2nd annual ace_0.pdf
TRANSCRIPT
-
1
Preparing for and Handling anPreparing for and Handling an FDA Inspection at Your Facility Dawn TavalskySanofi Pasteur, Inc.
2
-
2
Objectives
3
FDAs Authority to Inspect
4
-
3
FDAs Authority to Inspect
5
Inspection Process
6
-
4
7
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
8
Office of Regulatory Affairs Organization.
-
5
Office of Regulatory Affairs (ORA)http://www.fda.gov/ora/
Headquarters:
Rockville, MD
Regional Office: Philadelphia, PA
District Office:
D i MI
9
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.
10
-
6
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
11
7. Present Findings
8. Depart (483)9. Write Report (EIR)
10. Classify Inspection
Overview of FDA Enforcement Actions
12
-
7
FDA Forms
13
14
-
8
15
16
-
9
Selection Criteria
17
Preparing for the Audit
18
-
10
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
19
We will now discuss preparing for a PAI inspection however many of the points apply to any type of FDA audit.
20
-
11
21
22
-
12
23
24
-
13
25
26
-
14
27
28
-
15
29
30
-
16
31
32
-
17
33
34
-
18
35
36
-
19
37
38
-
20
39
40
-
21
41
42
-
22
43
44
-
23
45
46
-
10/3/2011
1
Best Practices to Develop DeployBestPracticestoDevelop,DeployandMaintainaRiskBasedACE
ProgramPresentedbyKarenSGinsbury
For IVTs ACE ConferenceForIVT sACEConferenceAmsterdam,Netherlands
October2011
RiskManagement
Startswithphilosophy Understandingthelawsofnaturehelps: NaturehasatendencytoDISORDER Howdoyouperceivewhatisgoingtohappentomorrowmorningatyourfacility:
-
10/3/2011
2
ItwillbeOK
Whatcouldgowrongtoday
-
10/3/2011
3
Letsmakealist
Cleaning
Letsmakealist
Asepticprocessing
-
10/3/2011
4
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.
-
10/3/2011
5
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.
-
10/3/2011
6
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.
-
10/3/2011
7
MHRAFindingsApril2008 March2009
WEdwardsDeming1900 1993
Wehavelearnedtoliveinaworldofmistakesanddefectiveproductsasiftheywerenecessarytolife
IfIhadtoreducemymessageformanagementtojustafewwords,Idsayitallhadtodowithreducingvariation
-
10/3/2011
8
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
-
10/3/2011
9
Uncertainty=RiskWherethereisvariability=uncertainty=Risk
Whatcontrolsdoyouhaveinplacetostopitgoingwrong?
Riskmanagement: Riskassessment Riskmitigation thecontrolsweputinplacetostopitgoingwrongfollowedby
Riskacceptanceand Riskcommunication
-
10/3/2011
10
Cleaning whatcontrols?
AsepticProcessing whatcontrols?
-
10/3/2011
11
EnvironmentalMonitoring.
EMisNOTacontrolorariskreductionmeasure
EMisthenextstepinourprocess Riskreview
h WeuseEMtomonitortheSTATEOFCONTROLthatwehaveachievedusingourriskmitigationmeasures
EnvironmentalMonitoring.
WhatinformationwillIusetodeploymy limited EM resources?mylimitedEMresources?
Howwillmyriskassessmenttiein ReassignthemostresourcestoHighriskactivities cleaningaconvolutedpieceofmultipurposepipingp p p p g
Makinganasepticconnection Machinesetup Cleaningonthegraveyardshift
-
10/3/2011
12
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
-
10/3/2011
13
AndKeepasking:Whatcouldgowrongtoday
TheEnemiesofControl
-
10/3/2011
14
Deviations
"Everydefectisatreasure,ifthecompanyitcanuncoveritscause
andworktopreventitacrossthecorporation KilchiroToyoda,founderofToyota
.oops!p
Changes
Change management is about controllingChangemanagementisaboutcontrollingchangestoensurethatinnovationhappenswithoutunintended/unforeseenconsequences
-
10/3/2011
15
InConclusion
Riskmanagementisabout:Id tif i i k Identifyingrisks
Investingenergytocontrolandreducethoserisks Communicatingastheriskmitigationmeasurestostakeholdersatalllevelsinthecompanybroadestpossiblecommunication
Event review and monitoringEventreviewandmonitoring Updatingtheassessmentwhenthereareindicatorsthatitisfailingormovinginthewrongdirection
Thankyouforyourattention
Anyquestions?
Contactme:[email protected]
-
10/3/2011
1
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
PCI Pharmaceutical Consulting Israel Ltd2
somewhere else
-
10/3/2011
2
Objective of Seminar
ReviewReviewRefreshRenewRefine
PCI Pharmaceutical Consulting Israel Ltd3
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
PCI Pharmaceutical Consulting Israel Ltd4
versionFDA Aseptic Processing Guide (2004)
-
10/3/2011
3
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
PCI Pharmaceutical Consulting Israel Ltd5
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
PCI Pharmaceutical Consulting Israel Ltd6
CAPA and Control StrategyDeviationChange Control
-
10/3/2011
4
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
PCI Pharmaceutical Consulting Israel Ltd7
an aseptic operationKPIs and feed items
Create Your Own Map (KPIs)What items need to be controlled
PCI Pharmaceutical Consulting Israel Ltd8
-
10/3/2011
5
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
PCI Pharmaceutical Consulting Israel Ltd9
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
-
10/3/2011
6
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
PCI Pharmaceutical Consulting Israel Ltd11
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
PCI Pharmaceutical Consulting Israel Ltd12
-
10/3/2011
7
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
PCI Pharmaceutical Consulting Israel Ltd13
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
PCI Pharmaceutical Consulting Israel Ltd14
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
-
10/3/2011
8
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
PCI Pharmaceutical Consulting Israel Ltd15
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
PCI Pharmaceutical Consulting Israel Ltd16
The current regulation mentions only validation of sterilization processes, not aseptic processes
-
10/3/2011
9
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
PCI Pharmaceutical Consulting Israel Ltd17
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
PCI Pharmaceutical Consulting Israel Ltd18
-
10/3/2011
10
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
PCI Pharmaceutical Consulting Israel Ltd20
Capping of (Freeze-Dried) Vials
-
10/3/2011
11
Previous
Now
PCI Pharmaceutical Consulting Israel Ltd21
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
PCI Pharmaceutical Consulting Israel Ltd22
analysis study and the results obtained during the classification of rooms and / or clean air devices
-
10/3/2011
12
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
PCI Pharmaceutical Consulting Israel Ltd23
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
PCI Pharmaceutical Consulting Israel Ltd24
-
10/3/2011
13
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
PCI Pharmaceutical Consulting Israel Ltd25
establish alert and action limitsAny contamination should be investigated
Media Simulations: Acceptance Criteria
PCI Pharmaceutical Consulting Israel Ltd26
-
10/3/2011
14
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
PCI Pharmaceutical Consulting Israel Ltd27
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
PCI Pharmaceutical Consulting Israel Ltd28
NOTE: effective 01 March 2010
-
10/3/2011
15
FDA Aseptic Processing Guide
PCI Pharmaceutical Consulting Israel Ltd29
FDA Aseptic Processing Guide
PCI Pharmaceutical Consulting Israel Ltd30
-
10/3/2011
16
(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
FDA Aseptic Processing Guide
PCI Pharmaceutical Consulting Israel Ltd32
-
10/3/2011
17
(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
PCI Pharmaceutical Consulting Israel Ltd33
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)
PCI Pharmaceutical Consulting Israel Ltd34
-
10/3/2011
18
FDA Aseptic Processing Guide
PCI Pharmaceutical Consulting Israel Ltd35
FDA Aseptic Processing Guide
PCI Pharmaceutical Consulting Israel Ltd36
-
10/3/2011
19
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
FDA Aseptic Processing Guide
PCI Pharmaceutical Consulting Israel Ltd38
-
10/3/2011
20
(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
PCI Pharmaceutical Consulting Israel Ltd39
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
PCI Pharmaceutical Consulting Israel Ltd40
-
10/3/2011
21
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
PCI Pharmaceutical Consulting Israel Ltd41
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
42
-
10/3/2011
22
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
44
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
-
10/3/2011
23
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,
PCI Pharmaceutical Consulting Israel Ltd45
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
PCI Pharmaceutical Consulting Israel Ltd46
performance) appropriate to the drug product dosage form being developedDrug product quality criteria (e.g., sterility, purity) appropriate for the intended marketed product
-
10/3/2011
24
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
PCI Pharmaceutical Consulting Israel Ltd47
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
-
10/3/2011
25
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
PCI Pharmaceutical Consulting Israel Ltd50
-
10/3/2011
26
Lifecycle Product Management
Developmentt
Process validation
Annua
CAPA
PCI Pharmaceutical Consulting Israel Ltd51
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
-
10/3/2011
27
Control StrategyList the items that need to be
t ll d d thi k b t hcontrolled and think about how to achieve that_______________________
PCI Pharmaceutical Consulting Israel Ltd53
______________________________________________
Personnel Training - KPIsDeviation operator error: recurrenceSterile Product(Capacity data)Testing of employee trainingOn the Job evaluationCompliance to curriculumCertification
PCI Pharmaceutical Consulting Israel Ltd54
Gowning results / EM dataMedia fill participationHealth Reporting
-
10/3/2011
28
Validation - KPIs
PCI Pharmaceutical Consulting Israel Ltd55
EM - KPIs
PCI Pharmaceutical Consulting Israel Ltd56
-
10/3/2011
29
Deviations, Complaints, Rejected Batches -KPIs
PCI Pharmaceutical Consulting Israel Ltd57
-
1
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
2
-
2
Environmental Monitoring Components
Water monitoring:Total organic carbonC d ti itConductivityMicrobial ContaminantsEndotoxin
3
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
4
-
3
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
5
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)
6
-
4
Regulatory Basis for Environmental Monitoring Program
CFR GMP regulationsFDA Guidance DocumentsUSP I f ti l Ch tUSP Informational Chapter
7
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
8
-
5
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.
9
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
10
-
6
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
11
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
12
-
7
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
13
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)
14
-
8
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
15
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
16
-
9
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
17
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
18
-
10
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
Nonviable Particulate Monitoring
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
Nonviable Particulate Monitoring
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
Microbial Monitoring
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
Microbial Monitoring
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
Microbial Monitoring
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
Microbial Monitoring
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
Microbial Monitoring
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
Microbial Monitoring
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
37 Wyeth Pharmaceuticals
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
42 Wyeth Pharmaceuticals
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
43 Wyeth Pharmaceuticals
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
Microbial Monitoring Devices
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
Microbial Monitoring Devices
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
Microbial Monitoring Devices
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
-
10/5/2011
1
Writing SOPs and Batch RecordsWritingSOPsandBatchRecords
Writing SOPs and Batch Records--Robert Pallo
WritingSOPsandBatchRecords
Robert PalloManager Fill and Finish Operationsg p36 years at Allergan
Opinions expressed in the presentation are those of the author and in no way represent those of Allergan
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
2
WritingSOPsandBatchRecordsDoitDoit
Writing SOPs and Batch Records--Robert Pallo
WritingSOPsandBatchRecordsDoitDoitWriteit
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
3
WritingSOPsandBatchRecordsDoitDoitWriteitTestit
Writing SOPs and Batch Records--Robert Pallo
WritingSOPsandBatchRecordsSOPWritingEssentialsSOPWritingEssentials
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
4
WritingSOPsandBatchRecordsSOPWritingEssentialsSOPWritingEssentials
Be BriefBe Brief
Writing SOPs and Batch Records--Robert Pallo
WritingSOPsandBatchRecordsSOPWritingEssentialsSOPWritingEssentials
AskemployeesusingtheSOPfortheirinput
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
5
SOPWritingEssentials
WritingSOPsandBatchRecordsSOPWritingEssentials
AskemployeesusingtheSOPfortheirinputPrepareafirstdraft
Writing SOPs and Batch Records--Robert Pallo
SOPWritingEssentials
WritingSOPsandBatchRecordsSOPWritingEssentials
AskemployeesusingtheSOPfortheirinputPrepareafirstdraftRunawalkthrough
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
6
SOPWritingEssentials
WritingSOPsandBatchRecordsSOPWritingEssentials
AskemployeesusingtheSOPfortheirinputPrepareafirstdraftRunawalkthroughSolicitfeedbackandmakecorrections
Writing SOPs and Batch Records--Robert Pallo
SOPWritingEssentials
WritingSOPsandBatchRecordsSOPWritingEssentials
AskemployeesusingtheSOPfortheirinputPrepareafirstdraftRunawalkthroughSolicitfeedbackandmakecorrectionsMakeitofficial!
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
7
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
Writing SOPs and Batch Records--Robert Pallo
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
Decreasetrainingtime
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
8
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
DecreasetrainingtimeIncreaseconsistency
Writing SOPs and Batch Records--Robert Pallo
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirements
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
9
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasures
Writing SOPs and Batch Records--Robert Pallo
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasuresRetainandtransferknowledge
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
10
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasuresRetainandtransferknowledgeDocumentimprovementandchange
Writing SOPs and Batch Records--Robert Pallo
BenefitsofsolidSOPs
WritingSOPsandBatchRecordsBenefitsofsolidSOPs
DecreasetrainingtimeIncreaseconsistencyFulfillCompliancerequirementsCommunicateeffectivenessmeasuresRetainandtransferknowledgeDocumentimprovementandchangeDecreaseerrorrate
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
11
UnderstandingtheProcess
WritingSOPsandBatchRecordsUnderstandingtheProcess
BallisticProcessCharacteristicofthemotionofobjectsmovingundertheirownmomentumIfthereisnowaytoprovidefeedbacktochangeoradjustaprocess,thisisaballisticprocessTheBallisticProcessismostcommonE.g.Anautoclavecycle;amanufacturingprocedure
Writing SOPs and Batch Records--Robert Pallo
UnderstandingtheProcess
WritingSOPsandBatchRecordsUnderstandingtheProcess
BallisticProcessControlledprocess
MonitortheinputsandoutputsandmakecorrectivechangestotheprocessinordertoachievethedesiredoutputE.g.afillingmachinewherethefillweightisconstantlyadjusted.adjusted.
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
12
UnderstandingtheProcess
WritingSOPsandBatchRecordsUnderstandingtheProcess
BallisticProcessControlledprocessAdaptiveProcess
AprocessthatlearnsCanchangeovertimetoimproveeffectivenessE.g.allowsausertoidentifyiftheprocessneedsmodificationandtheycanhavetheoptiontoupdatetheprocedureNotagoodGMPidea
Writing SOPs and Batch Records--Robert Pallo
WritingaProcedure
WritingSOPsandBatchRecordsWritingaProcedure
DiscoveryDesignDevelopmentDeployment
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
13
WritingaProcedureDiscovery
WritingSOPsandBatchRecords
DiscoveryUnderstandtheproblemorprocessAprocedureisneededtodescribethestepsofabusinessprocess.Sobeforewecanwritethat,weneedtodiscoverwhatisexpected.Needtounderstand
Whoarethesources/resourcesWhoarethesources/resourcesWhataretheinputsandoutputsWhoarethecustomersWhataretheeffectivenesscriteriaWhatisthecorrectiveactioniftheprocessdoesntwork
Writing SOPs and Batch Records--Robert Pallo
WritingaProcedure
WritingSOPsandBatchRecordsWritingaProcedure
DiscoveryDesign
ThisiswhereyouspendyourtimeAprocessmapwillhelpcommunicatetheproceduraldesignandcollectfeedbackbeforewewriteoutthewrittenstepsPerformawalkthroughwiththedesignPerformawalkthroughwiththedesignRememberPDCA(PLAN DO CHECK ACT)
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
14
WritingaProcedure
WritingSOPsandBatchRecordsWritingaProcedure
DiscoveryDesignDevelopment
Importantquestion:Whoistheaudience?Novices,occasionalusersorfrequentusers?
Writing SOPs and Batch Records--Robert Pallo
WritingaProcedureforfrequentusers
WritingSOPsandBatchRecordsWritingaProcedureforfrequentusers
DonotrequirealotofexplanationMightonlyneedachecklistPriorityisnavigationratherthanexplanation
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
15
WritingaProcedureforoccasionalusers
WritingSOPsandBatchRecordsWritingaProcedureforoccasionalusers
MaynotnecessarilybeexperiencedMayfillinforsomeonefromtimetotimeMayrequiremoreexplanationorsomehowandwhyPriorityisexplanation,notnavigation
Writing SOPs and Batch Records--Robert Pallo
WritingaProcedureforthenovice
WritingSOPsandBatchRecordsWritingaProcedureforthenovice
LeaveoutthedetailMakeitastepbystepprocedureProvidethedetailsinanaccompanyingtrainingdocumentand
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
16
WritingaProcedureforthenovice
WritingSOPsandBatchRecordsWritingaProcedureforthenovice
LeaveoutthedetailMakeitastepbystepprocedureProvidethedetailsinanaccompanyingtrainingdocumentand
NoticethattheBESTSOPsarewritteninthisstyle!
Writing SOPs and Batch Records--Robert Pallo
Reviewofthewrittenprocedure
WritingSOPsandBatchRecordsReviewofthewrittenprocedure
ThesevenCsContextConsistencyCompletenessControlComplianceComplianceCorrectnessClarity
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
17
WritingaProcedure
WritingSOPsandBatchRecordsWritingaProcedure
DiscoveryDesignDevelopmentDeployment
Writing SOPs and Batch Records--Robert Pallo
Deployment
WritingSOPsandBatchRecordsp yTrainingAuditingContinuousimprovement
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
18
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
SOP Writing EssentialsSOP Writing EssentialsggBe BriefBe BriefBe Clear and ConciseBe Clear and Concise
Writing SOPs and Batch Records--Robert Pallo
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
SOP Writing EssentialsSOP Writing EssentialsBe BriefBe BriefClear and ConciseClear and ConciseThe shorter, the betterThe shorter, the better
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
19
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
Pictures are worth a thousand wordsPictures are worth a thousand words
-
10/5/2011
20
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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)
Writing SOPs and Batch Records--Robert Pallo
y p )y p )
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
Works well for well understood tasksWorks well for well understood tasks
-
10/5/2011
21
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
Writing SOPs and Batch Records--Robert Pallo
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
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
22
Writing SOPs and Batch RecordsWriting SOPs and Batch RecordsTypes of SOPs?Types of SOPs?Annotated Pictures.Annotated Pictures.
Writing SOPs and Batch Records--Robert Pallo
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.
Writing SOPs and Batch Records--Robert Pallo
Apply the Apply the ParetoPareto Rule Rule
-
10/5/2011
23
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
Writing SOPs and Batch Records--Robert Pallo
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
Writing SOPs and Batch Records--Robert Pallo
0
5
MachineSetup
Highplatecounts
Highparticlecounts
PoorAirFlow Gowning Technique Supplies FacilityDisinfection
-
10/5/2011
24
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
SOP FormatSOP FormatPurpose and ScopePurpose and ScopeDefinitionsDefinitionsMaterials and equipment neededMaterials and equipment neededAssignment of responsibilityAssignment of responsibility
St b t dSt b t d
Writing SOPs and Batch Records--Robert Pallo
Step by step procedureStep by step procedureReferencesReferencesApproval signaturesApproval signatures
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
The Standard Operating The Standard Operating FormFormggGatewayGateway to Excellent SOP Complianceto Excellent SOP Compliance
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
25
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
Operator signs off each critical step, Operator signs off each critical step, assuring compliance with the SOP.assuring compliance with the SOP.
-
10/5/2011
26
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
Master Record approval signaturesMaster Record approval signaturesFinal Batch approval signaturesFinal Batch approval signatures
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
SOF TipsSOF TipsSOF TipsSOF TipsDo not make the form too busyDo not make the form too busy
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
27
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
Writing SOPs and Batch RecordsWriting SOPs and Batch Records
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
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
28
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
Writing SOPs and Batch Records--Robert Pallo
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
Writing SOPs and Batch Records--Robert Pallo
-
10/5/2011
29
WritingSOPsandBatchRecordsExampleSOFExampleSOF
MANUFACTURING REVIEWED BY/DATE QUALITY ASSURANCE REVIEWED BY/DATE
Writing SOPs and Batch Records--Robert Pallo
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
Writing SOPs and Batch Records--Robert Pallo
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.
-
10/5/2011
30
WritingSOPsandBatchRecordsFINALCOMMENTSFINALCOMMENTS
Phone: 714-246-4413
Email: [email protected]
Writing SOPs and Batch Records--Robert Pallo
_ g
-
1
Cleaning Validation Cleaning Validation Coverage StudiesJeff FelkerSanofi Pasteur, Inc.
D T l kDawn TavalskySanofi Pasteur, Inc.
Background Information
2
-
2
Background Information
3
Background Information
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
11
Required Flow Rate Compared to Static
12
-
7
13
14
-
8
15
16
-
9
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
-
6
11
-
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