2nd annual ace_0.pdf

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Preparing for and Handling anPreparing for and Handling an FDA Inspection at Your Facility Dawn TavalskySanofi Pasteur, Inc.

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Objectives

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FDAs Authority to Inspect

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FDAs Authority to Inspect

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Inspection Process

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Centers and Offices

Office of the Commissioner Organization Center for Biologics Evaluation and Research Organization g gCenter for Devices and Radiological Health Organization. Center for Drug Evaluation and Research Organization Center for Food Safety and Applied Nutrition Organization. Center for Tobacco Products Organization Center for Veterinary Medicine Organization National Center for Toxicological Research Organization Office of Regulatory Affairs Organization

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Office of Regulatory Affairs Organization.

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Office of Regulatory Affairs (ORA)http://www.fda.gov/ora/

Headquarters:

Rockville, MD

Regional Office: Philadelphia, PA

District Office:

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Detroit, MI

FDA Field Investigators

Conduct inspections to enforce the Food, Drug and Cosmetic ActTrain themselves in evidence collection

If its not documented, it didnt happen.

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FDA Office Site Location

FDA Inspection Process

1. Select Site

2. Contact Site

3. Schedule Site

4. Arrive (482)

5. Review Records

6. Interview Staff

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7. Present Findings

8. Depart (483)9. Write Report (EIR)

10. Classify Inspection

Overview of FDA Enforcement Actions

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FDA Forms

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Selection Criteria

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Preparing for the Audit

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While there are several types of audits with several different types of focus:

A l Fl V iAnnual Flu Vaccine Bi-annual auditPre Approval Inspection (PAI)For Cause AuditEtc

We will now discuss preparing for a PAI inspection

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We will now discuss preparing for a PAI inspection however many of the points apply to any type of FDA audit.

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Best Practices to Develop DeployBestPracticestoDevelop,DeployandMaintainaRiskBasedACE

ProgramPresentedbyKarenSGinsbury

For IVTs ACE ConferenceForIVT sACEConferenceAmsterdam,Netherlands

October2011

RiskManagement

Startswithphilosophy Understandingthelawsofnaturehelps: NaturehasatendencytoDISORDER Howdoyouperceivewhatisgoingtohappentomorrowmorningatyourfacility:

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ItwillbeOK

Whatcouldgowrongtoday

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Letsmakealist

Cleaning

Letsmakealist

Asepticprocessing

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Letsmakealist

Environmentalmonitoring

CleaningValidationcitations1.Processtanksareroutinelyreusedbeforecleaning,andnocleaningvalidationdataareavailabletosupportthispractice.

2.Nodataexisttosupportthemanualcleaningofcentrifugebowls.

3.Approvedcleaningproceduresarenotspecificandarenotvalidatable

4.Inadequatecleaningoflyophilizer,inthatworstcasesamplinglocationsarenotidentified,andsamplingtechniqueshavenotbeenvalidated.

5.Inadequateproductiontankcleaningproceduresexist.Specifically,validatedholdtimesarenotincludedinthecleaningprocedure;cleaningvalidated hold times are not included in the cleaning procedure; cleaningSOPslacksufficientdetail;andnoverificationofvisualinspectionforcleanliness.

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CleaningWarningLetter

FDAWarningLetter Feb2011

1.Yourfirmhasnotestablishedorfollowedappropriatewrittenproceduresdesignedtopreventmicrobiologicalcontaminationofdrug products purporting to be sterile [21 C F R 211 113(b)] Fordrugproductspurportingtobesterile[21C.F.R. 211.113(b)]. Forexample,

Forexample,inJune2010,yourfirmfailedtoidentifytheorganismsrecoveredfromasterilitytestforApidra lot#OF100. Identificationofmicroorganismsrecoveredfromasterilitytestisessentialwhenconductingasterilityfailureinvestigation.Inaddition,theidentificationoforganismsisalsoafundamental part of any investigation of environmental orfundamentalpartofanyinvestigationofenvironmentalorpersonnelmonitoringexcursions.

Yourfirmsfailuretoidentifyorganismsrecoveredfromasterility

testwasalsodiscussedduringtheDecember2008inspection.

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Fromthesameletter

Anadequateenvironmentalmonitoringh ld b t bli h d b fi Itprogramshouldbeestablishedbyyourfirm. It

shouldcapturemeaningfuldataandactasanearlywarningsystemtodetectpossibleenvironmentalcontaminantsthatmayimpactthesterilityofdrugproductsmanufacturedatyourfacilitythatpurporttobesterile.

October2010

b.Yourasepticprocessingcontrolsystemsandoperationsdonotprovideassurancethattheproductionroomsandequipmentmaintain aseptic conditions Additionally your environmentalmaintainasepticconditions.Additionally,yourenvironmentalmonitoringpracticesdonotincludeadequateroutineexaminationofthefacilitiesandequipmenttoensurethatpossiblecontaminantscanbedetected.

Theinspectiondocumentedmoldcontaminationintheclass100productionroomandpoorconditionsofawallinthefreezedryerroom,eventhoughmaintenanceisconductedonthefreezedryerevery 6months. An incident report, initiated in November 2009,every 6months.Anincidentreport,initiatedinNovember2009,identifiesholesintheceilingandvisiblelightcomingfromtheroofneartheventilationsystem,bubblingofthevinyland disintegrationofthewallundervinylinthefreezedryerroom,visibleblackmoldonthewall,apoordrainsystemforthefreezedryersteamventingsystem,andasoft(spongy)wall.

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MHRAFindingsApril2008 March2009

WEdwardsDeming1900 1993

Wehavelearnedtoliveinaworldofmistakesanddefectiveproductsasiftheywerenecessarytolife

IfIhadtoreducemymessageformanagementtojustafewwords,Idsayitallhadtodowithreducingvariation

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CauseandEffect

Allmanufacturingprocessesaredesignedtof ll i f t hi h i t li k dfollowaseriesofstepswhichareinterlinkedandinterdependent(causeandeffect)

Variationexistsinallprocesses Understanding and controlling variation willUnderstandingandcontrollingvariationwillalwaysimproveyourprocess

CauseandEffect

Asepticprocessing:variationcanleadtoNONt il d tsterileproduct

Cleaning:variationcanleadtocrosscontaminationorcontamination

EM:variationcanleadtofalserepresentationof the state of control of a processofthestateofcontrolofaprocess

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Uncertainty=RiskWherethereisvariability=uncertainty=Risk

Whatcontrolsdoyouhaveinplacetostopitgoingwrong?

Riskmanagement: Riskassessment Riskmitigation thecontrolsweputinplacetostopitgoingwrongfollowedby

Riskacceptanceand Riskcommunication

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Cleaning whatcontrols?

AsepticProcessing whatcontrols?

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EnvironmentalMonitoring.

EMisNOTacontrolorariskreductionmeasure

EMisthenextstepinourprocess Riskreview

h WeuseEMtomonitortheSTATEOFCONTROLthatwehaveachievedusingourriskmitigationmeasures

EnvironmentalMonitoring.

WhatinformationwillIusetodeploymy limited EM resources?mylimitedEMresources?

Howwillmyriskassessmenttiein ReassignthemostresourcestoHighriskactivities cleaningaconvolutedpieceofmultipurposepipingp p p p g

Makinganasepticconnection Machinesetup Cleaningonthegraveyardshift

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FDAWarnedAtLeast43DrugPlantsInRecentMonthsOverManufacturingPractices

USA Today (5/27, Young) reportsUSAToday(5/27,Young)reports "Atleast43drugfactoriessupplyingmedicationtothousandsofUS

consumershavereceivedgovernmentwarningsinrecentmonthsforfailingtocorrectshoddymanufacturingpracticesthatmayhaveexposedpatientstohealthrisks...."

Violations"include: plantsusingequipmentandingredientscontaminatedwithbacteriaorinsects failingtodopropertestingtoensuredrugstrengthandpurity,andignoring

consumercomplaintsthatproductsweremakingthemsick."F 2002 t 2006 " th h lf f i ti t d ti d l t From2002to2006,"morethanhalfofinspectionsatdomesticdrugplantsand62%atforeignplantssupplyingtheUShadviolationsthatdidn'tpromptwarningletters,butwereclassifiedasrequiringcorrection,FDAdatapublishedbytheGovernmentAccountabilityOfficeshow."

EstablishingandMaintainingaStateofControlWhathaschanged?

1)Lessexperiencedinspectorswithmisalignedperceptionsofhowsystemsshouldworkamplifiedbytheresultantpostinspection"

( )ConsultantCreep"(Actionandreaction)2)Downsizingofworkforce,sometimesbelowthelevelrequiredto

operategoodqualitysystems.3)Lackofleadership/technicalexperienceintheQAstaff.4)PoororganizationplacementofQA.5)PoorInspectionmanagementonpartoffirms.6) Failure to understand validation and its purpose Textbook exercise6)Failuretounderstandvalidationanditspurpose.Textbookexercise

vs.actualproductandequipmentbasedtestdesign.7)Increasedagencyemphasisonquickenforcement,sometimes

withoutdialogue

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AndKeepasking:Whatcouldgowrongtoday

TheEnemiesofControl

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Deviations

"Everydefectisatreasure,ifthecompanyitcanuncoveritscause

andworktopreventitacrossthecorporation KilchiroToyoda,founderofToyota

.oops!p

Changes

Change management is about controllingChangemanagementisaboutcontrollingchangestoensurethatinnovationhappenswithoutunintended/unforeseenconsequences

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InConclusion

Riskmanagementisabout:Id tif i i k Identifyingrisks

Investingenergytocontrolandreducethoserisks Communicatingastheriskmitigationmeasurestostakeholdersatalllevelsinthecompanybroadestpossiblecommunication

Event review and monitoringEventreviewandmonitoring Updatingtheassessmentwhenthereareindicatorsthatitisfailingormovinginthewrongdirection

Thankyouforyourattention

Anyquestions?

Contactme:[email protected]

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Quality Management System

Presented by: Karen S GinsburyPCI Pharmaceutical Consulting Israel LtdFor IVT ACE ConferenceA t d O t b 2011

Aseptic Processing

Amsterdam, October 2011

PCI Pharmaceutical Consulting Israel Ltd1

Lewis CarrollAlice in Wonderland

If you don't know where youIf you don t know where youwant to goYou are likely to end upsomewhere else


somewhere else

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Objective of Seminar

ReviewReviewRefreshRenewRefine


and develop a robust QMS forAseptic Processing

Part I: Regulations, Revisions and Guidance

21 CFR: US GMPs on aseptic processing and latest revisionsAnnex 1: EU GMPs on aseptic processing: February 2008 version


versionFDA Aseptic Processing Guide (2004)

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II. Aseptic Product and Process Lifecycle

ICH Q8: Product Development:T t P d t P filTarget Product ProfileCritical Quality Attributes (CQA)Linking Parameters to CQAsRisk AssessmentControl Strategy


Control StrategyLifecycle Management

ICH Q9: Risk Management

III ICH Q10 Developing a Robust Quality System for Aseptic ProcessingInvestigational ProductSterility Assurance IssuesSterility Assurance IssuesPersonnel TrainingValidation, Operation and Environmental ControlsCAPA and Control Strategy


CAPA and Control StrategyDeviationChange Control

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Interactive Bit! (to be all along)Develop a CAPA system

develop a reporting and assessment system for monitoring the quality metrics of an aseptic operation


an aseptic operationKPIs and feed items

Create Your Own Map (KPIs)What items need to be controlled


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gregulationsAseptic Processing - Sterilization

Section 211.67(a) Equipment cleaning and maintenance is being revised to add themaintenance is being revised to add the phrase and/or sterilized after the word sanitized in the current regulationThis change updates the terminology to reflect the fact that, in the context of sterile drug products the appropriate form of


drug products, the appropriate form of sanitization would be sterilizationThis is consistent with our interpretation of this regulation for more than 20 years and reflects the currently accepted industry practice

KPIs for depyrogenation tunnelTemperatureTimeAir quality (post cycle: particles well now / depends Karen says YES!)says YES!)Line speedDirection of air flowing into the tunnelPCI Pharmaceutical Consulting Israel Ltd10

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2008 / 9 Changes to GMP regulationsAseptic Processing Microbial ControlsSection 211.84(d)(6) Testing and approval or rejection of components drug productor rejection of components drug product containers, and closures, is being revised to change the phrase that is liable to microbiological contamination, to with potential for microbiological contamination


We believe this revision provides additional clarity without changing the meaning or intent of the regulation

KPIs on microbial specsLook at trends on incoming

t i l / tmaterials / components


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Changes to GMP regulationsAseptic Processing - Depyrogenation

Section 211.94(c) Drug product containers and closures is being revised to clarify that validation is required for the depyrogenation processesthe depyrogenation processesTo assure that certain drug products are suitable for their intended use, drug product containers and closures are required to be sterilized and depyrogenated to remove microbial contamination and pyrogens or endotoxinIt has been longstanding industry practice to validate the sterilization and depyrogenation processes to


the sterilization and depyrogenation processes to assure consistent removal of microbial contamination and pyrogens or endotoxinLack of evidence of such validation and inadequacies in the validation studies have been cited in FDA actions throughout the years based on this regulation. Accordingly, this rule simply clarifies 211.94(c) by adding a new sentence at the end which states:Such

Changes to GMP regulationsAseptic Processing - Depyrogenation

Industry Objections Risk ManagementWhere containers and closures are actively yrendered non-pyrogenic by a designated depyrogenation process, the depyrogenationprocess shall be validatedNot ALL containers and closures require active depyrogenationSome containers and closures are non-pyrogenic


by nature and/or design of their manufacturing process(es) or have been qualified not to require active depyrogenationHandling procedures are also designed and controlled (e.g., bulk packaging, incoming parts control, storage, personnel control) to minimize the risk of pyrogen contamination during finished

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Changes to GMP regulationsAseptic Processing - Bioburden

Paragraph (a) of 211.110 Sampling and g p ( ) p gtesting of in-process materials and drug products is being revised to include bioburden process control procedures and tests, where appropriateThe re ised reg lation ill add biob rden


The revised regulation will add bioburden testing as the sixth example of process control procedures (five others are already listed)

Changes to GMP regulationsAseptic Processing Microbial Control

Paragraph (b) of 211 113 Control ofParagraph (b) of 211.113 Control of microbiological contamination is being revised to include validation of aseptic processes for drug products that are purported to be sterile


The current regulation mentions only validation of sterilization processes, not aseptic processes

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Changes to GMP regulationsAseptic Processing Microbial Control

Even before 1987, when the Guideline for Sterile Drug Products Produced by AsepticSterile Drug Products Produced by Aseptic Processing was issued, industry routinely conducted validation studies that substituted microbiological media for the actual product to demonstrate that its aseptic processes were validated. These parts of validation studies are


poften referred to as media fills. We believe that this revision clarifies existing practices and serves to harmonize the CGMP requirements with Annex 1 of the EU GMPs, which requires such validation


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KPIs for microbial controlTrending of EM dataTrending of personnel monitoringTrending of personnel monitoring dataSuccessful gowning qualificationFrom total of six different locations less than 5 cfuO it l th 20????????On exit less than 20????????During certification take MORE location than during routine monitoring and consider variants in persons build and agePCI Pharmaceutical Consulting Israel Ltd19

Main Changes

Particulate Classification(Airborne particles 5 micron)Media SimulationsBioburden monitoringCapping of (Freeze Dried) Vials


Capping of (Freeze-Dried) Vials

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Previous

Now


Cleanroom and clean air device monitoring: RISK ANALYSIS REQUIRED!

Cleanrooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results


analysis study and the results obtained during the classification of rooms and / or clean air devices

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Duration of MonitoringGrade A: full duration of critical processing, including equipment assembly except where justified e.g. live organisms, radiological hazards (then do it prior to operations and using simulated operations)Monitor Grade A at frequency and sample size that all interventions, transient events and system deterioration would be captured and alarms triggered if alert limits are exceeded


May not always be possible to demonstrate low levels of 5.0 micron particles at the point of fill during filling because of particle generation / droplets from product

Sample Size


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Media Simulations: Previous Acceptance Criteria

The target should be zero th b t t i ti tgrowth but a contamination rate

of less than 0.1% with 95% confidence limit is acceptableThe manufacturer should


establish alert and action limitsAny contamination should be investigated

Media Simulations: Acceptance Criteria


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Bioburden: Added TextBioburden assay should be performed on each batch for both aseptically filled and p yterminally sterilised productsFor overkill sterilisation products, bioburden might be monitored only at suitable scheduled intervalsFor parametric release systems, bioburden


p y ,assays should be performed on each batch and considered as an in-process test

Capping of Freeze Dried Vials Added Text

Partially stoppered freeze drying i l h ld b i t i dvials should be maintained

under Grade A conditions at all times until the stopper is fully inserted


NOTE: effective 01 March 2010

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FDA Aseptic Processing Guide




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(K)PIs for ISO 5 areasAirflows: patterns operational and compare to previousVelocityVelocityNumber of air changes in surrounding room: compare to previous and compare to design specificationNumber of particles (total)Microbiological monitoringHEPA filter integrity testg yPressure differentialsPersonnel monitoringImplementation of cleaning procedures as writtenHow are cleaning implements STOREDEfficacy of disinfectants with our isolatesPCI Pharmaceutical Consulting Israel Ltd31



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(KPIs) for Time limitations in production

Look at unit operations and gather data to support maximum timedata to support maximum time periodsVisual inspection of any sterilized item immediately prior to use for integrity of packageg y p gKPI media fills and lack of sterility test failures (which is a lousy KPI)KPI: environmental monitoring


KPIs for personnelMonitoringSupervisionpMedia fillsGowning qualificationGMP refreshers / micro / aseptic: frontal training and demonstrations / tests of some kindsO th j b l ti ith t tOn-the-job evaluations with respect to specific procedures / SOPs / written instructions (aseptic review/ process confirmation documented reviews)


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KPIs on validation / qualification/ calibration / PM / malfunction maintenance

Number and frequency of machine malfunctions and review of PMmalfunctions and review of PM recordsEnsure that we capture data relating to maintenance operations in useable and trend-able formats develop documentation that supports thisAny failures are captured and placed in our trending systemsPCI Pharmaceutical Consulting Israel Ltd37



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(K)PIs for the aseptic process itself

Data pertaining to: the Sterilization processSteam (autoclave)Dry heat (depyrog)Dry heat (depyrog)Ethylene oxide

Have a validated stencil for the chart recordINVESTIGATE ALL deviations from that stencil as representing a

shiftFiltration

Sterilization process for filterWetting out of filter before start of filtrationIntegrity before and afterg yPressure differential duringTime of filtrationVolume of filtratebioburden

gamma


Part II Product Development

Target Product ProfileCritical Quality Attributes (CQAs)

Linking CQA to Production Parameters

Part II Product Development

Risk AssessmentControl Strategy

Lifecycle Product Management


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TPPTarget Product ProfileA prospective and dynamic summary of p p y ythe quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realisedThe target product profile forms the


e ta get p oduct p o e o s t ebasis of design for the development of the product

CPPs vs CQAs

Critical Process P t

Critical Quality Att ib tParameter

A measured variable that has a known effect upon a product quality attributeA process parameter that

t b t ll d ithi

Attributephysical, chemical, biological, or microbiological property or characteristic th t h ld b ithimust be controlled within a

specified range to assure product quality

that should be within an appropriate limit, range, or distributionto ensure product quality

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Product and Process and Variation

Sterility (Y): CQA affected by Variable Inputs (X)

Indi

vid

ual

Val

ue

115

110

105

100

95

90

_X=99.63

UCL=111.55

LCL=87.71

I Chart

People

Equipment

Measurement

INPUT

y = (x)

y

Inputs to the processcontrol variability

of the Output

Indi

vid

ual

Val

ue

120

115

110

105

100

95

90

_X=102.37

UCL=116.68

LCL=88 05

I Chart

Observation

Indi

vid

ual

Val

ue

6058565452504846444240

115

110

105

100

95

90

85

80

_X=97.94

UCL=112.65

LCL=83.23

I Chart

Observation

Ind

ivid

ual V

alu

e

6058565452504846444240

115

110

105

100

95

90

85

80

_X=97.94

UCL=112.65

LCL=83.23

I Chart

Observation8078767472706866646260

C 8

Indi

vidu

al V

alue

115

110

105

100

95

_X=99.95

UCL=114.17

I Chart

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Process

Materials

Environment

S(X)

OUTPUT

Observation4038363432302826242220

LCL 88.05

Observation

Indi

vid

ual

Val

ue

8078767472706866646260

115

110

105

100

95

90

_X=99.63

UCL=111.55

LCL=87.71

I Chart

Observation

Ind

ivid

ual V

alu

e

10098969492908886848280

110

105

100

95

90

85

_X=98.76

UCL=111.17

LCL=86.35

I Chart

Observation9181716151413121111

90

85 LCL=85.72

Adapted from slide by Moheb Naser, FDA

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Control StrategyControl StrategyA planned set of controls, derived from

t d t dcurrent product and process understanding, that assures process performance and product quality.The controls can include parameters and attributes related to drug substance and drug product materials and components,


g p pfacility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control

TPP continuedConsiderations for the target product profile should include:p

Dosage form and route of administrationDosage form strength(s)Therapeutic moiety release or delivery and pharmacokinetic characteristics (e.g., dissolution; aerodynamic performance) appropriate to the drug


performance) appropriate to the drug product dosage form being developedDrug product quality criteria (e.g., sterility, purity) appropriate for the intended marketed product

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Risk Assessment, CQAs, Process Parameters

Risk assessment early in development identifies:Material attributesProcess parametersProcess parametersthat have an effect on CQAs

Repeat the risk assessment as development progresses / knowledge is gainedIdentify and rank parameters (e.g., operational, equipment, input material) with potential to have an impact on product quality based on prior knowledge and initial experimental data


and initial experimental dataInitially long list, narrowed down as process understanding increases and through DOE(understand interaction of variables)

Risk Ranking TableRisk Category Ranking / Definition

Low Medium High

SeveritySEV

If the event occurs and is not detected it is NOT likely to harm the patient

If the event occurs and is not detected it may cause moderate harm to the patient

Direct and severe impact to the patient; life threatening

Likelihood of The possibility that the cause occurs

There is a reasonable

ibilit th t th

High possibility of occurrence;

OccurrenceOCC

the cause occurs is rare; unusual event

possibility that the cause may occur from time to time

occurrence; common / known event

Likelihood of DetectionDET

If the event occurs there is a HIGHlikelihood of detection

If the event occurs it might be detected

If the event occurs it probably will NOT be detected

48 PCI Pharmaceutical Consulting Israel Ltd

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Risk Priority Number

Scale 1 - 5 RPN

SEV xOCC X

< 10 ?

11 29 ?OCC XDET

11 29 ?

30 ?

49 PCI Pharmaceutical Consulting Israel Ltd

Sterility Control Strategy


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Lifecycle Product Management

Developmentt

Process validation

Annua

CAPA


Commercial

Annual

Product

Review

ICH Q10 Robust Quality System

Investigational ProductSterility Assurance Issues

Personnel TrainingV lid i O i d E i l

for Aseptic Processing

Validation, Operation and Environmental Controls

CAPA and Control StrategyDeviation

Change ControlPCI Pharmaceutical Consulting Israel Ltd52

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Control StrategyList the items that need to be

t ll d d thi k b t hcontrolled and think about how to achieve that_______________________


______________________________________________

Personnel Training - KPIsDeviation operator error: recurrenceSterile Product(Capacity data)Testing of employee trainingOn the Job evaluationCompliance to curriculumCertification


Gowning results / EM dataMedia fill participationHealth Reporting

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Validation - KPIs


EM - KPIs


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Deviations, Complaints, Rejected Batches -KPIs


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Points to Consider WhenPoints to Consider When Investigating Environmental Monitoring FailuresDawn TavalskySanofi Pasteur, Inc.

Environmental Monitoring Components

Airborne nonviable particulate monitoringAirborne viable contaminant monitoringVi bl t i t it i f fViable contaminant monitoring of surfacesViable contaminant monitoring of personnelTemperature and humidity monitoringPressure differential monitoring

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Environmental Monitoring Components

Water monitoring:Total organic carbonC d ti itConductivityMicrobial ContaminantsEndotoxin

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General Environmental Monitoring Considerations

Monitoring frequencies and strategiesEstablishment of a meaningful and manageable program

Sampling and testing proceduresSampling and testing proceduresEstablishment of effective alert and action limitsTrending of results

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General Environmental Monitoring Considerations

Investigation and evaluation of trends as well as excursions from alert and action limitsC ti ti t b i l t d i tCorrective actions to be implemented in response to environmental monitoring excursionsPersonnel training - sampling, testing, investigating excursions, aseptic technique

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Scope of Environmental Monitoring Program

Should include monitoring of all environments where products and their components are manufactured

All h h i i k f d i iAll areas where there is a risk of product contaminationShould include monitoring of all water used for product manufacturing as well as feed water to the final water purification system (WFI System)

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Regulatory Basis for Environmental Monitoring Program

CFR GMP regulationsFDA Guidance DocumentsUSP I f ti l Ch tUSP Informational Chapter

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21 CFR 211.42

Aseptic processing areas:Easy to clean and maintainT t d h idit t ll dTemperature and humidity controlledHEPA filtered airEnvironmental monitoring systemCleaning and disinfecting proceduresScheduled equipment maintenance and calibration

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21 CFR 211.46

Ventilation, air filtration, air heating and cooling:Adequate control over microorganisms, dust, humidity and temperaturetemperature.Air filtration systems including prefilters and particulate matter air filters for air supplies to production areas.

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Guideline on Sterile Drug Products Produced by Aseptic Processing

Defines critical and controlled manufacturing areasRecommends airborne nonviable and viable

t i t li itcontaminant limitsProvides some guidance on monitoring frequencies for critical areas

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Guideline on Sterile Drug Products Produced by Aseptic Processing

Recommendations for air pressure differentialsIncludes guidance on aseptic media fillsN t Thi id d t itt i 1987 dNote: This guidance document was written in 1987 and is in need of revision

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Microbial Evaluation and Classification of Clean Rooms and Clean Zones

USP General Information Chapter Establishment of clean room classifications

F d l S d d 209EFederal Standard 209EImportance of EM programPersonnel training in aseptic processingEstablishment of sampling plans and sites

suggested sampling frequencies

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Microbial Evaluation and Classification of Clean Rooms and Clean Zones

Establishment of alert and action limitsSuggests limits for airborne, surface and personnel

t i t l lcontaminant levels.Methods and equipment for samplingIdentification of isolatesAseptic media fillsEmerging technologies - barrier; isolator

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Federal Standard 209E

Airborne Particulate Cleanliness Classes in Clean Rooms and Clean ZonesA d b th GSA f b ll F d l A iApproved by the GSA for use by all Federal AgenciesFrequently referenced for controlled environment particulate requirements: Classes 100, 10,000 and 100,000 (based on particles > 0.5)

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Guidance for Industry for Sterile Validation Process Validation in Applications for Human and Veterinary Drug Products

Scope limited to final drug product manufacturing and data required for application submission (NDA, BLA)Requests information on:q

Buildings and facilitiesManufacturing operations for drug product

Filter validationValidation of hold times

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Guidance for Industry for Sterile Validation Process Validation in Applications for Human and Veterinary Drug Products

Requests information on:Sterilization and depyrogenationMedia fills and actions taken when they failMedia fills and actions taken when they failMicrobiological monitoring of the environment

Airborne microorganisms, personnel, surfaces, water system, product component bioburden

Yeasts, molds, anaerobesExceeded EM limits

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Viable and Nonviable Contaminant Limits

Nonviable (>0.5) Viable (CFU) Classifi-cation ft3 m3 ft3 m3

Class 100

100 3,530 0.1 3.5

Class 10,000 353,000 0.5 18

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10,000 , ,

Class 100,000

100,000 3,530,000 2.5 88

Controlled Area

Preparation or manufacturing area where nonsterile product, in-process materials and product-contact

i t f t i d lequipment surfaces, containers and closures are exposed to the environmentControl nonviable and viable contaminants to reduce product /process bioburdenClass 100,000 or Class 10,000

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Controlled Area

Capping areas are now considered controlled manufacturing areas

Sh ld b li d i h HEPA fil d iShould be supplied with HEPA filtered airShould meet class 100,000 conditions during static conditions

19

Critical Area

Aseptic processing area where sterile products, components or in-process products are exposed to the

i t d f th i illenvironment and no further processing will occur.Air quality must be Class 100 during processingLocal Class 100 areas are often utilized during open processing steps during drug substance manufacture.

20

11

Critical Area

The area just preceding the sterile core should be one classification higher than the core.

21

Nonviable Particulate Monitoring

Airborne cleanliness classifications should be met during operationsN i bl it i h ld ti l d iNonviable monitoring should occur routinely during operationsMonitoring during static conditions is done as part of HVAC qualification and may be done periodically after that to insure area meets acceptable conditions before use or following cleaning

22

12


Locations for monitoring should be established during performance qualification; probes placed close to work

fsurfaceMonitoring frequencies vary:

For aseptic processing areas, during each useFor other, controlled areas, varies from each use to weekly or less depending on use of area

23


HVAC Validation and Maintenance Considerations:Air velocity, airflow patterns and turbulence should be validated; smoke studies to determine flow patterns duringvalidated; smoke studies to determine flow patterns during static and dynamic conditionsHEPA filter integrity testing HEPA filter efficiency testingAir pressure differentials

24

13

Microbial Monitoring

Airborne viable contaminantsSurface contaminants

llwallsequipment surfacescountertopsfloors

Personnel contaminants

25


Monitoring methods should be capable of detecting molds and yeastsSh ld l b bl t d t t bShould also be able to detect anaerobes

Most often, this is an issue associated with products filled anaerobically (with nitrogen overlay)

All lots of media for EM sampling should be growth promotion tested

26

14


Routine microbial monitoring should take place during operations (for airborne contaminants) and i di t l f ll i ti (f f dimmediately following operations (for surfaces and personnel).Airborne monitoring frequencies:

Each use for aseptic processing areasVaries from daily to weekly to less frequently for controlled areas depending on use

27


Personnel and surface monitoring frequencies vary:Aseptic processing - after every fillOth t ll d i f d il t kl lOther controlled areas - varies from daily to weekly or less for surfaces Personnel monitoring often restricted to aseptic area personnel and personnel working in Class 100 hoods performing tasks such as inoculation

28

15


Monitoring of surfaces and airborne contaminants during rest periods (following cleaning)

I f fi i d f l i dImportant for confirming adequacy of cleaning proceduresIndicates whether HVAC system is operating properlyNOTE: Disinfectant effectiveness studies also required for cleaning agents used in the facility

29


Monitoring frequencies and procedures are influenced by a number of factors:

S f f iStage of manufacturing Open or closed manufacturing stepSingle or multiple product manufacturing

30

16


Establishment of monitoring locations should be based on performance qualification studies during dynamic

diticonditionsgridding study to determine worst case locations/most meaningful locations

Should also establish common flora - will aid in investigations

31

Setting Alert and Action Limits

Action limits (for the most part) have been established in a variety of guidance documentsAl t li itAlert limits

Lower than action limits Reflect actual historical results under normal processing conditions

32

17

33

34

18

Exceeding Limits

Alert limits are designed to provide some warning that environmental quality is approaching action limit and ll ti t tallow you time to correct.

Exceeding alert limit triggers a warning response - i.e., alert affected area personnelExceeding multiple alerts - triggers action level response

35

Investigations

In response to excursions outside the action limits and out-of-trend results the following will be reviewed: identification of the isolates & a determination of their possible originan investigation of the status of the

36 Wyeth Pharmaceuticals

environmental control systems the occurrence of atypical activity in the processing area

19

Investigations

review of product & component sterilization & aseptic filling processmicrobial monitoring historymedia fill recordequipment & facilities maintenance documentation


sanitization recordtraining status of the personnellevel of supervision

Exceeding Limits

Action limit excursions require investigationsSpeciation of organism(s)R i b t h d f d t f iReview batch records from date of excursionReview other recent EM data (trends)Review cleaning recordsInterview personnelProduct impact - must quarantine until determined

38

20

Exceeding Limits

Excursions from action limits require corrective actions that may include:

M i ddi i l i iMore rigorous or additional monitoringMore rigorous cleaningRetraining of personnelProcedural changes - change to or addition of disinfection procedures, for exampleHVAC maintenance

39

Investigations and Corrective Actions

The investigation procedures to be followed should be pre-established and included in SOPsD di th t f th i ti tiDepending on the outcome of the investigation, corrective actions should be pre-established to the extent possible

40

21

Imperative that EM results be linked to product release so that affected products are not released until i ti ti l t d

Investigations and Corrective Actions

investigation completedMaterial Review Board or equivalent should be consulted prior to releasing product that was potentially affected by adverse environmental conditions

41

Corrective Actions

Additional environmental controlsmore intense sampling p grevision to aseptic practices review of cleaning & sanitization practicesdetermine sensitivity of the isolate to disinfectant


disinfectantenhanced supervisionretraining of clean room personneladditional product testing

22

Corrective Actions

f i iDevelopment of a check list is strongly recommended to document the corrective actionsLaboratory and manufacturing investigation reports needed to justify


continued production and release of product

Trending

Should trend monitoring results (environmental and water)

P i di ( l hl ) i b QA d hPeriodic (quarterly or monthly) review by QA and othersRe-evaluation of action and alert limits on an annual basisThis trending information is generally included in the Annual Product Review

44

23

Temperature and Humidity

Control of temperature and humidity required for aseptic processing areas

21 CFR 211 42( )(10)(ii)21 CFR 211.42(c)(10)(ii)Generally 65 F and 35-50% humidity are average

Too high - Increases personnel sheddingToo low - Increase static electricity

45

Temperature and Humidity

Temperature should be controlled throughout all manufacturing areasT t d h idit h ld b it d dTemperature and humidity should be monitored and controlled in warehouse areas where temperature/humidity sensitive raw materials are stored

If not able to control humidity, need procedure to follow if humidity exceeds limit

46

24

Water Requirements

Test Potable Purified WFIWater Water

TOC none 500 ppb 500 ppb

Conduc-tivity

none See USP Table

Micro 500 100 10 CFU/

47

Micro. Purity

500 CFU/ml

100 CFU/ml

10 CFU/ 100 ml

Endo- Toxin

none none 0.25 EU/ml

Water For Injection

Defined by USPWater purified by distillation or reverse osmosisP d f t l i ith th U S EPAPrepared from water complying with the U.S. EPA National Primary Drinking Water RegulationsContains no added substance

48

25

Purified Water

Defined in USPObtained by a suitable process, usually one of the f ll ifollowing:

deionizationreverse osmosiscombination

49

Potable Water

Meets National Drinking Water Regulations40 CFR Part 141P i di it i i h ll i diPeriodic monitoring in-house as well as periodic certificates from municipality (if applicable)

50

26

Water System Monitoring

WFI SystemsMicrobial quality and endotoxin

Daily system monitoringDaily system monitoringEach use point at least weekly

TOC and ConductivityWeekly system monitoringcan be taken from worst case point (end of loop, return to tank)

51

Water System Monitoring

Purified Water SystemsWeekly monitoring of system for:

i bi l litmicrobial qualityTOC conductivity

52

27

Water Use

WFI Solvent for preparation of parenteral solutionsF l ti f li ll lt diFormulation of mammalian cell culture mediaFormulation of purification buffersFinal product formulationVial and stopper washing Final rinse for product equipment

53

Water Use

Purified WaterPreparation of terminally sterilized microbiological mediaI iti l i i / l iInitial rinsing/cleaningLaboratory useFeed for WFI system

54

28

Water Use

Potable WaterNon-product contact usesF d f ifi d t tFeed for purified water system

55

Microbial Monitoring Devices

Slit-to-Agar (STA) - Powered by vacuum, air taken in through a slit below which is a slowly revolving plate.Si i t V d i i th hSieve impactor - Vacuum draws in air through perforated cover which is impacted onto petri dish containing nutrient agar

56

29


Centrifugal Sampler - consists of a propeller that pulls a known volume of air into the unit and then propels the i t d t i t t i t t iair outward to impact on a nutrient agar strip

Sterilizable Microbiological Atrium (SMA)- similar to sieve impactor; cover contains uniformly spaced orifices; vacuum draws in air which is impacted on agar plate

57


Surface Air System Sampler - An integrated unit containing an entry section with an agar contact plate; b hi d i t d t bi th t ll i i th hbehind is a motor and turbine that pulls air in through the perforated cover and exhausts it beyond the motor.Settle plates - qualitative; may be useful in worst case locations

58

30


Surface contaminant monitoring devices:Contact Plates - plates filled with nutrient agar; for regular surfacessurfacesSwabs - useful for hard to reach or irregular surfaces; swab placed in suitable diluent and inoculated onto microbiological plate

59

Monitoring Considerations

Remote sampling probes - validate use of tubing Must sample adequate quantity of air to be statistically

i f lmeaningful.80-100 ft3/min

Must validate growth promotion after exposure of settle plates (or other plates) for prolonged time periods.

60

1

Fluid flow and CleaningFluid flow and Cleaning Validation A Turbulent Relationship Jeffrey FelkerSanofi Pasteur, Inc.Sanofi Pasteur, Inc.

Dawn TavalskySanofi Pasteur, Inc.

Fluids in Motion

Fluids can move or flow in many waysFluids can move or flow in many ways.

Water may flow smoothly and slowly in a quiet stream or violently over a waterfall.

The air may form a gentle breeze or a raging tornado.

To deal with such diversity, it helps to identify some of the basic types of fluid flow

2

the basic types of fluid flow.

2

Steady or Unsteady Fluid Flow

In steady flow the velocity of the fluid particles at any point is constant as time passes

3

any point is constant as time passes.

Unsteady flow exists whenever the velocity at a point in the fluid changes as time passes.

Turbulent Flow

Turbulent flow is an extreme kind of funsteady flow and occurs when there are sharp obstacles or bends in the path of a fast-moving fluid.

In turbulent flow, the velocity at a point changes erratically from moment to moment both in magnitude and

4

moment, both in magnitude and direction.

3

Compressible or Incompressible Fluid Flow

Most liquids are nearly incompressible; that is, the density of a liquid remains almost constant as the pressure changes.

To a good approximation, then, liquids flow in an incompressible manner.

In contrast, gases are highly compressible. However, there are situations in which the density of a flowing gas remains

t t h th t th fl b id d

5

constant enough that the flow can be considered incompressible.

Viscous or Nonviscous Fluid Flow

A viscous fluid, such as honey, does not flow readily and is said to have a large viscosity. g y

In contrast, water is less viscous and flows more readily; water has a smaller viscosity than honey.

The flow of a viscous fluid is an energy-dissipating process.

A fluid with zero viscosity flows in an unhindered manner with no dissipation of energy

6

with no dissipation of energy.

Although no real fluid has zero viscosity at normal temperatures, some fluids have negligibly small viscosities.

An incompressible, nonviscous fluid is called an ideal fluid.

4

Streamline Flow

When the flow is steady, streamlines are often used to represent the trajectories of the fluid particles.

7

A streamline is a line drawn in the fluid such that a tangent to the streamline at any point is parallel to the fluid velocity at that point.

Steady flow is often called streamline flow.

(a) In the steady flow of a liquid, a colored dye reveals the streamlines (b) A smoke streamer reveals a streamline

8

streamlines. (b) A smoke streamer reveals a streamline pattern for the air flowing around this pursuit cyclist, as he tests his bike for wind resistance in a wind tunnel.

5

The Equation of Continuity

Q: Have you ever used your thumb to control the water flowing f th d f h ?

9

from the end of a hose?

The Equation of Continuity

Q: Have you ever used your thumb to control the water flowing f th d f h ?

10

from the end of a hose?

A: When the end of a hose is partially closed off, thus reducing its cross-sectional area, the fluid velocity increases.

This kind of fluid behavior is described by the equation of continuity.

6

Equation of Continuity

11

Bernoulli's Equation

12

7

Bernoullis Equation

For steady flow, the speed, pressure, and elevation of an incompressible and nonviscous fluid are related by an equation discovered by Daniel Bernoulli (17001782).

13

Bernoullis Equation

In the steady flow of a nonviscous, incompressible fluid of

14

y , pdensity , the pressure P, the fluid speed v, and the elevation y at any two points (1 and 2) are related by

8

Applications of Bernoulli's Equation

15

The tarpaulin that covers the cargo is flat when the truck is stationary but bulges outward when the truck is moving.

Household Plumbing

16

In a household plumbing system, a vent is necessary to equalize the pressures at points A and B, thus preventing the trap from being emptied. An empty trap allows sewer gas to enter the house.

9

Curveball Pitch

17

Airplane

18

10

Images - Laminar/Turbulent Flows

Laser - induced florescence image of an incompressible turbulent boundary layer

Laminar flow (Blood Flow)

19

Simulation of turbulent flow coming out of a tailpipe

Laminar flowTurbulent flow

http://www.engineering.uiowa.edu/~cfd/gallery/lim-turb.html

Lets Discuss Turbulent Flow

20

11

21

22

12

23

Criterion for Turbulent vs. Laminar Flow in a Pipe

The behavior of flow in pipes is determined by the Reynolds number Re.

Flow tends to become turbulent when Re > 3000.Flow is always laminar when Re < 2000.

For 2000 < Re < 3000, the behavior is unpredictable and often switches back and forth between laminar and t b l t

24

turbulent.

When conditions are carefully controlled so that the flow is perfectly motionless at the inlet of the pipe and the pipe is free of vibrations, then it is possible to maintain laminar flow even at Re > 3000.

13

Shear stress distribution across a pipe section

25

For steady, uniform flow, the momentum balance in s for the fluid cylinder yields

Turbulent flow is less efficient than laminar flow:

Velocity profilefor turbulent flow

Velocity profileif flow were laminareverywhere

Thin, laminar boundary layer

If fl ld i l i th i ld t t

26

If flow could remain laminar, the pipe could transport more fluid for a given pressure gradient.

The swirls and eddies associated with turbulence make the fluid appear as though it had a much higher viscosity where flow is turbulent.

14

Energy Loss in Valves

Function of valve type and valve positionThe complex flow path through valves can result in high head loss (of course, one of the

E v = KU 2

2

esu t g ead oss (o cou se, o e o t epurposes of a valve is to create head loss when it is not fully open)Ev are the loss in terms of velocity heads

27

2

h v = p

= K vU 2

2 g= 2 f

L eqD

U 2

g

Flow at pipe inlets and losses from fittings

Rounded inlet Sharp-edged inlet

Head loss for inlets, outlets, and fittings:

28

where K is a parameter that depends on the geometry.For a well-rounded inlet, K = 0.1, for abrupt inlet K = 0.5(much less resistance for rounded inlet).

15

Bends in pipes:

Sharp bends result inSharp bends result in separation downstream of the bend.

The turbulence in the separation zone causes flow resistance.

29

Greater radius of bend reduces flow resistance.

30

16

31

Energy Loss due to Gradual Expansion

E E = K EU 1 U 2( )

2

2 0.10.20.30.40.50.60.70.8

KE

A2

A1

32

2

E E = K EU 2

2

2 1( ) 2

= A 2A1

angle ()

00 20 40 60 80

17

Sudden Contraction (Orifice Flowmeter)

Orifice flowmeters are used to determine a liquid or gas flowrate by measuring the differential pressure P1-P2 across the orifice P1 P2differential pressure P1 P2 across the orifice plate

Q = C d A 22 ( p1 p 2 ) (1 2 )

1 / 2

0 850.9

0.951

dD

Flow

33

0.60.650.7

0.750.8

0.85

102 105 106 107

Re

CdReynolds number based on orifice diameter Red

103 104

Boundary layer buildup in a pipe

Because of the shear force near the pipe wall, a boundary layer forms on the inside surface and occupies a large portion of the flow area as the distance downstream from the pipe entrance i A l f hi di h b d l fill h

Pipe

increase. At some value of this distance the boundary layer fills the flow area. The velocity profile becomes independent of the axis in the direction of flow, and the flow is said to be fully developed.

34

Pipe Entrance

v vv

18

Pipe Flow Head Loss(constant density fluid flows)

Pipe flow head loss is proportional to the length of the pipeproportional to the square of the velocity

Pipe flow head loss is proportional to the length of the pipeproportional to the square of the velocityproportional to the square of the velocity (high Reynolds number)Proportional inversely with the diameter of the pipeincreasing with surface roughnessindependent of pressureTotal losses in the pipe system is obtained by summing individual head losses of

f

proportional to the square of the velocity (high Reynolds number)Proportional inversely with the diameter of the pipeincreasing with surface roughnessindependent of pressureTotal losses in the pipe system is obtained by summing individual head losses of

f

35

roughness, fittings, valves ..itcroughness, fittings, valves ..itc

36

19

37

38

20

39

40

21

41

42

22

43

44

23

45

46

24

47

48

25

49

50

26

51

52

27

53

54

28

55

56

29

57

58

30

59

60

31

61

62

32

63

64

33

65

66

34

Reynolds Number Calculation

Diameter DViscosity D it Density Velocity V

67

Circuit Size Length (ft)/# Volumein out L

311 2.5" 5.583 Line-2.5" 2.37 5.583 10.0 37.9 0.7 13,291 0.0287 0.8 0.01 4.84311 2" 23.667 Line-2" 1.87 23.667 10.0 37.9 1.2 16,844 0.0270 4.1 0.09 12.78311 1" 27.667 Line-1" 0.87 27.667 10.0 37.9 5.4 36,206 0.0225 8.6 3.88 3.23311 75" 0 833 Li 3/4" 0 62 0 833 10 0 37 9 10 6 50 805 0 0209 0 3 0 59 0 05

Vmax, ft/s Nre f ,Cv,or bD, Inch

# or L, ft Q, GPM Q, LPMCommon Supply to 311 K DP, ft

311 .75" 0.833 Line-3/4" 0.62 0.833 10.0 37.9 10.6 50,805 0.0209 0.3 0.59 0.05311 2.5" valve 2 ITT DiaV-2.5"/DN50 2.50 2 10.0 37.9 0.7 12,600 95 3.9 0.05311 2" valve 1 ITT DiaV-2.00"/DN50 2.00 1 10.0 37.9 1.0 15,750 70 2.9 0.05311 1" valve 2 ITT DiaV-1.00"/DN25 1.00 2 10.0 37.9 4.1 31,499 18.6 2.6 1.33311 2" x 1.5" 1 Red-contract (2 x 1.5) 1.87 1.37 0.245 10.0 37.9 2.2 0.73 0.2 0.01311 1" x 0.75" 1 Red-contract (1 x 3/4) 0.87 0.62 0.245 10.0 37.9 10.6 0.71 0.2 0.33311 2.5" elbow 1 Elbow-2.5" 2.37 1 10.0 37.9 0.7 13,291 0.0287 0.4 0.00311 2" elbow 3 Elbow-2" 1.87 3 10.0 37.9 1.2 16,844 0.0270 0.4 0.02311 1" elbow 18 Elbow-1" 0.87 18 10.0 37.9 5.4 36,206 0.0225 0.3 2.56311 2.5" T 2 2.5" T-Branch (Equal) 2.37 2 10.0 37.9 0.7 13,291 0.0287 1.7 0.03311 2" T 2 2" T-Branch (Equal) 1.87 2 10.0 37.9 1.2 16,844 0.0270 1.6 0.07311 1" T 4 1" T-Branch (Equal) 0.87 4 10.0 37.9 5.4 36,206 0.0225 1.3 2.44

11.46 feetSUBTOTAL

68

35

Vessel 311 Length (ft) Flow Rate (LPM) Reynolds Number Velocity (ft/s) Pressure Drop (ft) Circuit Volume (L)

Line-2.5" 5.6 13,291 0.7Line-2" 23.7 16,844 1.2Line-1" 27.7 36,206 5.4

Line-3/4" 0.8 50,805 10.6

Supply Header

Path 1

37.9 11.46

Line-1" 2.7 36,206 5.4Line-1/2" 8.8 85,133 29.8

Line-1.5" 0.3 22,992 2.2Line-1" 2.7 36,206 5.4

Line-3/4" 1.1 50,805 10.6Line-1/2" 8.8 85,133 29.8

Line-1" 1.9 36,206 5.4Line-1/2" 6.7 85,133 29.8

Line-1" 2.7 36,206 5.4Line-1/2" 5.9 85,133 29.8

Line-1" 2.7 36,206 5.4Line-1/2" 5.4 85,133 29.8

37.9 757.30

Path 2

37.9 248.29

Path 3

37.9 215.88

Path 4

182.11

Path 5

37.9 162.24

62.64

37.9

69

Line-1" 2.7 36,206 5.4Line-1/2" 4.9 85,133 29.8

Line-1" 1.9 36,206 5.4Line-1/2" 8.0 85,133 29.8

Line-2.5" 40.0 13,291 0.7Line-1.5" 12.6 22,992 2.2

Path 6

Return Header

37.9 0.80

158.0137.9

Path 7

234.4537.9

Rule of Thumb

Instrument Tee for CIP: L/D

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Writing SOPs and Batch RecordsWritingSOPsandBatchRecords

Writing SOPs and Batch Records--Robert Pallo

WritingSOPsandBatchRecords

Robert PalloManager Fill and Finish Operationsg p36 years at Allergan

[email protected]

Opinions expressed in the presentation are those of the author and in no way represent those of Allergan


10/5/2011

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WritingSOPsandBatchRecordsDoitDoit


WritingSOPsandBatchRecordsDoitDoitWriteit


10/5/2011

3

WritingSOPsandBatchRecordsDoitDoitWriteitTestit


WritingSOPsandBatchRecordsSOPWritingEssentialsSOPWritingEssentials


10/5/2011

4


Be BriefBe Brief



AskemployeesusingtheSOPfortheirinput


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SOPWritingEssentials

WritingSOPsandBatchRecordsSOPWritingEssentials

AskemployeesusingtheSOPfortheirinputPrepareafirstdraft




AskemployeesusingtheSOPfortheirinputPrepareafirstdraftRunawalkthrough


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6



AskemployeesusingtheSOPfortheirinputPrepareafirstdraftRunawalkthroughSolicitfeedbackandmakecorrections




AskemployeesusingtheSOPfortheirinputPrepareafirstdraftRunawalkthroughSolicitfeedbackandmakecorrectionsMakeitofficial!


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BenefitsofsolidSOPs

WritingSOPsandBatchRecordsBenefitsofsolidSOPs


BenefitsofsolidSOPs


Decreasetrainingtime


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BenefitsofsolidSOPs


DecreasetrainingtimeIncreaseconsistency


BenefitsofsolidSOPs


DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirements


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BenefitsofsolidSOPs


DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasures


BenefitsofsolidSOPs


DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasuresRetainandtransferknowledge


10/5/2011

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BenefitsofsolidSOPs


DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasuresRetainandtransferknowledgeDocumentimprovementandchange


BenefitsofsolidSOPs


DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasuresRetainandtransferknowledgeDocumentimprovementandchangeDecreaseerrorrate


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UnderstandingtheProcess

WritingSOPsandBatchRecordsUnderstandingtheProcess

BallisticProcessCharacteristicofthemotionofobjectsmovingundertheirownmomentumIfthereisnowaytoprovidefeedbacktochangeoradjustaprocess,thisisaballisticprocessTheBallisticProcessismostcommonE.g.Anautoclavecycle;amanufacturingprocedure




BallisticProcessControlledprocess

MonitortheinputsandoutputsandmakecorrectivechangestotheprocessinordertoachievethedesiredoutputE.g.afillingmachinewherethefillweightisconstantlyadjusted.adjusted.


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BallisticProcessControlledprocessAdaptiveProcess

AprocessthatlearnsCanchangeovertimetoimproveeffectivenessE.g.allowsausertoidentifyiftheprocessneedsmodificationandtheycanhavetheoptiontoupdatetheprocedureNotagoodGMPidea


WritingaProcedure

WritingSOPsandBatchRecordsWritingaProcedure

DiscoveryDesignDevelopmentDeployment


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WritingaProcedureDiscovery

WritingSOPsandBatchRecords

DiscoveryUnderstandtheproblemorprocessAprocedureisneededtodescribethestepsofabusinessprocess.Sobeforewecanwritethat,weneedtodiscoverwhatisexpected.Needtounderstand

Whoarethesources/resourcesWhoarethesources/resourcesWhataretheinputsandoutputsWhoarethecustomersWhataretheeffectivenesscriteriaWhatisthecorrectiveactioniftheprocessdoesntwork


WritingaProcedure


DiscoveryDesign

ThisiswhereyouspendyourtimeAprocessmapwillhelpcommunicatetheproceduraldesignandcollectfeedbackbeforewewriteoutthewrittenstepsPerformawalkthroughwiththedesignPerformawalkthroughwiththedesignRememberPDCA(PLAN DO CHECK ACT)


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WritingaProcedure


DiscoveryDesignDevelopment

Importantquestion:Whoistheaudience?Novices,occasionalusersorfrequentusers?


WritingaProcedureforfrequentusers

WritingSOPsandBatchRecordsWritingaProcedureforfrequentusers

DonotrequirealotofexplanationMightonlyneedachecklistPriorityisnavigationratherthanexplanation


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WritingaProcedureforoccasionalusers

WritingSOPsandBatchRecordsWritingaProcedureforoccasionalusers

MaynotnecessarilybeexperiencedMayfillinforsomeonefromtimetotimeMayrequiremoreexplanationorsomehowandwhyPriorityisexplanation,notnavigation


WritingaProcedureforthenovice

WritingSOPsandBatchRecordsWritingaProcedureforthenovice

LeaveoutthedetailMakeitastepbystepprocedureProvidethedetailsinanaccompanyingtrainingdocumentand


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WritingaProcedureforthenovice

WritingSOPsandBatchRecordsWritingaProcedureforthenovice

LeaveoutthedetailMakeitastepbystepprocedureProvidethedetailsinanaccompanyingtrainingdocumentand

NoticethattheBESTSOPsarewritteninthisstyle!


Reviewofthewrittenprocedure

WritingSOPsandBatchRecordsReviewofthewrittenprocedure

ThesevenCsContextConsistencyCompletenessControlComplianceComplianceCorrectnessClarity


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WritingaProcedure


DiscoveryDesignDevelopmentDeployment


Deployment

WritingSOPsandBatchRecordsp yTrainingAuditingContinuousimprovement


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Writing SOPs and Batch RecordsWriting SOPs and Batch Records

SOP Writing EssentialsSOP Writing EssentialsggBe BriefBe BriefBe Clear and ConciseBe Clear and Concise



SOP Writing EssentialsSOP Writing EssentialsBe BriefBe BriefClear and ConciseClear and ConciseThe shorter, the betterThe shorter, the better


10/5/2011

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SOP Writing EssentialsSOP Writing EssentialsBe BriefBe BriefClear and ConciseClear and ConciseThe shorter, the betterThe shorter, the betterSOPs should say what to do, not how to SOPs should say what to do, not how to

do itdo it



SOP Writing EssentialsSOP Writing EssentialsBe BriefBe BriefClear and ConciseClear and ConciseThe shorter, the betterThe shorter, the betterSOPs should say what to do, not how to SOPs should say what to do, not how to

do itdo it


Pictures are worth a thousand wordsPictures are worth a thousand words

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Why Do I Need SOPs?Why Do I Need SOPs?ConsistencyConsistencySOPs Reduce VariationSOPs Reduce VariationSOPs facilitate trainingSOPs facilitate trainingPeople can support SOPs (particularly if People can support SOPs (particularly if

they help write them)they help write them)


y p )y p )


Types of SOPs?Types of SOPs?

Simple Steps or checklistSimple Steps or checklist

Easy to write and easy to follow.Easy to write and easy to follow.Works well for well understood tasksWorks well for well understood tasks


Works well for well understood tasksWorks well for well understood tasks

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Writing SOPs and Batch RecordsWriting SOPs and Batch RecordsTypes of SOPs?Types of SOPs?Hierarchical stepsHierarchical stepspp

This is an extension of Simple Steps.This is an extension of Simple Steps.Works well for more complex stepsWorks well for more complex steps1.1. Start the MixerStart the Mixer

1 1 Ch k S f i1 1 Ch k S f i


1.1 Check Safeties1.1 Check Safeties1.2 Zero the propeller speed1.2 Zero the propeller speed1.3 Press the start button1.3 Press the start button

Writing SOPs and Batch RecordsWriting SOPs and Batch RecordsTypes of SOPs?Types of SOPs?Annotated Pictures.Annotated Pictures.

Works well when there are language Works well when there are language barriers.barriers.

Shortens complex and detailed SOPsShortens complex and detailed SOPs


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Writing SOPs and Batch RecordsWriting SOPs and Batch RecordsTypes of SOPs?Types of SOPs?Annotated Pictures.Annotated Pictures.


Writing SOPs and Batch RecordsWriting SOPs and Batch RecordsWhen to Write an SOPWhen to Write an SOP

If there are key areas of concernIf there are key areas of concern

Identify one or two top priority areas Identify one or two top priority areas for attention. for attention.


Apply the Apply the ParetoPareto Rule Rule

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PARETOS LAWVilfredo Pareto (1848-1923)

Writing SOPs and Batch RecordsWriting SOPs and Batch RecordsLANGIAPPE (a little something extra!)LANGIAPPE (a little something extra!)

( )

(a) 80 percent of the results are achieved by 20 percent of the group.

(b) 20 percent of your effort will generate 80 percent of your results.

(c) In any process, few elements (20 percent) are vital and l (80 ) i i l


many elements (80 percent) are trivial.

(d) If you have to do ten things, two of those are usually worth as much as the other eight put together.

(e) 20 percent of the tasks account for 80 percent of the value.

PARETOCHART(EXCEL)

40

Count

10

15

20

25

30

35

Count


0

5

MachineSetup

Highplatecounts

Highparticlecounts

PoorAirFlow Gowning Technique Supplies FacilityDisinfection

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SOP FormatSOP FormatPurpose and ScopePurpose and ScopeDefinitionsDefinitionsMaterials and equipment neededMaterials and equipment neededAssignment of responsibilityAssignment of responsibility

St b t dSt b t d


Step by step procedureStep by step procedureReferencesReferencesApproval signaturesApproval signatures


The Standard Operating The Standard Operating FormFormggGatewayGateway to Excellent SOP Complianceto Excellent SOP Compliance


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The Standard Operating FormThe Standard Operating FormggGateway to Excellent SOP Gateway to Excellent SOP ComplianceCompliance Includes the critical parts of a procedure Includes the critical parts of a procedure

in a batch record formatin a batch record format



The Standard Operating FormThe Standard Operating FormggGateway to Excellent SOP Gateway to Excellent SOP ComplianceCompliance Includes the critical parts of a procedure Includes the critical parts of a procedure

in a batch record formatin a batch record formatOperator signs off each critical step Operator signs off each critical step


Operator signs off each critical step, Operator signs off each critical step, assuring compliance with the SOP.assuring compliance with the SOP.

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SOF FormatSOF FormatSOF FormatSOF FormatStep by step procedureStep by step procedure Indication of target parametersIndication of target parametersPlace to indicate actual dataPlace to indicate actual dataPlace to sign and datePlace to sign and date


Master Record approval signaturesMaster Record approval signaturesFinal Batch approval signaturesFinal Batch approval signatures


SOF TipsSOF TipsSOF TipsSOF TipsDo not make the form too busyDo not make the form too busy


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SOF TipsSOF TipsSOF TipsSOF TipsDo not make the form too busyDo not make the form too busyProvide plenty of room to record dataProvide plenty of room to record data



SOF TipsSOF TipsSOF TipsSOF TipsDo not make the form too busyDo not make the form too busyProvide plenty of room to record dataProvide plenty of room to record dataTry to reduce the requirement for Try to reduce the requirement for

signatures to an acceptable minimumsignatures to an acceptable minimum


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WritingSOPsandBatchRecordsSTEP OPERATION DATA/RESULTS P/B C/B DATE

1 Check cleaning log.

2 Perform a pre-production line clearance per SOP 07007.

Room No.: _____________

3 Sanitize stationary equipment as per SOP 07712 prior to set up.

4 All Operators / Personnel sign in / out sheet.Note: Only the validated number of personnel (SEVEN) are allowed inside the fill room at one time. Additional signatures may be placed on the back of this page.

Total number of technicians present at one time:

_________________

NAME TIME IN CHECK OPERATIONS TIME


NAME TIME IN CHECK OPERATIONS TIME OUT

MS CT CL

AC MO EM OTHER

WritingSOPsandBatchRecordsExampleSOF

FLEXICON PF6

P/B C/B DATE

Description Volume Tube DiameterSetting

Pump RPM Reverse Actual Tube Diameter

Specification Per BPO 6 mm As needed As needed 6 mm

Actual


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WritingSOPsandBatchRecordsExampleSOFExampleSOF

MANUFACTURING REVIEWED BY/DATE QUALITY ASSURANCE REVIEWED BY/DATE


WritingSOPsandBatchRecordsFinalCommentsFinalComments

1.1. Educate employees about the new SOP.Educate employees about the new SOP.

2.2. Control procedural drift by ensuring that Control procedural drift by ensuring that the SOP is followed consistently overtime.the SOP is followed consistently overtime.

33 E t bli h l ti d i t tE t bli h l ti d i t t


3.3. Establish an evaluation and review system to Establish an evaluation and review system to be certain that over time all the steps of an be certain that over time all the steps of an SOP are still correct and appropriate for the SOP are still correct and appropriate for the production system.production system.

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WritingSOPsandBatchRecordsFINALCOMMENTSFINALCOMMENTS

Phone: 714-246-4413

Email: [email protected]


_ g

1

Cleaning Validation Cleaning Validation Coverage StudiesJeff FelkerSanofi Pasteur, Inc.

D T l kDawn TavalskySanofi Pasteur, Inc.

Background Information

2

2


3


4

3

Cleaning Methods

5

Cleaning Parameters

6

4

TACT Cleaning Parameters

7

TACT Cleaning Parameters

8

5

Cleaning Equipment

9

Required Flow Rate for Static Spray Ball

10

6

Required Flow Rate Compared to Static

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Required Flow Rate Compared to Static

12

7

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14

8

15

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Cleaning Technology

17

What is a Riboflavin Coverage Test?

Riboflavin

18

10

Riboflavin

Riboflavin, also known as vitamin B2

Rib fl i i b t k i ll th it i hi hRiboflavin is best known visually as the vitamin which imparts the orange color to solid B-vitamin preparations, the yellow color to vitamin supplement solutions, and the unusual fluorescent-yellow color to the urine of persons who supplement with high-dose B-complex preparations (no other vitamin imparts any

19

color to urine).

Riboflavin

20

1

Riboflavin under UV Light

1

Other Components Used for Coverage Studies or Added to Riboflavin

Vitamin KHydroxyethyl cellulose (HEC)C St hCorn StarchSucroseNaClDried Detergent

2

2

Vitamin K Fluorescence

3

Detecting Riboflavin

4

3

Uses for The Riboflavin Test

5

* A coverage test also qualifies that a final rinse sample taken during cleaning validation or cleaning monitoring, is a composite sample from all surfaces

6

4

Objective of the Coverage Test

Objective:The objective of this test is to verify that the

b ll / d /b i t d ith th tsprayballs/wands/bars associated with the system are capable of delivering cleaning solutions to all exposed product contact surface areas. Often spray ball coverage testing is performed as part of the final vessel factory acceptance test. Coverage testing may be performed on-site using the actual equipment that

7

will be used to clean the vessel.

Procedure:Note: Care must be taken when working around cleaning systems. Solutions containing chemicals at high concentrations and temperatures are used in the normal operation of the system. Good practice is to have the system operator available at all times while this testing is being performed.g p

1. For vessels with sprayballs/wands/bars that have already been tested (for example as part of FAT), audit the test documentation and verify that the following information is available and has been recorded for each sprayball/wand/bar:1.1 Vessel Identification

1.2 Sprayball/Wand/Bar Identification

1.3 Date of Test

1.4 Test Method (Riboflavin, Salt, Other)

1.5 Feed Solution Pressure or Flow Rate

8

1.5 Feed Solution Pressure or Flow Rate

1.6 Results

1.7 Conclusion (Pass/Fail)

5

Flowrate and Pressure

More Pressure and More Flow are Good Right??

9

Wrong

1010

6

Too Little OR Too Much Pressure is Bad!

11

2. For vessels with sprayballs/wands/bars that have not had coverage testing performed, perform the following tests for each spray ball/wand/bar:

2.1 Prepare the vessel/equipment item to be tested per normal operational cleaning dprocedures.

2.2 Prepare a solution of dilute riboflavin in a spray bottle per approved procedures (0.2 gm/L).

2.3 Spray the product contact surfaces of the vessel/equipment item with the riboflavin solution being sure to coat all exposed areas - especially those that may be masked by vessel appurtenances.2.4 Initiate a cleaning cycle using (if possible) the minimum pressures/flow rates to simulate worst case conditions.

2.5 At the completion of the cleaning cycle, inspect the vessel product contact

12

2.5 At the completion of the cleaning cycle, inspect the vessel product contact surfaces using an ultraviolet light. Look for traces of fluorescence - indications that the spray ball coverage failed to contact the surface in that location.

2.6 Document the locations of any fluorescence observed.

7

Use an Atomizing Sprayer to Apply Riboflavin

13

Acceptance Criteria:1. For vessels with sprayballs/wands/bars that have l d b t t d th t t t i di talready been tested, the test reports indicate

successful sprayball coverage and contain the following information:Vessel Identification Sprayball/Wand/Bar Identification Date of Test, Test Method (Riboflavin, Salt, Other)

14

Feed solution pressure or flow rate Results Conclusion (Pass/Fail)

8

2. For vessels with sprayballs/wands/bars that are tested directly as part of this test, there will be 100% coverage as indicated by the observance of no fluorescence.Note: If fluorescence is observed and can not be corrected byNote: If fluorescence is observed and can not be corrected by modification of the spray ball or cleaning cycle, the system will most likely have to have a manual cleaning step performed in order to effectively clean the area that is not covered by the sprayball/wand/bar.

Acceptance Criteria Met?

Yes No Initials/Date: /

15

Yes ____ No ____ Initials/Date:____ /____

If No, explain in comments:

Reviewed By:_______________________ Date: __________

Talking Specifics

Riboflavin wet or dry?What do you do with small spots left?F ll l i l j t i l ?Full cleaning cycle or just rinse cycle?Bursts or Flow?

16

9

Impact of Coverage

17

Rotary Spray Head in Action

18

10

Rotary Jet Head In Action

19

Stationary Spray Ball Technology

20

1

1

2

2

3

4

3

Installation in Process Tanks

5

6

4

7

8

5

Rotary Jet Head Technology

9

10

1

Cleaning Case

1

Rotary Jet Head

2

2

Cleaning Behind the Agitator Shaft

3

Cleaning of Shadow Areas

4

3

5

6

4

7

8

5

9

10

Effective Strategies to Design a Aseptic Facility

1

Effective Strategies Effective Strategies ggto Design a to Design a

Aseptic FacilityAseptic Facility

AmjadAmjad

MoreMore QualityQuality isis betterbetter qualityquality oror MoreMore moneymoney spentspent toto designdesigninin qualityquality thethe betterbetter cancan causecause asas manymany asas problemsproblems asas thethelacklack ofof qualityquality inin aa facilityfacility designdesign..

1. Architectural Design and Construction1. Architectural Design and Construction

AsepticAseptic DesignDesign CriteriaCriteria AsepticAseptic facilityfacility layoutlayout mustmust bebe anan integratedintegrated designdesign thatthat satisfiessatisfiespp yy yy gg gg

processprocess andand equipmentequipment layoutlayout requirementsrequirements whilewhile cateringcatering forforgoodgood levelslevels ofof accessaccess forfor operability,operability, maintenance,maintenance, personnel,personnel,product,product, componentcomponent andand rawraw materialmaterial movementsmovements..

ArchitecturalArchitectural designdesign shouldshould provideprovide aa containedcontained environment,environment,withwith selectedselected roomroom finishesfinishes toto enhanceenhance hygiene,hygiene, environmentenvironmentandand safetysafety levellevel andand thethe designdesign mustmust complycomply withwith relevantrelevant firefirecodescodes andand buildingbuilding regulationsregulations..

StructuralStructural frameworkframework andand buildingbuilding fabricfabric mustmust alsoalso bebe

AmjadAmjad

StructuralStructural frameworkframework andand buildingbuilding fabricfabric mustmust alsoalso bebeconsideredconsidered forfor anyany impactimpact onon thethe finishedfinished roomroom environmentenvironment..

FundamentalFundamental aspectsaspects ofof buildingbuilding locationlocation andand blockblock layoutlayoutshouldshould bebe consideredconsidered.. CarefulCareful attentionattention shouldshould bebe givengiven toto thethelocationlocation ofof airair intakesintakes andand exhaustsexhausts inin relationrelation toto thethe prevailingprevailingwindwind direction,direction, neighboringneighboring facilitiesfacilities exhaust