A cGMP Primer

A A cGMP cGMP PrimerPrimer

Chet FrenchOctober 2011

A cGMP Primer Chet French Oct 2011

A cGMP PrimerAgenda

What is What is cGMPcGMP?? Basic PrinciplesBasic Principles ImplicationsImplications

Drug Regulation History Drug Regulation History The FDAThe FDAInspectional MethodologyInspectional Methodology cGMP cGMP SubpartsSubpartsSummarySummary


Regulations; properly applied confer benefits and protections

Nuclear Power

Airlines

Utilities

Construction

Banking

Minerals & MiningPharmaceuticals

Regulated Industries


cGMP cGMP RegulationsRegulations 21CFR 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 What are the cGMPscGMPs??A: General ProvisionsA: General ProvisionsB: Organization & PersonnelB: Organization & PersonnelC: Buildings and FacilitiesC: Buildings and FacilitiesD: EquipmentD: EquipmentE: Control of ComponentsE: Control of ComponentsF: Production and Process ControlsF: Production and Process ControlsG: Packaging & LabelingG: Packaging & LabelingH: Holding & DistributionH: Holding & DistributionI: Laboratory ControlsI: Laboratory ControlsJ: Records & ReportsJ: Records & ReportsK: 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 misbrandedProhibited interstate commerce in misbrandedand adulterated foods, drinks, and drugsand adulterated foods, drinks, and drugs


Drug Regulation HistoryFormularies 1920’s


Drug Regulation HistoryElixir of Sulfanilamide Tragedy 1937

Sulfa drugs were a commoditySulfa drugs were a commodity

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

Used Used diethylene diethylene glycolglycol as solvent as solvent

240 gallons produced and sold 240 gallons produced and sold

107 Deaths; 107 Deaths; Suicide Suicide of chemistof chemist


Drug Regulation HistoryFederal Food Drug and Cosmetics Act of 1938

Must demonstrate scientific proof that new products could beMust demonstrate scientific proof that new products could besafelysafely 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 fordrugs.drugs.

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

Specific authority conferred forSpecific authority conferred forconducting inspections.conducting inspections.

Federal court injunctions againstFederal court injunctions againstviolations were added to the previousviolations were added to the previouslegal remedies of legal remedies of product seizuresproduct seizures and andcriminal prosecutionscriminal prosecutions..


Drug Regulation HistoryThalidomide Tragedy 1961

Thalidomide

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


Drug Regulation HistoryKefauver Hearings 1960 - 1962

Regulation AmendmentsRegulation Amendments Tightened control overTightened 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 theBar”

Tamper-proofpackaging


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 reviewsReauthorized 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 Drugand Cosmetic Act of 1938

Determines the state ofcompliance by conducting siteinspections

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 RegulationSafety 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 andthat 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 dueTrials often last only weeks to months; identification of reactions due

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

Drug Regulation Patient Safety Takes “Center Stage”


Drug Development and CommercializationStakeholders - Competing Interests

Accessible Accessible Inexpensive Inexpensive ““Latest & GreatestLatest & Greatest”” Safe & Effective Safe & Effective

Thorough Reviews Thorough Reviews Safe & Effective Safe & Effective

Preserve Status Quo Preserve Status Quo Balance Competing Interests Balance Competing Interests Allocate Resources Judiciously Allocate Resources Judiciously

Quick Review Quick Review Quick to Market Quick to Market First-in-Class First-in-Class Profitable Profitable


FDA

CBER

Team Biologics

ORACDER

U.S. Dept of Health & Human Services

Preapproval Inspections

BiennialInspections

FDAPartial 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 InspectionsTypes

Goal of the Goal of the InvestigatorsInvestigators::

1.1. Verify the integrity of informationVerify the integrity of informationsupporting the application (PAS)supporting the application (PAS)

2.2. Determine conformance toDetermine conformance tocGMPs cGMPs at the facility used forat the facility used formanufacturingmanufacturing, , processingprocessing,,packagingpackaging,, and and holdingholding of the of thedrug 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 Revenue Loss of Revenue Business Viability - Time Business Viability - Time Jobs Jobs Company Company’’s Reputations Reputation Credibility Credibility More Rigorous Future Scrutiny More 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 PreparationRelevant Documentation

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

Specialized training (Specialized training (frequentfrequent and and recurringrecurring):): Human PsychologyHuman Psychology Interview Techniques Interview Techniques

Inspection TeamInspection Team 1-5 Investigators with Lead 1-5 Investigators with Lead

CDER Office of ComplianceCDER Office of Compliance Office of Biotechnology Products Office of Biotechnology Products CDER District Office CDER District Office

Mix and MatchMix and Match 1- 3 weeks duration 1- 3 weeks duration No vested interest in organizations No vested interest in organizations’’ success success……

Application for approval must stand on own merits!!

The FDA InvestigatorsInspectional Experts

QualitySystem

LaboratoryControlSystem

MaterialsSystem

ProductionSystem

Facilities &Equipment

System

Packagingand

LabelingSystem

One System out of control = Noncompliance

The FDA InspectionSystems-Based Approach

Credentials Credentials –– Agency represented 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 NoticeNoticeof 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, FailureInvestigations, Prior InspectionCorrective 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 copies Make 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 Errors Recordkeeping Errors

Documentation Inconsistencies Documentation Inconsistencies LogsbooksLogsbooks, , BRsBRs, Validation Protocols, Validation Protocols

Procedures not followed Procedures 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 FDA 483 Form –– List of Observations List of Observations Most Most significantsignificant listed first listed first Type Type important; not important; not numbernumber

Final Wrap-up Session Final 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 2010by 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 O

fficialA

ction Indicated

Criminal Charges

Corrective Actions

FDA Inspectional OutcomesCompliance or Biennial Inspection


Civil Money Penalties*Civil Money Penalties* 11Seizures*Seizures* 66 (-44%)(-44%)Injunctions*Injunctions* 1212ConvictionsConvictions 344344Warning LettersWarning Letters 471471 (-39%)(-39%)Recalls*Recalls* 5,5855,585FDA 483 ObservationsFDA 483 Observations 5,1005,100 (-1%)(-1%)Inspections*Inspections* 15,58115,581Import RefusalsImport Refusals 49,98849,988Fines/Restitutions*Fines/Restitutions* $1.92 BBL$1.92 BBL

Source: FDA PDUFA Goals Report 2008

(*)= Voluntary

Trend is to focus on moreserious 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 theresponsibility and authority to review production recordsto assure that no errors have occurred or, if errors haveoccurred, 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

Records M

atch

Records and Reports - Good DocumentationSubpart J

Records Match


The drug regulatory programThe drug regulatory programdepends on the reliability,depends on the reliability,truthfulness, completeness andtruthfulness, completeness andaccuracy of data and informationaccuracy of data and informationon record.on record.

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

HowHow data is entered into data is entered into cGMPcGMPdocuments is important because this isdocuments is important because this isthe the documented evidencedocumented evidence of of GMPGMPactivities.activities.

FDA’s View on Documentation/Recordkeeping


04/14/2008 – 6:00pm eSlide - P4815 - MedImmune Template

… shall have the education, experienceand training or any combination thereof toenable each individual to perform theirassigned 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 andappropriate for state ofcontrol*

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


Production & Process ControlsSubpart F

A Typical Biopharmaceutical Process:A Typical Biopharmaceutical Process: Raw Material Storage/HandlingRaw Material Storage/Handling Weigh/DispenseWeigh/Dispense Media/Buffer/Component Preparation & HoldMedia/Buffer/Component Preparation & Hold Inoculum Inoculum PreparationPreparation Fermentation/Cell CultureFermentation/Cell Culture Recovery/HarvestRecovery/Harvest PurificationPurification Bulk FillingBulk Filling CIP/SIPCIP/SIP Biowaste Biowaste DeactivationDeactivation


MMV (Parvovirus)

Personnel

RawMaterials

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 statisticalverification of a state of control ofprocess 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 siteThe FDA is required by law to periodically conduct siteinspections to assess our level of compliance with theinspections to assess our level of compliance with theregulations.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 toinspections to assure a sustained state of controlinspections to assure a sustained state of control

Robust quality systems are the centerpiece to complianceRobust quality systems are the centerpiece to compliancewith the with the cGMPscGMPs


Q & A

Questions/CommentsQuestions/Comments

?

A cGMP Primer

Documents

Transcript of A cGMP Primer