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Production Records & DocumentationProduction Records & Documentation
Diane Kadidlo MT(ASCP) SBBDiane Kadidlo MT(ASCP) SBBUniversity of MinnesotaUniversity of Minnesota
Joanna Stanson, M.S.Joanna Stanson, M.S.University of PittsburghUniversity of Pittsburgh
Production RecordsProduction Records
This SessionThis Session::Production RecordsProduction Records
Basic ElementsBasic ElementsRegulatory ConcernsRegulatory ConcernsDocumentation PracticeDocumentation Practice
Practical Example of Production RecordPractical Example of Production Record
Questions & DiscussionQuestions & Discussion
Production Records Production Records -- OverviewOverview
Common elementsCommon elementsPreparationPreparationProcessing EventsProcessing EventsFinal ReviewFinal Review
Regulatory ConcernsRegulatory ConcernsAABB, FDA, FACTAABB, FDA, FACT
Documentation PracticesDocumentation PracticesRecord RetentionRecord Retention
Product Manufacturing RecordsProduct Manufacturing Records
General DefinitionGeneral DefinitionDetailed, stepDetailed, step--byby--step instructions of a task step instructions of a task that are required to manufacture a product.that are required to manufacture a product.
It is all about controlling the processIt is all about controlling the process
Production Record Design Production Record Design
Rules:Rules:Be compliant with applicable standards Be compliant with applicable standards
FDAFDA’’s GMP, s GMP, GTPsGTPsAABBAABBFACTFACT
Be compliant with regulatory submissionsBe compliant with regulatory submissionsInvestigational New Drug (IND) applicationsInvestigational New Drug (IND) applications
Facilitate complete and accurate data entryFacilitate complete and accurate data entryIncorporate validation limits & controlsIncorporate validation limits & controls
Production Records DesignProduction Records Design
Production Records Production Records shouldshould::Reduce/minimize Reduce/minimize redundant or redundant or unnecessary data unnecessary data entryentryReduce/minimize Reduce/minimize signaturessignaturesAllow records to be Allow records to be completed, logically completed, logically and chronologically, and chronologically, as work proceedsas work proceeds
RegulationsRegulations
FDAFDAGMPsGMPs Current Good Current Good Manufacturing Practice Manufacturing Practice for Finished for Finished Pharmaceuticals (21 Pharmaceuticals (21 CFR 211)CFR 211)GTPsGTPs 21 CFR 127121 CFR 1271
Process ControlsProcess ControlsFACTFACTAABBAABB
Production Record OutlineProduction Record OutlinePreparationPreparation
Bill of MaterialsBill of MaterialsPreparation DirectivesPreparation DirectivesProcess ClearanceProcess Clearance
Processing EventsProcessing EventsCompliance with INDCompliance with INDManufacturing StepsManufacturing StepsProcess controlsProcess controls
Record Review/Close outRecord Review/Close outRole of 2Role of 2ndnd PersonPersonReconciliationReconciliationExpected Yields/Acceptance CriteriaExpected Yields/Acceptance CriteriaAttachmentsAttachments
Preparation Preparation –– Bill of MaterialsBill of Materials
Bill of Materials CFR211.186) Bill of Materials CFR211.186) A listing of supplies, materials & equipment A listing of supplies, materials & equipment used in the process used in the process Materials that come in contact with product Materials that come in contact with product throughout its shelf life (reagents, bags, vials)throughout its shelf life (reagents, bags, vials)Often used as a checklist to ensure all Often used as a checklist to ensure all materials acceptable before usematerials acceptable before use
Supplies & EquipmentSupplies & EquipmentSuppliesSupplies
ItemItemPart #Part #ManufacturerManufacturerLot #,Lot #,Expiration DateExpiration Date
EquipmentEquipmentNameNameManufacturerManufacturerModelModelSerial NumberSerial NumberLast calibration dateLast calibration date
SuppliesSupplies
Item Part Number Manufacturer Lot Number Expiration
Date Recorded by/ Date
Cobe 2991 Triple processing set
MA165283
Isolymph CH100081
0.9% sodium chloride, injection, 1000 mL
CH100008
Human serum albumin, 5%, 500 mL
CH100087
DMSO CH142790
Transfer bag, 300 mL MA191613
EquipmentEquipment
EQUIPMENT MANUFACTURER MODEL SERIAL NUMBER
CALIBRATION CURRENT?
CliniMACS Cell Separation Device Miltenyi
15101 12555F Yes
Cell Processor COBE 2991 385987 Yes
Centrifuge, floor model Sorvall RC-3B BB-6677 Yes
Incubator, 36-38°C 4-6% CO2
Forma Scientific 3033 35479-12 Yes
Cell Analyzer Coulter ACT Diff II AJ38560 Yes
Fluorescent Microscope Carl Zeiss, Inc. 16160 3925609004 Yes
Preparation DirectivesPreparation Directives
Brief entries that describe preparation Brief entries that describe preparation eventsevents
Provides a link to associated preparation Provides a link to associated preparation record.record.
Ex. Room sanitization, reagent preparation Ex. Room sanitization, reagent preparation
Process ClearanceProcess Clearance
Also known as Also known as ““Line ClearanceLine Clearance””A check to ensure that the processing area A check to ensure that the processing area is ready for production and all is ready for production and all requirements have been met.requirements have been met.
Ex. Documenting the Biological Safety Cabinet Ex. Documenting the Biological Safety Cabinet is free of potential cross contaminants before is free of potential cross contaminants before initiating work.initiating work.Ex. Labeling Ex. Labeling
Production Record OutlineProduction Record OutlinePreparationPreparation
Bill of MaterialsBill of MaterialsPreparation DirectivesPreparation DirectivesProcess ClearanceProcess Clearance
Processing EventsProcessing EventsCompliance with INDCompliance with INDManufacturing StepsManufacturing StepsProcess controlsProcess controlsRole of 2Role of 2ndnd PersonPerson
Record Review/Close outRecord Review/Close outReconciliationReconciliationExpected Yields/Acceptance CriteriaExpected Yields/Acceptance CriteriaAttachmentsAttachments
Production Record & CMCProduction Record & CMC
Must be compliant with regulation submissions Must be compliant with regulation submissions ––egeg. . INDsINDsSection 7 of the INDSection 7 of the INDCritical component in the trial/IND submissionCritical component in the trial/IND submission
Product manufacturing & characterization informationProduct manufacturing & characterization informationProduct testing (including lot release testing) Product testing (including lot release testing) informationinformationProduct stability informationProduct stability informationOtherOther
Product labeling, tracking, etc.Product labeling, tracking, etc.
CMC ElementsCMC ElementsProcurementProcurementInfectious disease testing & Infectious disease testing & preventationpreventation of of cross contaminationcross contaminationProcessProcess
DescriptionDescriptionFlow diagramFlow diagram
ReagentsReagentsProduct TestingProduct Testing
Lot releaseLot releasePost release & additional testingPost release & additional testing
FDA FDA GuidancesGuidances
Guidance for ReviewersGuidance for Reviewers-- Instructions and Instructions and Template for Chemistry, Manufacturing, and Template for Chemistry, Manufacturing, and Control (CMC) Reviewers of Human Somatic Cell Control (CMC) Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications Therapy Investigational New Drug Applications ((INDsINDs). August 2003.). August 2003.
Guidance for Industry: Guidance for Industry: INDsINDs--Approaches to Approaches to Complying with CGMP During Phase IComplying with CGMP During Phase I
Processing Events Processing Events
Production Records Production Records shallshall include:include:Documentation that each significant step in Documentation that each significant step in manufacturing was accomplished including:manufacturing was accomplished including:
DatesDatesEquipment usedEquipment usedMaterials usedMaterials usedWeights & measures of components usedWeights & measures of components usedInIn--process & laboratory controlsprocess & laboratory controls
21 CFR 211.18821 CFR 211.188
21CFR 211.188 cont21CFR 211.188 cont’’d d
Batch Record Batch Record shallshall include:include:Inspection of packaging & labeling area before and Inspection of packaging & labeling area before and after useafter useCalculations of YieldsCalculations of YieldsLabeling recordsLabeling recordsDrug container & closuresDrug container & closuresSamples takenSamples takenID of person performing & reviewing ID of person performing & reviewing Any investigationsAny investigationsResults of packaging & label examinationsResults of packaging & label examinations
Responsibility of the OperatorResponsibility of the Operator
Document observations as they occurDocument observations as they occurSignature or initials of operator implies the Signature or initials of operator implies the data data
Accurately describes what is observedAccurately describes what is observedAuthentic Authentic –– person signing is the person who person signing is the person who observed or performedobserved or performedMeets all expectations, no unfinished workMeets all expectations, no unfinished work
Role of 2Role of 2ndnd PersonPerson
Review critical processes (calculations, label Review critical processes (calculations, label checks)checks)
22ndnd person does not necessarily have to watch the work person does not necessarily have to watch the work performed, but must be able to audit and edit the data performed, but must be able to audit and edit the data collection. collection.
Verification Verification Generally refers to a 2Generally refers to a 2ndnd person actually observing the person actually observing the work being done.work being done.
Weighing a productWeighing a productAddition of critical reagentAddition of critical reagent
22ndnd PersonPerson’’s Roles RoleKnowing the process Knowing the process AccuracyAccuracy
Verifying calculationsVerifying calculationsEnsuring that the data is recorded properlyEnsuring that the data is recorded properly
CompletenessCompletenessData legible, logical Data legible, logical
Complies with Standards & institutional policiesComplies with Standards & institutional policiesOften a QA functionOften a QA functionConfirming specifications met or not metConfirming specifications met or not metEnsuring that the document complies with crossEnsuring that the document complies with cross--outs, outs, signatures, signatures, sigsig--fig, averaging policies.fig, averaging policies.
Production Record OutlineProduction Record OutlinePreparationPreparation
Bill of MaterialsBill of MaterialsPreparation DirectivesPreparation DirectivesProcess ClearanceProcess Clearance
Processing EventsProcessing EventsManufacturing StepsManufacturing StepsProcess controlsProcess controlsRole of 2Role of 2ndnd PersonPerson
Record Review/Close outRecord Review/Close outReconciliationReconciliationExpected Yields/Acceptance CriteriaExpected Yields/Acceptance CriteriaAttachmentsAttachments
ReconciliationReconciliation
What was used and how muchWhat was used and how muchReconciliation/accountability of Reconciliation/accountability of components used for production. 21CFR components used for production. 21CFR 211.184211.184
Ex. Labels, vials, product #Ex. Labels, vials, product #’’ssDoes not include product and its container Does not include product and its container as that is controlled through product as that is controlled through product inventory.inventory.Suggest establishing limits (Suggest establishing limits (++ %)%)
Expected YieldsExpected Yields
Expected yields, objective end points, Expected yields, objective end points, accepted rangesaccepted ranges……
Requirement for Requirement for GMPsGMPs, FACT & AABB, FACT & AABBInvestigate when not metInvestigate when not met
Based uponBased uponManufacturerManufacturerLiteratureLiteratureStandardsStandardsYour historical data Your historical data
Acceptance CriteriaAcceptance Criteria
List of information that must fulfilled to List of information that must fulfilled to consider a production record acceptable.consider a production record acceptable.
Lot ReleaseLot Release
AttachmentsAttachments
LabelsLabelsSource documents (printouts, charts)Source documents (printouts, charts)Contract testingContract testingDeviations & InvestigationsDeviations & Investigations
Documentation PracticesDocumentation Practices
PrintoutsPrintoutsIdentify and sign all printouts, charts, source Identify and sign all printouts, charts, source datadata
Making changes afterwardsMaking changes afterwardsAny changes to original data must be signed Any changes to original data must be signed & dated& datedDo not obscure original entryDo not obscure original entryDetermine if changes warrant procedural Determine if changes warrant procedural change or investigationchange or investigation
Record ControlRecord Control
Controlled document and comply with Controlled document and comply with institutioninstitution’’s document control policiess document control policiesMaintain indefinitelyMaintain indefinitely
NextNext……..
Practical ApplicationsPractical Applications
Production Records and Production Records and DocumentationDocumentation
Joanna Stanson, M.S.Joanna Stanson, M.S.Senior Specialist Cellular Products LaboratorySenior Specialist Cellular Products Laboratory
University of Pittsburgh Cancer InstituteUniversity of Pittsburgh Cancer Institute
TopicsTopicsCellular Products Laboratory (CPL)Cellular Products Laboratory (CPL)General requirements for production and General requirements for production and documentationdocumentationFlow Chart for the implementation of a Flow Chart for the implementation of a production process (somatic cell culture)production process (somatic cell culture)Steps associated with the DC generationProduction Records and Control Production Records and Control Release CriteriaRelease CriteriaProduct acceptance and AccessioningProduct acceptance and Accessioning
Cellular Products Cellular Products cGMPcGMP/GTP /GTP Laboratory (CPL)Laboratory (CPL)
The CPL handles somatic cells from The CPL handles somatic cells from leukapheresis or smaller volumes of body fluids leukapheresis or smaller volumes of body fluids and human tissues for processing to single cell and human tissues for processing to single cell suspensionssuspensionsThe recovered cells are variously manipulated: The recovered cells are variously manipulated: purified, activated, cultured etc purified, activated, cultured etc Most of the products are for autologous useMost of the products are for autologous use
Steps associated with the human dendritic cell (DC) production
LeukapheresisMonocyte separation by elutriation (ELUTRA TM System)Culture of monocytes in Aastrom Replicelle closed system in the presence of IL-4 and GM-CSFiDC recovery and testingDC maturation in cytokinesTesting of the vaccine (the generated product)Release of the vaccine
The production processThe production process : human DC: human DCProduct ReleaseProduct Release
LeukapheresisLeukapheresisLeukapheresis
Elutra Elutra Monocyte Monocyte IsolationIsolation
1
2
Cell recoveryViability
MycoplasmaEndotoxin Phenotype SterilityPotency
CLINICAL OUTCOMECLINICAL OUTCOME
Adherence to plastic Adherence to plastic to isolate APCto isolate APC
Aastrom DC Aastrom DC CultureCulture
Antigen Loading
Maturation and Maturation and Harvest
Cell recoveryCell recoveryViability Viability
MycoplasmaMycoplasmaEndotoxin Endotoxin Phenotype Phenotype SterilitySterilityPotencyPotency
HarvestAntigen Loading
Cell counts, Viability,
Mycoplasma, Phenotype Sterility
Cell counts, Cell counts, Viability, Viability,
Mycoplasma, Mycoplasma, Phenotype Phenotype SterilitySterility
DCsinjection
DCsinjection
Flow Chart for the implementation of a Flow Chart for the implementation of a production processproduction process
IND Approval on fileIND Approval on fileInitiate ManufacturingInitiate ManufacturingMaintain batch records throughout manufactureMaintain batch records throughout manufactureInIn--process Testingprocess TestingRelease TestingRelease TestingQA/QC ReviewQA/QC ReviewBatch record completedBatch record completedProduct release for clinical use & shipment to investigatorProduct release for clinical use & shipment to investigatorReceipt documentation from the investigator (clinical Receipt documentation from the investigator (clinical coordinator)coordinator)Infusion Reactions & adverse reactions reported by Infusion Reactions & adverse reactions reported by Investigator to FDAInvestigator to FDA
Product acceptance and Product acceptance and Accessioning Accessioning
Leukapack is the primary source of patient cells. Leukapack is the primary source of patient cells. Visual inspection of each raw material, check Visual inspection of each raw material, check for damage, cells clotting etc. for damage, cells clotting etc. Assign CPL unique identification number (UIN)Assign CPL unique identification number (UIN)Cerner Database assigned ID based on Julian Cerner Database assigned ID based on Julian calendar: calendar: 0606--094094--000001 000001 UIN ID labeling on each container throughout UIN ID labeling on each container throughout the product tenure at the CPL the product tenure at the CPL
Production and DocumentationProduction and DocumentationGeneral RequirementsGeneral Requirements
ManufactureManufacture of all cellular products: in the facility of all cellular products: in the facility operated as operated as cGMPcGMP and based on and based on INDsINDsComponentsComponents: All are specified in the SOPs; : All are specified in the SOPs; COAsCOAs on fileon fileEquipmentEquipment: Production equipment description and ID are : Production equipment description and ID are included in the SOP and specified on worksheetsincluded in the SOP and specified on worksheetsProcedureProcedure: Production steps are specified in the SOPs: Production steps are specified in the SOPsBatch RecordsBatch Records: Maintained through all production steps on : Maintained through all production steps on forms unique to each productforms unique to each productDocumentationDocumentation of all production steps: retained in a of all production steps: retained in a subjects folderssubjects foldersFoldersFolders: Placed and maintained in a secure location within : Placed and maintained in a secure location within the CPLthe CPL
Production and Documentation cont.Production and Documentation cont.
Batch RecordsBatch Records
Records concurrent with performance of each Records concurrent with performance of each significant step. Accurate, indelible, legible, significant step. Accurate, indelible, legible, operator identified. Detailed. operator identified. Detailed. In CPL: Patient folders/files are created for each In CPL: Patient folders/files are created for each
specimen received, entered in log book and assigned specimen received, entered in log book and assigned a UIN consisting of the access # with a prefix a UIN consisting of the access # with a prefix indicating study protocol.indicating study protocol. Example: EGExample: EG--0606--00110011
Production and Documentation cont.Production and Documentation cont.Changes / Deviations during productionChanges / Deviations during production
Changes in procedure and production process: Changes in procedure and production process: approved in writing by the directorapproved in writing by the directorRecord all departures from the SOPRecord all departures from the SOPNot completed batch products: include explanation Not completed batch products: include explanation of early terminationof early terminationDisruptions, difficulties, problems: record and Disruptions, difficulties, problems: record and explainexplainRecords should be maintained in a way that allows Records should be maintained in a way that allows the complete history of a product batch to be the complete history of a product batch to be reviewed before distributionreviewed before distribution
Production recordsProduction recordsCritical steps recorded on the daily worksheetCritical steps recorded on the daily worksheetCalculations; data integrity verified by a second Calculations; data integrity verified by a second technologisttechnologistSignature of the observer/ verifying person Signature of the observer/ verifying person
Traceability to primary records of the facility:Traceability to primary records of the facility:Support services: Sterility assays performed by Microbiology Support services: Sterility assays performed by Microbiology
lab, Myco/ Endo tests performed by CPL lab, Myco/ Endo tests performed by CPL Environmental monitoring: particle counts, viable count, Environmental monitoring: particle counts, viable count, humidity, temperature recorded humidity, temperature recorded Supply and Reagents Supply and Reagents QC results: Viability, Phenotypic characterization prior to QC results: Viability, Phenotypic characterization prior to releasereleaseAll assembled into a file which is unique for each productAll assembled into a file which is unique for each product
Production controlProduction controlAll flasks/containers labeled with CPL assigned UIN, All flasks/containers labeled with CPL assigned UIN, batch number and color codedbatch number and color codedQC check on volume; documentation of cell count & QC check on volume; documentation of cell count & recordrecordIntermediate & final product check & prohibited Intermediate & final product check & prohibited product release until discrepancy resolved (if any product release until discrepancy resolved (if any detected)detected)Sample (at least 10% of a cell product) & test product Sample (at least 10% of a cell product) & test product before release before release CrossCross--contamination control: isolation (use one hood contamination control: isolation (use one hood per product), scheduling (one patient per room), per product), scheduling (one patient per room), cleaning (hood and incubator between different cleaning (hood and incubator between different products), products),
Quality Control / Criteria for releaseQuality Control / Criteria for release
Product qualification:Product qualification: Defined in the IND for human DCDefined in the IND for human DCRecovery: Variable (depends on the donor)Recovery: Variable (depends on the donor)Viability: normal range (70Viability: normal range (70--95%)95%)Product purity: Product purity: ≥≥70% 70% Endotoxin level: below 5EU/kg of body weightEndotoxin level: below 5EU/kg of body weightMycoplasma: negative Mycoplasma: negative Gram Stain negativeGram Stain negativePhenotype/Maturation: CD86+, CD80+, CD83+, Phenotype/Maturation: CD86+, CD80+, CD83+, CCR7+CCR7+Sterility: free of microbial contamination (available Sterility: free of microbial contamination (available after 14 days)after 14 days)Test for potency (not required but recommended)Test for potency (not required but recommended)
Cellular Product Release / Delivery FormCellular Product Release / Delivery Form
Patient Name: _______________________ Patient Name: _______________________ Product: ___________________________Product: ___________________________CPL No: ____________________________CPL No: ____________________________ Date: _____________________________Date: _____________________________Protocol: ____________________________Protocol: ____________________________ Course/Vaccine: ____________________Course/Vaccine: ____________________Cell #: _______________________Cell #: _______________________ Cell viability: _________________Cell viability: _________________CAUTION:CAUTION:New Drug Limited by Federal Law to Investigational Use.New Drug Limited by Federal Law to Investigational Use.
For Autologous Use Only.For Autologous Use Only.Product preparation/labeling by:Product preparation/labeling by:________________ ________________ Verification byVerification by____________________________________________
initials/dateinitials/dateProduct meets all specified release criteria, release authorizedProduct meets all specified release criteria, release authorized by:by:___________________________________ __________________________________________________ _______________signature/titlesignature/title
date/timedate/timeProduct delivered by:Product delivered by:_________________________________ _________________________________________________________ ________________________
SignatureSignature date/timedate/timeProduct received by:Product received by:__________________________________ __________________________________________________________ ________________________
SignatureSignature date/timedate/timeProduct administered by:Product administered by:___________________________________ __________________________________________________ _______________Signature/titleSignature/title
date/timedate/time
Warning:Warning: Product expires ____ hours from release time.Product expires ____ hours from release time.Warning:Warning: Advise patient of communicable disease risks. Product final steAdvise patient of communicable disease risks. Product final sterility pending.rility pending.Please fax completed form to CPL 412Please fax completed form to CPL 412--624624--0264.0264.
PRODUCT REVIEW FORMPRODUCT REVIEW FORM
UPCIUPCI--CPLCPLHCC, Suite 1.27, Pittsburgh, PA 15213HCC, Suite 1.27, Pittsburgh, PA 15213Ph: (412) 624Ph: (412) 624--00800080
PRODUCT REVIEW FORMPRODUCT REVIEW FORM
CPL Batch # ___________________________ Protocol # _____________CPL Batch # ___________________________ Protocol # _____________________________Patient Name_________________________ Vaccine # ____________Patient Name_________________________ Vaccine # ____________________________Sample Received___________________________ Sample Received___________________________ Date/Time Sample RecDate/Time Sample Rec’’d ______________________________d ______________________________Comments: Comments: Date for Product Release: _____________________Date for Product Release: _____________________
I certify that this product has met the release criteria as per I certify that this product has met the release criteria as per the IND filed for the above the IND filed for the above listed Protocol and the product is acceptable to be released forlisted Protocol and the product is acceptable to be released for its intended use.its intended use.
____________________________________________________________________________ ________________________________________Director Release SignatureDirector Release Signature DateDate
Overall ObjectivesOverall Objectives
Objective of the regulated production Objective of the regulated production processprocess
Clearly defined and documented production and Clearly defined and documented production and control procedures to prevent crosscontrol procedures to prevent cross--contamination and contamination and to ensure that the finished product meets to ensure that the finished product meets specifications as they are defined I the INDspecifications as they are defined I the IND
