Você está na página 1de 65

USP<1115>BioburdenControlof

NonsterileDrugSubstancesand
Products: Intent Implementation
Products:Intent,Implementation
andImpact
TonyCundell,Ph.D.
Consulting Microbiologist
ConsultingMicrobiologist
Scarsdale,NY

August4,2014 IVTMicrobiologyWeek 1
Disclosures
The
Theopinionsexpressedinthispresentation
opinions expressed in this presentation
aresolelymineandnotthoseofmyformer
employer Merck & Co the USP Microbiology
employerMerck&Co,theUSPMicrobiology
CommitteeofExpertsormycurrent
consulting clients
consultingclients.

August4,2014 IVTMicrobiologyWeek 2
IVT Microbiology Week
IVTMicrobiologyWeek
The
ThespeakerwishtothankIVTprogrammanager
speaker wish to thank IVT program manager
CurryWilson,conferencechairKarenGinsburg,and
eventcoordinatorKellyCarrfororganizingthis
outstandingconference.
Congratulations.

August4,2014 IVTMicrobiologyWeek 3
PresentationOutline
TheintentionoftheUSPMicrobiologyCommitteeof
Experts
ImplementationoftheUSPChapter
Implementation of the USP Chapter
ExpectedimpactofthenewUSPchapter<1115>
Extentofmicrobialcontaminationofnonsteriledrug
products
ContentoftheUSPChapter<1115>
Riskhierarchybydosageform
Risk hierarchy by dosage form
Factorsincreasingmicrobialcontaminationrisk
Drugsubstances
Pharmaceuticalexcipients
DrugProducts
RoleofManufacturing
Role of Manufacturing
August4,2014 IVTMicrobiologyWeek 4
What is the USP?
WhatistheUSP?
TheU.S.Pharmacopeial
p ConventionInc.isan
independentstandardsorganization,foundedin
1820,empoweredbytheU.S.FederalFood,Drug,
and Cosmetic (FD&C) Act as the official drug
andCosmetic(FD&C)Actastheofficialdrug
standardsettingorganizationintheU.S.fordrug
p
products.
ThePharmacopeial Conventionpublishesand
maintainstheUnitedStatesPharmacopoeia(USP),
N ti
NationalFormulary(NF),andUSPReference
lF l (NF) d USP R f
Standardsandsetsthequalitystandardsforboth
drugproductsandpharmaceuticalingredients.
gp p g

August4,2014 IVTMicrobiologyWeek 5
U.S. Pharmacopeia
U.S.Pharmacopeia
HardCopy
Hard Copy Electronic
ElectronicCopy
Copy
Maybedownloadfrom
theUSPwebsite:
www.usp.org/usp
nf/officaltext

August4,2014 IVTMicrobiologyWeek 6
USPIntention
ThenewUSPInformationalChapter<1115>
BioburdenControlofNonsterileDrugSubstances
andProductswaspublishedinthe2ndSupplement
toUSP37NF32July2014.Whatwastheintentofthe
USP in publishing this chapter?
USPinpublishingthischapter?
Intheabsenceofregulatoryguidance,theUSPhas
provided a pragmatic scientific approach to the
providedapragmaticscientificapproachtothe
managementofthemicrobialbioburdeninnon
steriledrugproductsinkeepingwithpatientriskand
gp p g p
contaminationcontrolobjectivesbasedonrisk
managementprinciples.

August4,2014 IVTMicrobiologyWeek 7
USP Intention
USPIntention
The
Thechaptercontainsinformationonmicrobial
chapter contains information on microbial
controlconsiderationsinproductdevelopment,
routinemanufacturing,equipmentdesignanduse,
microbialassessmentofthenonsterile
manufacturingenvironment,activemeasuresfor
microbialcontrol,andtheoverallmanagementofa
i bi l t l d th ll t f
microbiologicalcontrolprogram.
Note:Itisaninformationalchapterandnotan
Note: It is an informational chapter and not an
enforceablecompliancedocument.

August4,2014 IVTMicrobiologyWeek 8
Presentation Outline
PresentationOutline
TheintentionoftheUSPMicrobiologyCommitteeof
Experts
ImplementationoftheUSPchapter
ExpectedimpactofthenewUSPchapter
Expected impact of the new USP chapter <1115>
1115
Extentofmicrobialcontaminationofnonsteriledrug
products
ContentoftheUSPChapter<1115>
Content of the USP Chapter <1115>
Riskhierarchybydosageform
Factorsincreasingmicrobialcontaminationrisk
Drugsubstances
Pharmaceuticalexcipients
RoleofManufacturing
Role of Manufacturing

August4,2014 IVTMicrobiologyWeek 9
Industry Implementation
IndustryImplementation
How
Howshoulddrugsubstanceanddrugproduct
should drug substance and drug product
manufacturersreacttothepublicationofthis
chapter?
Iwouldhopethattheyshouldadoptamorerisk
basedapproachtobioburdencontrolinnonsterile
drugdevelopmentandmanufacturingbasedonan
understandingofwhatdeterminesthepresenceof
microorganisms in their manufacturing facilities and
microorganismsintheirmanufacturingfacilitiesand
theirpersistenceorproliferationintheirdrug
products.
products.
August4,2014 IVTMicrobiologyWeek 10
Expert Opinion
ExpertOpinion
David
DavidHussong,FDACDERMicrobiologyDirector,
Hussong, FDA CDER Microbiology Director,
stated:Forthemicrobiologist,this(quality
initiatives)emphasizestheimportanceofprocess
knowledgetoreplacerelianceontestingsamplesof
finishedproduct.Avoidingmicrobiological
adulterationyieldsamorereliableindicatorof
d lt ti i ld li bl i di t f
quality,whichagreeswiththeassertionthatquality
cannot be tested into the product
cannotbetestedintotheproduct.

August4,2014 IVTMicrobiologyWeek 11
Industry Implementation
IndustryImplementation
Manufacturers
Manufacturersshouldappreciatethatwhether
should appreciate that whether
microorganismsfoundinanonsterileproductwill
beobjectionableinthatproductdependstheir
numberandspecies,theproductattributes,dosing
regimen,routeofadministration,andtargeted
patientpopulation.
ti t l ti
Anyenvironmentalmonitoringprogramwouldbe
risk based in terms of sample selection and
riskbasedintermsofsampleselectionand
frequencyandwouldbeusedtoconfirmmicrobial
control and would not be linked to product release.
controlandwouldnotbelinkedtoproductrelease.
August4,2014 IVTMicrobiologyWeek 12
PresentationOverview
TheintentionoftheUSPMicrobiologyCommitteeofExperts
ImplementationoftheUSPChapter
ExpectedimpactofthenewUSPchapter<1115>
Extentofmicrobialcontaminationofnonsteriledrug
products
ContentoftheUSPChapter<1115>
Risk hierarchy by dosage form
Riskhierarchybydosageform
Factorsincreasingmicrobialcontaminationrisk
Drugsubstances
Pharmaceuticalexcipients
DrugProducts
RoleofManufacturing
August4,2014 IVTMicrobiologyWeek 13
Industry Impact
IndustryImpact
WhatistheexpectedimpactoftheUSPchapter?
at s t e e pected pact o t e US c apte
Theexpectationistherewouldbeimprovedandcost
effectivebioburdencontrolsfornonsteriledrug
productstoalevelconsistentwithpatientsafety.
Thismayreduceproductrecallsformicrobial
contamination.
t i ti
Manufacturerswillbeabletobenchmarktheir
bioburden control programs against the
bioburdencontrolprogramsagainstthe
recommendationswithinthechapterandadjusttheir
programsaccordingly.

August4,2014 IVTMicrobiologyWeek 14
Presentation Outline
PresentationOutline
TheintentionoftheUSPMicrobiologyCommitteeof
Experts
ExpectedimpactofthenewUSPchapter<1115>
Extentofmicrobialcontaminationofnonsteriledrug
Extent of microbial contamination of non sterile drug
products
ContentoftheUSPChapter<1115>
Riskhierarchybydosageform
Factorsincreasingmicrobialcontaminationrisk
Drugsubstances
Drug substances
Pharmaceuticalexcipients
RoleofManufacturingg

August4,2014 IVTMicrobiologyWeek 15
Microbial Contamination
MicrobialContamination
The
Thecontaminationofmarketedproductswith
contamination of marketed products with
objectionablemicroorganismscontinuestobean
infrequentbutchronicproblemforourindustry.
Therearetheorderof20U.S.recallsonnonsterile
productsannuallyformicrobialcontamination.

August4,2014 IVTMicrobiologyWeek 16
What are Objectionable Microorganisms?
WhatareObjectionableMicroorganisms?
Theyaredefinedbyspecificdosageforms.
Theyincludespecifiedmicroorganisms,frank
pathogensandopportunisticpathogensthatare
known from the clinical literature to cause
knownfromtheclinicalliteraturetocause
infectionintherecipientviatherouteof
administrationormicroorganismsthatgrowin
theproductovercomingthepreservativesystem
p g p y
Also,theymayincludeorganismsassociated
withmajorrecallsformicrobialcontamination
If these microorganisms are present in the drug
Ifthesemicroorganismsarepresentinthedrug
productbelowthemicrobiallimit,thebatch
wouldberejected.

August4,2014 IVTMicrobiologyWeek 17
U.S. Congressional Hearings
U.S.CongressionalHearings

August4,2014 IVTMicrobiologyWeek 18
U.S.Recalls
ArecentU.S.surveyreported144recallscomposed
of nonsterile
ofnon sterilebrandedpharmaceuticaldrug
branded pharmaceutical drug
products(5%),overthecounterdrugproducts
(
(42%),cosmetics(31%),medicaldevices(14%)and
) ( ) ( )
dietarysupplements(8%ofthetotalrecalls)for
microbiologicallyrelatedissuesforthe7year
periodfrom2004through2011
f h h
Thesurveyhighlightedthatthemajorityofthese
recalls(72%)wereassociatedwithobjectionable
ll (72%) i t d ith bj ti bl
microorganismsandnotforexceedingthemicrobial
enumeration limits (Sutton and Jimenez 2012)
enumerationlimits(SuttonandJimenez,2012).
August4,2014 IVTMicrobiologyWeek 19
Microorganisms Implicated
MicroorganismsImplicated
The
Themostfrequentlycitedmicroorganismsinthe
most frequently cited microorganisms in the
recallsweretheBurkholderiacepacia complex(34
occurrences),unspecifiedfungalcontamination(19
occurrences),Bacilluscereus (9occurrences),
Pseudomonasaeruginosa (6occurrences),
Eli b thki i
Elizabethkingiameningoseptica
i ti (5occurrences),
(5 )
Enterobactergergovia (5occurrences),
Pseudomonas putida (3occurrences),Pseudomonas
Pseudomonasputida (3 occurrences) Pseudomonas
spp.(2occurrences)andSalmonella spp.(2
occurrences).
)

August4,2014 IVTMicrobiologyWeek 20
Burkholderia cepacia Complex
BurkholderiacepaciaComplex
The
TheprominenceoftheGram
prominence of the Gramnegative,
negative,oxidase
oxidase
positivebacteriumB.cepaciainnonsterileproduct
recallsistheresultofitprevalenceinwater,
metabolicversatility,anditsresistancetomany
disinfectantsandantimicrobialpreservative
systems.
t
B.cepaciaisacommonopportunisticpathogenand
infects cystic fibrosis sufferers
infectscysticfibrosissufferers.

August4,2014 IVTMicrobiologyWeek 21
Unidentified Fungi
UnidentifiedFungi
The
Thesecondmostprevalentrecallcategorywas
second most prevalent recall category was
unidentifiedfungi.Thisreinforcesthat
pharmaceuticalmicrobiologistsdoapoorjob
identifyingmold.
ForfurtherinformationseeCundell,A.M.2013
MoldContaminationinPharmaceuticalDrug
productsandMedicalDevicesEuropean
Pharmaceutical Review 18 (6): 67 75
PharmaceuticalReview18(6):6775

August4,2014 IVTMicrobiologyWeek 22
Presentation Outline
PresentationOutline
TheintentionoftheUSPMicrobiologyCommitteeof
Experts
ExpectedimpactofthenewUSPchapter<1115>
Extentofmicrobialcontaminationofnonsteriledrug
Extent of microbial contamination of non sterile drug
products
ContentoftheUSPChapter<1115>
Riskhierarchybydosageform
Factorsincreasingmicrobialcontaminationrisk
Drugsubstances
Drug substances
Pharmaceuticalexcipients
RoleofManufacturingg

August4,2014 IVTMicrobiologyWeek 23
ContentsoftheUSPChapter
p
Introduction
RiskHierarchyy
USP<61>,<62>and<1111>
USRegulatoryGuidanceDocuments
MicrobialControlConsiderationDuringProduct
Development
MicrobialControlConsiderationDuring
i bi l C l C id i i
Manufacturing
MicrobialControlofDrugSubstanceManufacturing
Microbial Control of Drug Substance Manufacturing
EquipmentDesignanduse
Personnel
TheManufacturingEnvironment
Th M f i E i

August4,2014 IVTMicrobiologyWeek 24
Content of the USP Chapter
ContentoftheUSPChapter
Microbial
MicrobialAssessmentofNon
Assessment of Nonsterile
sterileProduct
Product
ManufacturingEnvironment
MicrobialSampling
MicrobialIdentification
ActiveMeasuresforMicrobialControl
Overall
OverallManagementofaMicrobiologicalControl
Management of a Microbiological Control
Program
References

August4,2014 IVTMicrobiologyWeek 25
Presentation Outline
PresentationOutline
TheintentionoftheUSPMicrobiologyCommitteeof
Experts
ExpectedimpactofthenewUSPchapter<1115>
Extentofmicrobialcontaminationofnonsteriledrug
Extent of microbial contamination of non sterile drug
products
ContentoftheUSPChapter<1115>
Riskhierarchybynonsteriledosageform
Factorsincreasingmicrobialcontaminationrisk
Drugsubstances
Drug substances
Pharmaceuticalexcipients
Manufacturingg

August4,2014 IVTMicrobiologyWeek 26
Risk Hierarchy
RiskHierarchy
Hierarchyofriskduetomicrobialcontaminationby
route of administration (High to low):
routeofadministration(Hightolow):
Metereddoseanddrypowderinhalants
Nasalsprays
p y
Otics
Vaginalsuppositories
Topicals
Rectalsuppositories
Oralliquids(aqueous)
Liquidfilledcapsules
Compressed tablets and powder filled capsule
Compressedtabletsandpowderfilledcapsule
August4,2014 IVTMicrobiologyWeek 27
Presentation Outline
PresentationOutline
TheintentionoftheUSPMicrobiologyCommitteeof
Experts
ExpectedimpactofthenewUSPchapter<1115>
Extentofmicrobialcontaminationofnonsteriledrug
Extent of microbial contamination of non sterile drug
products
ContentoftheUSPChapter<1115>
Riskhierarchybydosageform
Otherfactorsincreasingmicrobialcontaminationrisk
Drugsubstances
Drug substances
Pharmaceuticalexcipients
Manufacturingg

August4,2014 IVTMicrobiologyWeek 28
Increased Microbial Risk
IncreasedMicrobialRisk
Thedevelopmentofnoveldrugdeliverysystems
e g dry powder inhalants nasal sprays
e.g.,drypowderinhalants,nasalsprays,
transdermalpatches,anddrugcoated
transplantedmedicaldevicesthatmayincrease
patientrisktomicrobialcontaminationdueto
ti t i k t i bi l t i ti d t
theirinvasivenesswithinthehumanbody.
Thesourcingofdrugsubstancesfrom
The sourcing of drug substances from
manufacturingfacilitiesinthird worldcountries
withincreasedriskofpotentialproduct
contamination due to poor GMPs
contaminationduetopoorGMPs
Globalizationwithdrugsmanufacturedoutside
the US and transported around the world.
theUSandtransportedaroundtheworld.
August4,2014 IVTMicrobiologyWeek 29
Increased Microbial Risk
IncreasedMicrobialRisk
The
Thegrowthofoff
growth of offlabel
labeldosageregimesand
dosage regimes and
patientpopulationsasphysiciansseekwider
clinicalapplicationsandchangeadministration
pp g
practices.
Theincreasedaggressivenessandinvasiveness
The increased aggressiveness and invasiveness
ofmedicaltreatments.
Increasesinpatientswhoduetotheirageor
Increases in patients who due to their age or
medicalconditionareseriouslyimmunologically
compromisedandareaggressivelytreated.
p gg y
August4,2014 IVTMicrobiologyWeek 30
Presentation Outline
PresentationOutline
TheintentionoftheUSPMicrobiologyCommitteeof
Experts
ExpectedimpactofthenewUSPchapter<1115>
Extentofmicrobialcontaminationofnonsteriledrug
Extent of microbial contamination of non sterile drug
products
ContentoftheUSPChapter<1115>
Riskhierarchybydosageform
Factorsincreasingmicrobialcontaminationrisk
Drugsubstances
Drug substances
Pharmaceuticalexcipients
Manufacturingg

August4,2014 IVTMicrobiologyWeek 31
Drug Substances
DrugSubstances
ThebioburdenofDSmanufacturedby y
chemicalsynthesiswilllargelydependonthe
finalsynthetic,isolationandpurification
steps the drying process micronization for
steps,thedryingprocess,micronizationfor
particlesizereduction,andtoalesserextent
thedrugsubstancepackaging.
g p g g
Ingeneral,thechemicaltransformationsand
isolationofintermediatestypicallyinvolve
reactionsusingreagents,solvents,and
i i l d
elevatedtemperaturesthatareincompatible
with the survival of microorganisms
withthesurvivalofmicroorganisms.
August4,2014 IVTMicrobiologyWeek 32
Chemical Synthesis
ChemicalSynthesis

August4,2014 IVTMicrobiologyWeek 33
Drug Substances
DrugSubstances
The
Thebioburdenofthestartingmaterials,
bioburden of the starting materials
reagents,andintermediateswillhavelittleor
no impact on the bioburden of the drug
noimpactonthebioburdenofthedrug
substancesandmaybediscounted.
Thebioburdenofaplant
The bioburden of a plant oranimalderived
or animal derived
drugsubstancewilldependonthedegreeof
processes of the material
processesofthematerial.

August4,2014 IVTMicrobiologyWeek 34
Drug Substances
DrugSubstances
Theimpactofthefinalpurificationandisolation
e pact o t e a pu cat o a d so at o
stepsontheDSbioburdendependsonthe
solventusedinthemotherliquor,temperature
oftheisolationprocess,theinclusionofa
f h l h l f
bioburdencontrollingfiltrationstep,the
material recovery method and drying process
materialrecoverymethod,anddryingprocess.
Typically90%oftheisolationsemployorganic
solvent or a mixture of organic solvents and
solventoramixtureoforganicsolventsand
waterandnotwater,whichreducesthe
likelihoodofmicrobialcontamination.

August4,2014 IVTMicrobiologyWeek 35
Drug Substances
DrugSubstances
Themostcommonorganicsolventsusedin
g
industrialorganicsynthesesincludetoluene,
tetrahydrofuran,dichloromethane,ethyl
acetate 2 propanol methanol denatured
acetate,2propanol,methanol,denatured
alcohol,aceticacid,nheptane,and
acetronitrile.Allareinimicaltothesurvival
ofmicroorganisms
Ifwateristheprimarysolvent,purified
water,USPisusedforDSusedinnonsterile
i df di il
drugproductsandlowendotoxinpurified
water in sterile drug products
waterinsteriledrugproducts.
August4,2014 IVTMicrobiologyWeek 36
ProductDevelopment
Pointstobeconsideredwhenassessingthe
potentialmicrobialriskassociatedwithnonsterile
d
drugproducts:
d t
Synthesis,isolationandfinalpurificationofthedrugsubstance
Microbiological attributes of the drug substance
Microbiologicalattributesofthedrugsubstance
Formulationandphysicochemicalattributesofthedrugproduct
Wateractivityofthedrugproduct
Manufacturingprocess
Packaginganddeliverysystem
Storage conditions of the drug substance and product
Storageconditionsofthedrugsubstanceandproduct
Routeofadministration
Expectedtreatmentprocedureanddosageregimen
Ageandhealthconditionoftheintendedrecipientsofthedrug
August4,2014 IVTMicrobiologyWeek 37
U.S. Regulatory Documents
U.S.RegulatoryDocuments
FDA
FDAGoodManufacturingPracticesfoundin21CFR
Good Manufacturing Practices found in 21 CFR
Part211
211.42DesignandConstruction
211.46Ventilation,AirFiltration.AirheatingandCooling
211.56Sanitation
211.113ControlofMicrobiologicalContamination

August4,2014 IVTMicrobiologyWeek 38
Manufacturing Risk Factors
ManufacturingRiskFactors
Microbial risk factors in descending order:
Microbialriskfactorsindescendingorder:
Ingredientwater
Pharmaceuticalingredients
g
Processingequipment
Manufacturingpersonnel
Manufacturingenvironment

August4,2014 IVTMicrobiologyWeek 39
Pharmaceutical Water Systems
PharmaceuticalWaterSystems

August4,2014 IVTMicrobiologyWeek 40
ClassificationofPharmaceutical
Excipients
Binders Cakingagents
Caking agents
Disintegrants Buffers
Fillers(diluents) Preservatives
Lubricants Suspending/dispersing
Glidants(flow agents
enhancers)
Filmformers/coatings
Compressionaids
Colors
l Flavors
Sweeteners Printinginks

August4,2014 IVTMicrobiologyWeek 41
CommonExcipientsusedinSolid
DosageForms
Excipient Common Excipients
Classification
Diluent or Filler Lactose, Sucrose, Kaolin, Dibasic Calcium Phosphate,
Calcium Sulfate, and Calcium Carbonate
Binders Water, Alcohol
Water Alcohol, Starch Paste
Paste, Gelatin Solutions
Solutions,
Tragacanth, Sodium Alginate, Carboxymethyl
Cellulose, Polyethylene Glycol and Povidone
Lubricants Magnesium Stearate,
Stearate Calcium Stearate,
Stearate Talc
Talc, Stearic
Acid, Starch, Mineral Oil, Sodium Chloride, Sodium
Benzoate, and Carbowax 4000 or 6000
Disintegrating Corn Starch
Starch, Methylcellulose
Methylcellulose, Sodium Carboxymethyl
Agents Cellulose, Alginic Acid, Microcrystalline Cellulose and
Gums
g
Sweetening Mannitol,, Lactose,, Sorbitol,, Fructose,, Saccharine,, and
Agents Aspartame

August4,2014 IVTMicrobiologyWeek 42
RiskAnalysisofPharmaceutical
Excipients
Classification ExamplesofExcipients MicrobialRisk
y
Synthetic Povidone(polyvinylpyrrolidone)and
(p y y py ) Littleornone
Material Crospovidone(Ahomopolymerofcross
linkedNvinyl2pyrrolidone)
Semisynthetic
y Captisol(Chemicallymodifiedcylodextrin)
p ( y y ) Lowto
material andHydroxypropylMethylcellulose moderate
Plantderived CornStarch,MicrocrystallineCellulose,and Moderate
Material Sucrose
Animal Lactose(Extractive),MagnesiumStearate Moderateto
derived (Processedchemicallyfromtallow),and high
Material Gelatin (Purified from bone or hide)
Gelatin(Purifiedfromboneorhide)
Mineral Talc(Extractive)andDibasicCalcium Lowto
derived Phosphate(Processedchemicallyfroma moderate
Material mineral calcium carbonate and phosphoric
mineralcalciumcarbonateandphosphoric
acid)
August4,2014 IVTMicrobiologyWeek 43
Talc Mining
TalcMining

August4,2014 IVTMicrobiologyWeek 44
Lactose Production
LactoseProduction
Wheyproteinconcentratesarepowdermadebydrying
yp p y y g
theretentate fromtheUltraFiltrationofwhey.The
concentrationofwheyproteinsisprimarilyachievedby
UF and Diafiltration
UFandDiafiltration.
ThepermeateofUFmembraneishighinlactose
content,sothatisusedformanufacturinglactose
powder.Permeaterecoveredisconcentratedto
d di d
minimum62%TSlevelinanevaporatorandthen
cooledundercontrolledconditionsforLactose
crystallization.Crystalsarewashed,decantedandspray
driedtoproducepharma gradelactose.

August4,2014 IVTMicrobiologyWeek 45
Lactose Manufacturing
LactoseManufacturing
Lactosespraydryer
Lactose spray dryer

August4,2014 IVTMicrobiologyWeek 46
Risk Assessment
RiskAssessment
InFailureModeandEffectsAnalysis(FMEA)terms
y ( )
riskwasdefinedintermsofoccurrence(O),severity
(S)anddetection(D).TheriskisexpressedasOxSX
D Using this tool risk is minimized if occurrences
D.Usingthistool,riskisminimizedifoccurrences
decrease,severityoftheeffectoffailureisdecreased,
andtheefficiencyofdetectionofafailureincreases.
Note:Thelessreadilythatmicrobialcontamination
canbedetectedthehigherthevalueofDandthe
overall risk
overallrisk.
ForadiscussionofriskanalysisseeICHQ9Quality
RiskManagement

August4,2014 IVTMicrobiologyWeek 47
Simple Risk Analysis
SimpleRiskAnalysis
Anapproachistoassignascorefrom1to3to
pp g
thefollowing:
Severity(S)asaconsequenceoffailure
Occurrence(O)asthelikelihoodoffailure
occurringbasedonpastexperience
Detection(D)asthelikelihoodthatfailure
detectionwilltakeplacewiththeproposed
monitoringsystem
TheriskisdeterminedbytheproductofSxO
xD
D
August4,2014 IVTMicrobiologyWeek 48
RiskAnalysis Occurrences(O),
Susceptibility(S)andDetectability(D)
bl ( ) d bl ( )
Excipient
p O S D OxSxD
Manufacturing
Process
Synthetic Material 1 2 1 2

Semi-synthetic 1 2 2 4
material

Plant-derived 2 3 2 12
Material
Animal-derived
Animal derived 3 3 2 18
Material
Mineral-derived 2 2 2 8
Material

August4,2014 IVTMicrobiologyWeek 49
ICH Q6A
ICHQ6A
Fordrugproductreleasetesting,ICHQ6ATest
gp g, Q
ProceduresandAcceptanceCriteriaforNewDrug
SubstancesandDrugProducts providesdecision
trees that guide manufacturers on necessary test
treesthatguidemanufacturersonnecessarytest
strategiesbasedonthenatureoftheproduct.
Theestablishmentofmicrobiologicalattributesare
The establishment of microbiological attributes are
describedinDecisionTree6(DrugSubstances)and
DecisionTree8(DrugProducts).
Lowwateractivityisahighlightedattributefor
reducedtestingstrategies.

August4,2014 IVTMicrobiologyWeek 50
ManufacturingEnvironment
Commondesignelementstocontrolmicrobial
contamination:
Nonporouswalls,ceilingsandfloorsthatarereadilycleanable
Floordrainsthatcanbeclosedduringprocessingorfittedwith
aairbreakifopenedduringareaandequipmentcleaning
Accessshouldbelimitedtoessentialpersonnel
Material,equipmentandpersonnelflowsshouldavoid
M t i l i t d l fl h ld id
contamination
Ventilationandairfiltrationshouldbeadequatetomaintain
q
thespecifiedcleanliness,spacepressurization,temperature
andhumidity

August4,2014 IVTMicrobiologyWeek 51
Manufacturing Equipment
ManufacturingEquipment
Forbioburdencontrolequipmentshouldhavethe
For bioburden control equipment should have the
followingattributes:
Sanitarydesign
y g
ReadilycleanedpreferablyusingaCIPsystem
Self
Selfdraining
drainingtoeliminatestagnatewater
to eliminate stagnate water
Preventativemaintenanceprogramtoperiodically
replacevalves,seals,filtersandhosing
p , , g
Inclusionofmicrobialmonitoringincleaning
validationprotocols
p

August4,2014 IVTMicrobiologyWeek 52
Dosage Forms
DosageForms
Over80%ofthecurrentdrugproductsbythe
number of prescription are marketed as oral solid
numberofprescriptionaremarketedasoralsolid
dosageforms,i.e.powder andliquid filled
capsulesandcompressedtablets,whichhaveavery
lowriskofmicrobialcontaminationbecauseoftheir
manufacturingprocesses,lowwateractivityand
route of administration
routeofadministration.
Manyothernonsteriledrugproducts,e.g.,oral
liquids,topicals,nasalsprays,etc,maybe
q , p , p y, , y
susceptibletomicrobialgrowthandhavemore
criticalroutesofadministrationthananoralsolid.

August4,2014 IVTMicrobiologyWeek 53
Risk Assessment
RiskAssessment
Whatothertoolsareavailableforthisriskassessment?
Inthe1960's,thePillsburyCompany,theU.S.Army,
andNationalAeronauticsandSpaceAdministration
(NASA) i t d d
(NASA)introducedasystemforassuringpathogen
t f i th
freefoodsforthespaceprogram.
Thissystem,calledHazardAnalysisandCritical
This system, called Hazard Analysis and Critical
ControlPoints(HACCP),isafocusoncriticalfood
safetyareasaspartoftotalqualityprogramsandmay
be a tool applicable to the pharmaceutical industry
beatoolapplicabletothepharmaceuticalindustry.

August4,2014 IVTMicrobiologyWeek 54
HACCP
HACCP
HACCPinvolvesacriticalexaminationofthe
involves a critical examination of the
entirefoodmanufacturingprocessto
determine every step where there is a
determineeverystepwherethereisa
possibilityofphysical,chemical,or
microbiological contamination of the food
microbiologicalcontaminationofthefood,
whichwouldrenderitunsafeor
unacceptable for human consumption. These
unacceptableforhumanconsumption.These
identifiedpointsarethecriticalcontrol
points (CCP).
points(CCP).
August4,2014 IVTMicrobiologyWeek 55
HACCP
TherearesevenprinciplestoHACCP:
There are seven principles to HACCP:
1.Analyzehazards,
2 determine CCPs
2.determineCCPs,
3.establishcriticallimits,
4 establish monitoring procedures
4.establishmonitoringprocedures,
5.establishdeviationprocedures,
6 establish verification procedures and
6.establishverificationprocedures,and
7.establishrecordkeepingprocedures

August4,2014 IVTMicrobiologyWeek 56
Tablet Manufacturing
TabletManufacturing
Ingeneral,themostcriticalprocessingstepswith
g , p g p
respecttopotentialmicrobialcontaminationare
theprocurementofpharmaceuticalingredients,
wet granulation and milling and tablet coating
wetgranulationandmillingandtabletcoating
(Boldedredinlistofmanufacturingsteps).For
example,theholdingtimeofaqueousfilmcoating
p g q g
solutionsmaybeacriticalcontrolpoint.
Incontrast,fluidbeddryingandcompressionare
potentiallybioburdenreductionsteps(Bolded
t ti ll bi b d d ti t (B ld d
green)

August4,2014 IVTMicrobiologyWeek 57
Tablet Manufacturing
TabletManufacturing
Forexample,theprocessingstepsforthemanufacture
of a filmcoated
ofafilm coatedcompressedtabletare:
compressed tablet are:
Procurementofpharmaceuticalingredients
Warehousingpharmaceuticalingredients
Batchingofthepharmaceuticalingredients
Blending
Wetgranulationandmilling
l i d illi
Drying
Tabletcompression
Tablet compression
Tabletcoating
Packaging
g g
Distribution
August4,2014 IVTMicrobiologyWeek 58
Tablet Manufacturing
TabletManufacturing
Unit
Unitprocessesinvolvedinmakingtabletsinclude
processes involved in making tablets include
particlesizereductionandsizing(milling),blending,
granulation,drying,compaction(compression),
(frequently)coatingandpackaging.

August4,2014 IVTMicrobiologyWeek 59
Tablet Manufacturing
TabletManufacturing

August4,2014 IVTMicrobiologyWeek 60
Risk Analysis for Tablet Manufacturing
RiskAnalysisforTabletManufacturing

Manufacturing Contamination Preventative Remarks


Step Potential Measures/Critical
Control Points

Wet granulation Moderate Equipment design. Emphasis on water


and milling Cleaning system validation and
validation. equipment cleaning to
Monitor purified prevent microbial
water used in contamination. Water
granulation activity measurement
solutions for may be used to evaluate
microbial counts the ability of the
(CCP). Holding granulation to support
Time (CCP). microbial growth

August4,2014 IVTMicrobiologyWeek 61
Risk Analysis for Tablet Manufacturing
RiskAnalysisforTabletManufacturing
Manufacturing Contamination Preventative Remarks
Step Potential Measures/Critical
Control Points

Tablet Coating Moderate to Equipment Water-based


High cleaning and coating
solution holding solution will
time (CCP) support
Incoming microbial growth.
microbial testing Holding times
of ingredients need to be
(CCP) justified.
Monitor purified
water used in
coating solutions
for microbial
counts (CCP)

August4,2014 IVTMicrobiologyWeek 62
Risk Analysis
RiskAnalysis
AfterAnastasiaLois,2013
After Anastasia Lois, 2013

August4,2014 IVTMicrobiologyWeek 63
Conclusions
Themanagementofasuccessfulmicrobiological
g g
controlprogramincludesthefollowing:
Identificationofsuitablesuppliersof
pharmaceuticalingredientsandexcipientsthathave
h l d d h h
goodmicrobiologicalquality
Conductingamicrobialriskassessmentofthedrug
Conducting a microbial risk assessment of the drug
formulation,manufacturingprocessandpackaging
systemandmitigatingthoserisks
Theestablishmentofanappropriatemonitoring
andcontrolsystem.

August4,2014 IVTMicrobiologyWeek 64
Contact Information
ContactInformation
TonyCundell,ConsultingMicrobiologist
Tony Cundell, Consulting Microbiologist
Emailaddress:tonycundell@gmail.com
Phonenumber:01914725
Phone number: 01 914 7253947
3947

August4,2014 IVTMicrobiologyWeek 65