InexpensiveInexpensive ““Latest & GreatestLatest & Greatest”” Safe & EffectiveSafe & Effective

Thorough ReviewsThorough Reviews Safe & EffectiveSafe & Effective

Preserve Status QuoPreserve Status Quo Balance Competing InterestsBalance Competing Interests Allocate Resources JudiciouslyAllocate Resources Judiciously

Quick ReviewQuick Review Quick to MarketQuick to Market First-in-ClassFirst-in-Class ProfitableProfitable


FDA

CBER

Team Biologics

ORACDER

U.S. Dept of Health & Human Services

Preapproval Inspections

Biennial Inspections

FDA Partial Organization Structure


Licensure/Surveillance Inspections (Planned) Pre-Approval Inspection for Licensure (BLA)

Prior Approval Supplement (PAS) GMP or Compliance Inspection (Biennial)

For-Cause Inspections (Unplanned): Product Complaint Adverse Event Industry “Triggered” event Market Withdrawal

Legal Authority for Inspections Sec. 704 of the Federal Food, Drug and Cosmetic Act of 1938 Sec. 351(c) of the Public Health Service Act (licensed biologics) 21 CFR 600.22 (licensed biologics)

FDA Inspections Types

Goal of the Goal of the InvestigatorsInvestigators::

1.1. Verify the integrity of information Verify the integrity of information supporting the application (PAS)supporting the application (PAS)

2.2. Determine conformance to Determine conformance to cGMPs at the facility used for cGMPs at the facility used for manufacturingmanufacturing, , processingprocessing, , packagingpackaging,, and and holdingholding of the of the drug product. drug product.

Goal of the Goal of the InspectedInspected::

““A favorable outcomeA favorable outcome””

The InspectionGoals & Objectives

Consequences of failure are Consequences of failure are extremeextreme::

Loss of RevenueLoss of Revenue

Business Viability - TimeBusiness Viability - Time

JobsJobs

CompanyCompany’’s Reputations Reputation

CredibilityCredibility

More Rigorous Future ScrutinyMore Rigorous Future Scrutiny

*Source: Tufts Center for the Study of Drug Development 2001

Drug-to-market costs: $800 million -$1.7 BBL*

Facility and Product LicensureThe Stakes


Documents compiled for review: Deviations/OOS/CAPAs Validation/Revalidation Data/Trending Logbooks P&ID Material Review Board Minutes Critical Systems

Systems Review – (examples) Cleaning Validations (Equipment and Facilities) Change Management Environmental Monitoring Stability Program HVAC/Water/Utilities Shipping/Receiving/Warehousing Raw Material In-Process Testing & Release

Interested in assessing capabilities

Inspection Preparation Relevant Documentation

Civil Servants - Strong belief in purpose Civil Servants - Strong belief in purpose

Specialized training (Specialized training (frequentfrequent and and recurringrecurring):):

Human PsychologyHuman Psychology

Interview TechniquesInterview Techniques

Inspection TeamInspection Team

1-5 Investigators with Lead 1-5 Investigators with Lead CDER Office of ComplianceCDER Office of Compliance

Office of Biotechnology ProductsOffice of Biotechnology Products

CDER District OfficeCDER District Office

Mix and MatchMix and Match

1- 3 weeks duration 1- 3 weeks duration

No vested interest in organizationsNo vested interest in organizations’’ success… success… Application for approval must stand on own merits!!

The FDA Investigators

Inspectional Experts

One System out of control = Noncompliance

The FDA Inspection

Systems-Based Approach

Credentials – Agency representedCredentials – Agency represented

Visitor badge issued; seated in lobbyVisitor badge issued; seated in lobby

Contact list notified Contact list notified in orderin order

Responsible Head is presented the Responsible Head is presented the Notice Notice of Inspectionof Inspection (FDA 482 Form) (FDA 482 Form)

EscortedEscorted and and SequesteredSequestered in Room(s) in Room(s) ((ControlledControlled Environment) Environment)

Ms. Investigator

FDA InspectionsReceiving the Investigators


Introductions

Review FDA 482

Establish & Negotiate Agenda

Inventory of Controlled Docs

Prepared Overview Presentations (SMEs)

CAPAs, Deviations, Failure Investigations, Prior Inspection Corrective Actions

Alert: Conduct Walkthroughs of Potential Inspection Touring Areas

Inspection LogisticsDay One

Runners

Scribe

Host

SMEs

Front RoomManager

A “well-choreographed dance”

Scribe

Host SME

SME

FDA Investigators

Inspection LogisticsInside the Inspection Room

What do they do?What do they do?

AskAsk lots of questions lots of questions

ReviewReview lots of documents lots of documents

Make copiesMake copies

TalkTalk to lots of employees to lots of employees

TourTour the facility (Start the facility (Start End) End)

ObserveObserve processes/equipment & processes/equipment & peoplepeople

Collect Collect SamplesSamples

The InspectionDay-by-Day

What do they find?What do they find?

Recordkeeping ErrorsRecordkeeping Errors

Documentation InconsistenciesDocumentation Inconsistencies Logsbooks, BRs, Validation ProtocolsLogsbooks, BRs, Validation Protocols

Procedures not followedProcedures not followed TimelinessTimeliness

ResponsibilitiesResponsibilities

Electronic IssuesElectronic Issues

Systems IssuesSystems Issues

BATCH RECORD



Daily Wrap-up Sessions

Chaired by Senior Quality Host Convey trends and anticipate next areas of focus Push for spot corrections Annotated 483s

FDA 483*

Final DayFinal Day

FDA 483 Form – List of ObservationsFDA 483 Form – List of Observations Most Most significantsignificant listed first listed first TypeType important; not important; not numbernumber

Final Wrap-up SessionFinal Wrap-up Session

FDA 483

Observation 1…….

Observation 2

Observation 3**



Number of FDA 483 Observations

Source: BioQuality May 2010

108 (27%)

55 (14%)

68 (17%)

31 (8%)

FDA 483 Observations Biologics 2010 by Category


FDA 483 Form

Corrective Actions

Withold Approval

Approval

Conditional Approval

Inadequateor Late

Reinspection

Adequate

FDA Inspectional OutcomesPreapproval Inspection (PAI)


FDA 483 Form

Establishment Inspection Report

Warning Letter

Consent Decree

NOIR

Official Action Indicated (OAI)

Continued Operation

No

Official

Actio

n In

dicated

Criminal Charges

Corrective Actions

FDA Inspectional OutcomesCompliance or Biennial Inspection


Civil Money Penalties*Civil Money Penalties* 1 1

Seizures*Seizures* 6 6 (-44%)(-44%)

Injunctions*Injunctions* 1212

ConvictionsConvictions 344344

Warning LettersWarning Letters 471 471 (-39%)(-39%)

Recalls*Recalls* 5,5855,585

FDA 483 ObservationsFDA 483 Observations 5,100 5,100 (-1%)(-1%)

Inspections*Inspections* 15,58115,581

Import RefusalsImport Refusals 49,98849,988

Fines/Restitutions*Fines/Restitutions* $1.92 BBL$1.92 BBL

Source: FDA PDUFA Goals Report 2008

(*)= Voluntary

Trend is to focus on more serious violations

Regulatory Inspection TrendsEnforcement Statistics

Searchable Database at the FDA Websitewww.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm


QA

FDA assigns quality oversight to the Quality division

211.22 The quality control unit shall have the responsibility and authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated.

Oversight

Quality by DesignA Model for cGMP Compliance

Product Mfg, Processing, Holding, Testing, Packaging, Labeling


Logbooks

Labels

Batch Records & Systems

All cGMP records must be:• Accurate• Legible• Complete• Timely• Truthful

and… reconcilable

Records Match

Record

s Match

Records and Reports - Good DocumentationSubpart J

Records Match


The drug regulatory program The drug regulatory program depends on the reliability, depends on the reliability, truthfulness, completeness and truthfulness, completeness and accuracy of data and information accuracy of data and information on record.on record.

“If it wasn’t documented; then it wasn’t performed”

How data is entered into cGMP How data is entered into cGMP documents is important because this is documents is important because this is the the documented evidencedocumented evidence of GMP of GMP activities.activities.

FDA’s View on Documentation/Recordkeeping


… shall have the education, experience and training or any combination thereof to enable each individual to perform their assigned function.

Training on cGMPs

Training ongoing and current

Be knowledgeable about: Be knowledgeable about: cGMP RegulationscGMP RegulationsPolicies, Procedures and Guidelines

Stay current on:Stay current on:Regulatory inspectional activityRegulatory inspectional activityChanging technologyChanging technology

Organization & PersonnelSubpart B


Process Drives Design

Separation of Operations Essential

Linear Facility: Parenterals and API

Reduced Heating and Cooling Costs

Shorter Pipe and Process Flows

Gravity Feed

Reduced Construction Costs

Compact Facility

Building and Facilities - Design ImplicationsSubpart C


Appropriate for intended purpose Adequate space & layout

Ensure a state of control

Components of an HVAC System: Terminal Diffusers

Controlled Cleanroom Airflow

Building and FacilitiesSubpart C

HEPA Filter


EquipmentSubpart D

Chromatography Very Large Scale

HPLC - Analytical Scale

Equipment adequate and appropriate for state of control*

Source: FDA Guidance for Industry cGMP for Phase 1 Investigational Drugs 2008


Production & Process ControlsSubpart F

A Typical Biopharmaceutical A Typical Biopharmaceutical Process:Process: Raw Material Storage/HandlingRaw Material Storage/Handling

Weigh/DispenseWeigh/Dispense

Media/Buffer/Component Preparation & HoldMedia/Buffer/Component Preparation & Hold

Inoculum PreparationInoculum Preparation

Fermentation/Cell CultureFermentation/Cell Culture

Recovery/HarvestRecovery/Harvest

PurificationPurification

Bulk FillingBulk Filling

CIP/SIPCIP/SIP

Biowaste DeactivationBiowaste Deactivation


MMV (Parvovirus)

Personnel

Raw Materials

Host Cells

BacteriaMycoplasmaSaprolegnia Mold

Production & Process ControlsSubpart F

Common Conduits of Contamination


Spore Dots

Production & Process Controls - Cleaning ValidationSubpart F

Riboflavin Surface Studies

TOC Swabbing

Validation: Scientifically and statistical verification of a state of control of process and equipment


QA Line Clearance Critical Step 100% Reconciliation of closures containers and labels

Packaging & LabelingSubpart G

Labeling: #1 root cause for recalls


Summary

The FDA regulates the drug industryThe FDA regulates the drug industry

The FDA is required by law to periodically conduct site The FDA is required by law to periodically conduct site inspections to assess our level of compliance with the inspections to assess our level of compliance with the regulations. regulations.

GMP GMP regulationsregulations are the intent of the law are the intent of the law

GMP GMP expectationsexpectations are the spirit of the law are the spirit of the law

FDA focusing attention on FDA focusing attention on quality systems approachquality systems approach to to inspections to assure a sustained state of controlinspections to assure a sustained state of control

Robust quality systems are the centerpiece to compliance Robust quality systems are the centerpiece to compliance with the cGMPswith the cGMPs


Q & A

Questions/CommentsQuestions/Comments

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