11/10/2016

GeneralChapters:<1150>PHARMACEUTICALSTABILITY

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1150

PHARMACEUTICALSTABILITY

Thetermstability,withrespecttoadrugdosageform,referstothechemicalandphysicalintegrityofthedosageunitand,
whenappropriate,theabilityofthedosageunittomaintainprotectionagainstmicrobiologicalcontamination.Theshelflife
ofthedosageformisthetimelapsefrominitialpreparationtothespecifiedexpirationdate.Themonographspecifications
ofidentity,strength,quality,andpurityapplythroughouttheshelflifeoftheproduct.
Thestabilityparametersofadrugdosageformcanbeinfluencedbyenvironmentalconditionsofstorage(temperature,
light,air,andhumidity),aswellasthepackagecomponents.Pharmacopeialarticlesshouldincluderequiredstorage
conditionsontheirlabeling.Thesearetheconditionsunderwhichtheexpirationdateshallapply.Thestoragerequirements
specifiedinthelabelingforthearticlemustbeobservedthroughoutthedistributionofthearticle(i.e.,beyondthetimeit
leavesthemanufactureruptoandincludingitshandlingbythedispenserorsellerofthearticletotheconsumer).Although
labelingfortheconsumershouldindicateproperstorageconditions,itisrecognizedthatcontrolbeyondthedispenseror
sellerisdifficult.Thebeyondusedateshallbeplacedonthecontainerlabel.

StabilityProtocols
Stabilityofmanufactureddosageformsmustbedemonstratedbythemanufacturer,usingmethodsadequateforthe
purpose.Monographassaysmaybeusedforstabilitytestingiftheyarestabilityindicating(i.e.,iftheyaccurately
differentiatebetweentheintactdrugmoleculesandtheirdegradationproducts).Stabilityconsiderationsshouldincludenot
onlythespecificcompendialrequirements,butalsochangesinphysicalappearanceoftheproductthatwouldwarnusers
thattheproduct'scontinuedintegrityisquestionable.
Stabilitystudiesonactivesubstancesandpackageddosageformsareconductedbymeansofrealtime,longtermtests
atspecifictemperaturesandrelativehumiditiesrepresentingstorageconditionsexperiencedinthedistributionchainofthe
climaticzone(s)ofthecountryorregionoftheworldconcerned.Labelingofthepackagedactivesubstanceordosageform
shouldreflecttheeffectsoftemperature,relativehumidity,air,andlightonitsstability.Labeltemperaturestoragewarnings
willbothreflecttheresultsoftherealtimestoragetestsandallowforexpectedseasonalexcursionsoftemperature.

ControlledRoomTemperature
Controlledroomtemperature(seeStorageTemperatureandHumidityinPreservation,Packaging,Storage,andLabeling
underGeneralNoticesandRequirements)delineatestheallowabletoleranceinstoragecircumstancesatanylocationinthe
chainofdistribution(e.g.,pharmacies,hospitals,andwarehouses).Thisterminologyalsoallowspatientsorconsumersto
becounseledastoappropriatestoragefortheproduct.ProductsmaybelabeledeithertostoreatControlledroom
temperatureortostoreattemperaturesupto25 wherelabelingissupportedbylongtermstabilitystudiesatthe
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GeneralChapters:<1150>PHARMACEUTICALSTABILITY

designatedstorageconditionof25 Kelvin(K)
.Controlledroomtemperaturelimitsthepermissibleexcursionstothoseconsistentwith
Fahrenheit( F) Celsius( C)
themaintenanceofameankinetictemperaturecalculatedtobenotmorethan25 .SeeMeanKineticTemperature.The
commoninternationalguidelineforlongtermstabilitystudiesspecifies252 at605%relativehumidity.Accelerated
studiesarespecifiedat402 andat755%relativehumidity.Acceleratedstudiesalsoallowtheinterpretationofdata
andinformationonshorttermspikesinstorageconditionsinadditiontotheexcursionsallowedbycontrolledroom
temperature.
Thetermroomtemperatureisusedindifferentwaysindifferentcountries,andforproductstobeshippedoutsidethe
continentalU.S.itisusuallypreferableforproductlabelingtorefertoamaximumstoragetemperatureortemperaturerange
indegreesCelsius.

MeanKineticTemperature
MeanKineticTemperature(MKT)isdefinedasthesinglecalculatedtemperatureatwhichthetotalamountofdegradation
overaparticularperiodisequaltothesumoftheindividualdegradationsthatwouldoccuratvarioustemperatures.Thus,
MKTmaybeconsideredasanisothermalstoragetemperaturethatsimulatesthenonisothermaleffectsofstorage
temperaturevariation.Itisnotasimplearithmeticmean.MKTiscalculatedfromtemperaturesinastoragefacility.The
temperaturesforcalculatingMKTcanbeconvenientlycollectedusingelectronicdevicesthatmeasuretemperaturesat
frequentintervals(e.g.,every15minutes).MKTcanbecalculateddirectlyorthedatacanbedownloadedtoacomputerfor
processing.Fordispensingsites,suchaspharmaciesandhospitals,wheretheuseofsuchinstrumentsmaynotbe
feasible,devicessuchashighlowthermometerscapableofindicatingweeklyhighandlowtemperaturesovera52week
periodmaybeemployed.Thearithmeticmeanoftheweeklyhighandlowtemperaturesisthenusedinthecalculationof
MKT.MKTiscalculatedbythefollowingequation(derivedfromtheArrheniusequation):

inwhichTk isthemeankinetictemperatureDHistheheatofactivation,83.144kJmole 1(unlessmoreaccurate

informationisavailablefromexperimentalstudies)Ristheuniversalgasconstant,8.314410 3kJmole 1degree 1
T1isthevalueforthetemperaturerecordedduringthefirsttimeperiod,e.g.,thefirstweekT2isthevalueforthe
temperaturerecordedduringthesecondtimeperiod,e.g.,secondweekandTnisthevalueforthetemperaturerecorded
duringthenthtimeperiod,e.g.,nthweek,nbeingthetotalnumberofstoragetemperaturesrecorded(minimumof52
weeklyentries)duringtheannualobservationperiod.[NOTEAlltemperatures,T,areabsolutetemperaturesindegrees
Kelvin(K).]
ThefollowingisanexampleofatypicalstorageanddistributiontemperaturerangeinKelvindegreesandtheconversion
factorsusedtoconvertthisrangeintodegreesFahrenheitandCelsius.

Kelvin(K)
288.1303.1

Fahrenheit( F)
5986

Celsius( C)
1530

ConversionFactors:
FahrenheittoKelvin={[( F 32)5/9]+273.1}
CelsiustoKelvin=273.1+ C
FahrenheittoCelsius=[( F 32)5/9]
ClimaticZones
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Forconvenienceinplanningforpackagingandstorage,andforstabilitystudies,internationalpracticeidentifiesfour
CalculatedData
DerivedData
climaticzones,whicharedescribedinTable1.TheUnitedStates,Europe,andJapanarecharacterizedbyzonesIandII.
%
%
ThevaluesinTable1arebasedonobservedtemperaturesandrelativehumidities,bothoutsideandinrooms,fromwhich
*
**
***
ClimaticZone
C
CMKT
RH mbar
C RH mbar
meankinetictemperaturesandaveragehumidityvaluesarecalculated.1Derivedvaluesarebasedoninspectionofdata
fromindividualcitiesandonallowancesforamarginofsafetyinassignmentofthesespecifiedconditions.
Table1.InternationalClimaticZones

ClimaticZone
I.Temperate
Japan
UnitedKingdom
NorthernEurope
Canada
Russia
UnitedStates
II.Mediterranean,Subtropical
UnitedStates
Japan
SouthernEurope
(PortugalGreece)
III.Hot,Dry
Iran
Iraq
Sudan
IV.Hot,Humid
Brazil
Ghana
Indonesia
Nicaragua
Philippines

C*
20.0

CalculatedData
%
**
CMKT
RH mbar***
20.0
42
9.9

DerivedData
%
C RH mbar
21 45
11.2

21.6

22.0

52

13.5

25

60

19.0

26.4

27.9

35

11.9

30

35

15.0

26.7

27.4

76

26.6

30

70

30.0

*Datarecordedas<19 calculatedas19 .
**Calculatedmeankinetictemperature.
***Partialpressureofwatervapor.
Adiscussionofaspectsofdrugproductstabilitythatareofprimaryconcerntothepharmacistinthedispensingof
medicationsmaybefoundunderStabilityConsiderationsinDispensingPractice 1191 .
Inasmuchasthischapterisforpurposesofgeneralinformationonly,nostatementhereinisintendedtomodifyorsupplant
anyofthespecificrequirementspertinenttopharmaceuticalpreparations,whicharegivenelsewhereinthisPharmacopeia.

AuxiliaryInformationStaffLiaison:DesmondG.Hunt,Ph.D.,SeniorScientificAssociate
ExpertCommittee:(PS05)PackagingandStorage05
USP29NF24Page2994
PharmacopeialForum:VolumeNo.29(5)Page1625
PhoneNumber:13018168341

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