Implementing GMP Implementing GMP Auditing Practices for Auditing Practices for Excipient SuppliersExcipient Suppliers

July 30, 2001July 30, 2001

Qualifying an Excipient SupplierQualifying an Excipient Supplier

Confirm adherence to cGMP'sConfirm adherence to cGMP's Include subcontractors, repackagers, and Include subcontractors, repackagers, and

distributorsdistributors

Periodically reconfirm adherence to cGMPPeriodically reconfirm adherence to cGMP All material traceable during lifecycleAll material traceable during lifecycle Acceptance testing or COAAcceptance testing or COA Notification of significant changesNotification of significant changes

Uniqueness of ExcipientsUniqueness of Excipients

ManufacturersManufacturers Manufacturing ProcessManufacturing Process ChemistryChemistry Scale of ManufactureScale of Manufacture CharacterizationCharacterization ApplicationsApplications

Where does GMP start?Where does GMP start?

Review the scenarios and identify the processing point at which GMP principles should be applied.

State your reasons as to why you feel this is the appropriate point to apply GMP.

Where does GMP start?Where does GMP start?

NaOH

Plant Site ChemistryPlant Site Chemistry

N O

CH CH2

Vinyl Pyrrolidone

O O

Butyrolactone

N O

H

2-Pyrrolidone

OHCH2CCH

Propargyl Alcohol 1,4-But-ynediol

CCH2OHHOCH2C

HO CH2CH CHCH2 OH

1,4-But-2-enediol

HOCH2CH2CH2CH2OH

Butanediol

H2C O

N O

RAlkyl Pyrrolidones

RNH2

NH3

ROH

Higher Vinylethers

Methyl Vinylether

EVEn-BVE

HBVEDVE-3CHVECVEPEPCDDVEEHVE

GAFGARD 233

Maleic Anhydride

GANTREZ AN

Formaldehyde

Methanol

GANTREZ S waterES 3351 IPAES 225 ethanolES 425/ES 435 butanolGANTREZ MS carbonates-H2O

NEP EthylHEP HydroxyethylLP100 OctylLP300 DodecylCHP Cyclohexyl

-2H2 H2 2H2

N O

CH CH2Vinyl Caprolactam

Caprolactam

Poly(vinylpyrrolidone)•PVP/PLASDONES•PVP-I (Iodine)•POLYCLAR Copolymers•PVP/VA (vinyl acetate)•GAFQUAT (DMEAMA)•POLECTRON (Styrene)•ACRYLIDONE •GANEX (Olefins)•GAFFIX

CHHCAcetylene

Povidone ChemistryPovidone Chemistry

N O

CH CH2

Vinyl Pyrrolidone

O O

Butyrolactone

N O

H

2-Pyrrolidone

1,4-But-ynediol

CCH2OHHOCH2C

HO CH2CH CHCH2 OH

1,4-But-2-enediol

HOCH2CH2CH2CH2OH

Butanediol

H2C O

NH3

Formaldehyde

Methanol

-H2O

-2H2

H2

2H2

Polyvinylpyrrolidone•Povidone•Povidone Iodine•Crospovidone

CHHCAcetylene

Assessing Excipient Supplier Assessing Excipient Supplier GMP ConformanceGMP Conformance

First party First party questionnairequestionnaire

Second party auditSecond party audit Third party auditThird party audit

Regulatory auditRegulatory audit ISO AuditISO Audit IPEA AuditIPEA Audit

Reference MaterialsReference Materials

GMP Guide for Bulk Pharmaceutical ExcipientsGMP Guide for Bulk Pharmaceutical Excipients GMP Audit Guideline for Bulk Pharmaceutical GMP Audit Guideline for Bulk Pharmaceutical

ExcipientsExcipients GMP Audit Guideline for Distributors of Bulk GMP Audit Guideline for Distributors of Bulk

Pharmaceutical ExcipientsPharmaceutical Excipients Significant Change Guide for Bulk Significant Change Guide for Bulk

Pharmaceutical ExcipientsPharmaceutical Excipients COA Guide for Bulk Pharmaceutical Excipients COA Guide for Bulk Pharmaceutical Excipients

IPEC GMP GuideIPEC GMP Guide

IntroductionIntroduction DefinitionsDefinitions General GuidanceGeneral Guidance Excipient Quality SystemsExcipient Quality Systems General Auditing ConsiderationsGeneral Auditing Considerations AppendixAppendix

IPEC Audit GuidesIPEC Audit Guides

Manufacturer-1998Manufacturer-1998 Detailed questions-GMP GuideDetailed questions-GMP Guide Reminder phrases-GMP GuideReminder phrases-GMP Guide Detailed questions-Audit FlowDetailed questions-Audit Flow

Distributor-2000Distributor-2000 Includes additional guidanceIncludes additional guidance

IPEC Audit GuideIPEC Audit GuideManufacturerManufacturer

GMP Audit FlowGMP Audit Flow General informationGeneral information Materials flow from component to excipientMaterials flow from component to excipient DocumentationDocumentation

Reconfirm Adherence to cGMPReconfirm Adherence to cGMP

Periodic re-auditPeriodic re-audit Purchase IPEA Audit ReportPurchase IPEA Audit Report

Valid for 2 yearsValid for 2 years

IPEC Audit GuideIPEC Audit GuideDistributorDistributor

GMP Audit FlowGMP Audit Flow General informationGeneral information Facilities, warehousing, computers Facilities, warehousing, computers

repack/relabelrepack/relabel DocumentationDocumentation

Additional GuidanceAdditional Guidance

Traceable During LifecycleTraceable During Lifecycle

Manufacture

Distribution

Pharm User

Consumer

COACOAIssuesIssues

Continuous processingContinuous processing Reduced lot sampling (What is a lot?)Reduced lot sampling (What is a lot?) Process control through SPCProcess control through SPC

Batch processingBatch processing Periodic (skip lot testing)Periodic (skip lot testing)

Compendia requirements versus commitments Compendia requirements versus commitments in NDA filing in NDA filing additional testingadditional testing

Inventory shelf lifeInventory shelf life

COACOAContentContent

Manufacturers name and facility addressManufacturers name and facility address Expiration or Re-evaluation dateExpiration or Re-evaluation date Reference to test result if not on finished Reference to test result if not on finished

lot samplelot sample Date retested (if appropriate)Date retested (if appropriate) Identify results not from QC approval Identify results not from QC approval

samplesample

COA and DistributorsCOA and Distributors

Manufacturer name and siteManufacturer name and site Identify source of test dataIdentify source of test data Retest if repackagedRetest if repackaged

Significant ChangeSignificant ChangeDefinitionDefinition

A change that alters an excipient physical A change that alters an excipient physical or chemical property from the normor chemical property from the norm

A change that may alter the excipient A change that may alter the excipient performance in the dosage formperformance in the dosage form

Significant ChangeSignificant ChangeConsiderationsConsiderations

SiteSiteScaleScaleEquipmentEquipmentProcessProcessPackagingPackagingSpecificationSpecification

Significant ChangeSignificant ChangeEvaluation CriteriaEvaluation Criteria

Chemical PropertiesChemical Properties Physical PropertiesPhysical Properties Impurity ProfileImpurity Profile MoistureMoisture FunctionalityFunctionality BioburdenBioburden

Significant ChangeSignificant ChangeRisk LevelsRisk Levels

Level 1-Minor ChangeLevel 1-Minor Change Level 2-Might be SignificantLevel 2-Might be Significant Level 3-Always SignificantLevel 3-Always Significant

Excipient GMP AuditExcipient GMP Audit

Audit ScopeAudit Scope Audit PurposeAudit Purpose Safety ConsiderationsSafety Considerations

AttireAttire Facial hairFacial hair

Audit PlanAudit Plan

Auditing TechniquesAuditing Techniques

Stop talkingStop talking Calm the auditeeCalm the auditee Focus on listeningFocus on listening Remove distractionsRemove distractions EmpathizeEmpathize PatiencePatience Hold your temperHold your temper QuestionQuestion Be humbleBe humble LISTENLISTEN

JudgeJudge EmbellishEmbellish InattentiveInattentive Speak unclearlySpeak unclearly Talk excessivelyTalk excessively Phrase yes/no questionsPhrase yes/no questions Display an attitudeDisplay an attitude ArgueArgue CriticizeCriticize Answer your questionAnswer your question

Do Don’t

Audit DocumentationAudit Documentation SOP Index and SOPsSOP Index and SOPs Quality ManualQuality Manual FDA Inspection & ResponseFDA Inspection & Response RecordsRecords

TrainingTraining Pest ControlPest Control InventoryInventory CalibrationCalibration BatchBatch LaboratoryLaboratory

ReportsReports Laboratory InvestigationsLaboratory Investigations ComplaintComplaint Annual Product Quality ReviewAnnual Product Quality Review

ValidationValidationEquipment QualificationEquipment QualificationProcessProcessAnalyticalAnalyticalCleaningCleaning

Audit FindingsAudit Findings

State observationsState observations Include supporting documentationInclude supporting documentation

Note omissions or concernsNote omissions or concerns Use examples of corrective measures for Use examples of corrective measures for

illustrationillustration

Audit ReportAudit Report

FormatFormat Preferably use format of audit flowPreferably use format of audit flow Complete facility overviewComplete facility overview Note observations in body of the reportNote observations in body of the report List attendeesList attendees

Note corrective actions taken during auditNote corrective actions taken during audit

Auditor EtiquetteAuditor Etiquette

Safety rulesSafety rules AttireAttire Don’t touchDon’t touch Stay clearStay clear Stay with escortStay with escort Don’t question in noisy areasDon’t question in noisy areas

A. Company OverviewA. Company Overview

Quality PolicyQuality Policy Management commitmentManagement commitment Annually reviewedAnnually reviewed

Organization ChartsOrganization Charts Customer RequirementsCustomer Requirements

DocumentedDocumented ProcessProcess WrittenWritten

B. PersonnelB. Personnel

StaffingStaffing Hygiene and AttireHygiene and Attire TrainingTraining ConsultantsConsultants

C. Quality SystemsC. Quality Systems

Quality ManualQuality Manual Quality UnitQuality Unit

IndependenceIndependence Approval activitiesApproval activities Second check of dataSecond check of data

AuditAudit

D. Management of ComponentsD. Management of Components

PurchasingPurchasing TraceabilityTraceability Incoming Inspection Incoming Inspection

and Testand Test Water SystemWater System

E. FacilitiesE. Facilities

Adequate SpaceAdequate Space MaintenanceMaintenance

HousekeepingHousekeeping

EnvironmentEnvironment Pest ControlPest Control

F. WarehousingF. Warehousing

Receiving & ShippingReceiving & Shipping PackagedPackaged BulkBulk

RecordsRecords ShippingShipping RecallRecall

G. Equipment (1)G. Equipment (1)

IdentificationIdentification QualificationQualification Closed SystemClosed System DedicatedDedicated CleaningCleaning

ProceduresProcedures ValidationValidation LogLog

G. Equipment (2)G. Equipment (2)

Post MaintenancePost Maintenance UtensilsUtensils ContaminationContamination

From operationsFrom operations workerworker

From equipmentFrom equipment environmentenvironment

ConstructionConstruction Product ExposureProduct Exposure

G. Equipment (3)G. Equipment (3)

MaintenanceMaintenance Production equipmentProduction equipment Lab equipmentLab equipment

CalibrationCalibration Production equipmentProduction equipment Lab equipmentLab equipment

Computer SystemsComputer Systems

H. Production (1)H. Production (1)

Materials IDMaterials ID StatusStatus TraceabilityTraceability

ProcessingProcessing Lot definitionLot definition UniformityUniformity Batch recordsBatch records Process changeProcess change In-process testingIn-process testing Rework, recycle, recoveryRework, recycle, recovery

H. Production (2)H. Production (2)

Packaging & LabelingPackaging & Labeling Label approvalLabel approval Label reconciliationLabel reconciliation Label contentLabel content Package approvalPackage approval Package storagePackage storage Container/closureContainer/closure Bulk shipmentsBulk shipments

Computerized SystemComputerized System

SugarSalt

I. Finished Product I. Finished Product Management (1)Management (1)

Testing and ReleaseTesting and Release Sampling planSampling plan MethodsMethods OOSOOS

Non-conforming ProductNon-conforming Product DispositionDisposition InvestigationInvestigation

Corrective and Preventive Corrective and Preventive ActionsActions InvestigationInvestigation EfficacyEfficacy

I. Finished Product I. Finished Product Management (2)Management (2)

StabilityStability Market containerMarket container SOPSOP

Retained SamplesRetained Samples StorageStorage

Returned ProductsReturned Products DispositionDisposition

J. DocumentationJ. Documentation

Standard Operating Standard Operating ProceduresProcedures Document controlDocument control AvailabilityAvailability

Production RecordsProduction Records Second checkSecond check RetentionRetention