excipient auditing
TRANSCRIPT
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