Introduction To Ethylene Oxide Sterilization And .

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Introduction toEthylene Oxide Sterilizationand Regulatory UpdatesDR. STEFAN REISBACHERTECHNICAL ADVISOR EO, EMEAA22 MAY 2019

Agenda Regulatory overview Ethylene Oxide Sterilization Process Definition Performance QualificationCONFIDENTIAL

Regulatory overviewCONFIDENTIAL2

Sterilization MethodsSterilization MethodsEthylene OxideRadiationOther Gamma ray Moist heat Accelerated electrons Dry heat X-rays Vaporized hydrogen peroxide Gas plasma LTSF(EO) gasMost common methodsfor terminal sterilization of single use medical devicesCONFIDENTIAL3

History - ISO 11135ISO11135:1994 – Sterilization of health care products – Ethylene OxideRequirements for development, validation and routine control of a sterilization process for medicaldevices. (Also contained Guidance section)ISO11135-1:2007 – Sterilization of healthISO/TS11135-2:2008 – Sterilization ofcare products – Ethylene Oxidehealth care products – Ethylene Oxide(Requirements plus limited Guidance section)Guidance on the application of ISO11135-1ISO11135:2014 – Sterilization of health care products – Ethylene OxideRequirements for development, validation and routine control of a sterilization process for medicaldevices. (Also contains comprehensive Guidance section)3-year transition period lasted until July 2017; Transition period is now closedCONFIDENTIAL

Relevant StandardsEO Sterilization and ValidationEO ResidualsISO 11135:2014Sterilization of medical devices – Requirements for thedevelopment; validation and routine Control of aSterilization Process for Medical Devices – EthyleneOxideISO 10993-7:2008 (R) 2012Biological evaluation of medical devices - Part 7:Ethylene oxide sterilization residualsBacterial Endotoxin Test (LAL)Bioburden United States Pharmacopeia (USP) Chapter 85 Bacterial Endotoxins Test European Pharmacopeia (EP) Chapter 2.6.14 BacterialEndotoxins Japanese Pharmacopeia (JP) Chapter 4.01 BacterialEndotoxins Test ANSI/AAMI ST72 : 2011 (R) 2016 – BacterialEndotoxins New draft document DIS11737-3 in progressISO 11737-1:2018Sterilization of medical devices (Microbiologicalmethods) Part 1: Determination of a population ofmicroorganisms on productsCONFIDENTIAL

Relevant StandardsProduct SterilityBiological Indicator Tests ISO 11737-2:2009 (R) 2014Sterilization of medical devices (Microbiologicalmethods) Part 2: Tests of sterility performed in thedefinition, validation and maintenance of a sterilizationprocess United States Pharmacopeia (USP) Chapter 71 Sterility Tests European Pharmacopeia (EP) Chapter 2.6.1 Sterility Japanese Pharmacopeia (JP) Chapter 54. Sterility Test ISO 11138-1:2017Sterilization of health care products (Biologicalindicators) Part 1: General requirements ISO 11138-2:2017Sterilization of health care products (Biologicalindicators)Part 2: Biological indicators for ethyleneoxide sterilization processes ISO 14161: 2009 (R) 2014Biological indicators. Guidance for the selection, useand interpretation of resultsQuality SystemsISO 13485: 2016Medical Devices, Quality Management SystemsCONFIDENTIAL

Ethylene Oxide SterilizationCONFIDENTIAL7

Ethylene Oxide – HistoryEthylene OxidediscoveredFirst productionof Ethylene OxidePatent forsterilization of spicesCharles WurzUnion Carbide ChemicalsLloyd Hall185919251938Use in sterilizationof materialsDr. Lloyd Augustus Hall, a food scientist (and aNorthwestern University classmate of Carroll L.Griffith) , while working for Griffith Laboratories,devised a process known as the Ethylene OxideVacugas treatment to control the growth ofmolds and bacteria. Griffith and Hall received USPatent 2,189,949 in 1940.CONFIDENTIAL1940

Ethylene OxideProperties Toxic gas “Sweet smell” from ca. 500 ppm concentration Forms with air explosive mixtures (2.6 %) Oncogenic by inhalation Irritating for skin and respiratory system Mutagenic for animals and very likely for humansCONFIDENTIAL

Ethylene OxideMode of Action Extremely reactive Irreversible reaction with DNAand proteins (alkylation)oThe molecule is loses functionoReplication stopsoThe cell diesCONFIDENTIAL

Ethylene Oxide SterilizationMost commonly used industrialmethod for medical devices,mainly used to sterilize: Heat-sensitive materialoProducts that cannot tolerate thehigh temperatures of Moist Heat(Steam) Sterilization Material sensitive to ionizingradiationoProducts can embrittle anddiscolor over time after exposureto ɣ, E-beam, X-rayCONFIDENTIAL

Considerations When Sterilizing Using Ethylene OxideDevice/packaging must be permeable to the gas(Be careful with tight-end valves, 3 way stopcocks,pouches, etc) No aqueous substances No protein-type materials Powders, batteries, electronic circuits have to beassessed (risk of explosion) Vacuum/heat can have adverse impact on somepackaging (bubble wrap packaging,polystyrene)CONFIDENTIAL

Critical Parameters for Effective EO onof MicroorganismsEtO DwellTimeTemperatureCONFIDENTIAL

Temperature (T)EtO killsmicroorganismsIndustrialsterilizationeven attemperatures below10 C (50oF)performed in 40-60 C(104–140oF)temperature rangeQ10 EffectTemperatureincreaseincrease by 10 C(18 F) 2x DeactivationRatemay increase ofpermeability ofgases throughmaterialsCONFIDENTIAL

Relative Humidity (RH)Necessary foralkylationreactionRelative humiditymay assistpenetration of EOthrough materialsEO is mosteffective atRH 30%CONFIDENTIAL

EO-ConcentrationEffective400–800 mg/LNo significantbenefitabove 800 mg/lAt constant T and RH – if EO concentration increases microbiological Deactivation ismore effective - up to c. 800 mg/l 500 mg/L @ 131 F 800 mg/L @ 86 FCONFIDENTIAL16

TimeMicrobiologicaldeactivationis more effectivewith longer gasdwell phaseIndustry cycles2 to 10 hours gasdwell phaseTypically 3-4 hoursCONFIDENTIAL

Sterilization ProcessThe sterilization process has 3 key phasesPreconditioningChamber cycleCONFIDENTIALAeration

PreconditioningPreconditioning, typically: 35–45 C 45–75 %RH75 %RelativeHumidity45 %125 F100 FCONFIDENTIALTemperature

Typical EO Cycle Design – Deep VacuumGENERIC CYCLE1000900gas dwellRelease toatmosphericpressure800Initial vacuumpressure (mbarA)700Gasevacuation600500Gas washes : firstnitrogen and then airGas injectionInertization400300200Steam injection andconditioning100Leak test0060120180240300time (min)CONFIDENTIAL360420480540

Aeration Aeration, typically:o35 – 50 CoForced circulationAir Circulation130 FTemperature100 FCONFIDENTIAL

Monitoring EO Sterilization ProcessesCONFIDENTIAL22

Monitoring EO Sterilization - Biological Indicators Usually, the BI contains at least a million spores of an organism that is highly-resistantto the EO process. The name of the bacterium is commonly Bacillus subtilis or B. subtilis.oIt has been renamed and is officially B. atrophaeus.SporeCONFIDENTIAL

Monitoring EO Sterilization - Biological IndicatorsBiological Indicators (BI) 106 Spores of resistant strain Bacillus atrophaeus Can come in many different designsCONFIDENTIAL

Monitoring EO Sterilization - Biological IndicatorsNegative: No GrowthPositive: GrowthMorphologyBIs in vial with MediumCONFIDENTIAL

Monitoring EO Sterilization – Biological IndicatorsWe design the validation to show that the BI is more difficult to kill than natural occurringbioburden (microorganisms in or on product)EO effective against wide range of organismsE. coliStrepSalmonellaVirusesCONFIDENTIALMolds

Process DefinitionCONFIDENTIAL27

Process DefinitionANSI/AAMI/ISO 11135:2014 Section 8.3oPerformed in development sterilizer or routine sterilizer. Section 8.6oBIs used: Shall be at least as resistant as product bioburden Be placed at worst case device locations, or placed within PCD.CONFIDENTIAL28

Customer Needs To DefineProductFamilies/ProcessingCategoriesFinalize PackagingLoad ConfigurationBioburdenCONFIDENTIALInternal PCD29

Customer Needs To DefineProduct Families Products shall be grouped into Families(collection of products determined to besimilar) Within a family, product representing“worst case sterilization challenge” may beselected as Internal PCD and used toevaluate the delivered lethality by theprocessCONFIDENTIAL30

Customer Needs To DefineProduct Families Different product families can be included in acommon EO cycle (e.g. processing category) evenif families are dissimilar in the details If including multiple Product Families in the sameEO cycle, then most resistant internal PCD amongall families should be used to ultimately developthe cycleCONFIDENTIAL31

Customer Needs To DefineFinalize Packaging and Load Configuration Finalize PackagingoPrototype Design is not advised Product packaging includes;oCorrugate, box thicknessoPouching materials (Tyvek)oSingle, Double pouching.oPacking count (quantity/box) Load ConfigurationoStacking pattern of shippers on the palletoDensity of loadoSecuring products on the pallet (e.g. Banding, wrapping)CONFIDENTIAL32

Customer Needs To DefineProcess Challenge Device (PCD)Item designed to constitute a defined resistance to the sterilization process and used toassess performance of the process Internal PCD (IPCD) External PCD (EPCD) Master PCD (MPCD)CONFIDENTIAL

Customer Needs To DefineInternal PCDBI disc in grommetCONFIDENTIAL34

Overview of External PCDExternal Process Challenge DevicesAlso known as:EPCDsTest PacksHere is an example of a processedpallet (arrow shows External PCD)External PCDCONFIDENTIAL35

Next StepsDesign Proposedcycle parametersUse design inputsgathered fromcustomerCONFIDENTIAL36

Fractional RunsANSI/AAMI/ISO 11135:2014, section 8.6Also known as ‘sublethal’“Process in which exposure time is reduced compared to thatspecified in the sterilization process”CONFIDENTIAL37

Fractional RunsDuring execution of Fractional Runs Appropriateness of BI vs Bioburden [NPRT] Cycle Development Definition of IPCD Comparison of IPCD’s Relative Resistance Test Pack Development [IPCD v EPCD]CONFIDENTIAL38

Fractional RunsHierarchy requiredExternal PCDInternal PCDProduct BioburdenCONFIDENTIAL39

Fractional RunsDefine Half Cycle Gas Dwell Time Provide full kill of Internal PCD You can allow BI positive in the External PCD during the Half-Cycle but Half-Cycle dwelltime must not be too short where External PCD positives can occur in projected FullCycle (routine processing)CONFIDENTIAL40

Fractional RunsD10 ValueTime required to achieveinactivation of 90% of apopulation of the testmicroorganism under statedconditions 90% reduction 1 log10reductionCONFIDENTIAL

Fractional RunsSterility Assurance Level (SAL) Probability of a single viable microorganism occurring onan item after sterilizationIs a quantitative value, generally 10-6– A probability of less than one-in-millionCONFIDENTIAL

Validation of an EO cyclePerformance QualificationCONFIDENTIAL43

Performance QualificationISO 11135:2014 PQ consists of both microbiological and physical performance qualification and isperformed in the equipment used to sterilize the productoMicrobiological Performance Qualification (MPQ) andoPhysical Performance Qualification (PPQ) Operationally these are referred to as the half and the full cycles, respectivelyCONFIDENTIAL

What is a “Half Cycle?”Compared to the normal type of cycle that you will run in routine production,the “Half cycle” uses one-half of the EO gas exposure timeRoutine cycleHalf cycle4 hours2 hoursof gasexposureof gasexposureCONFIDENTIAL

Why do we run a Half cycle?To confirm BI lethalityDemonstrate total inactivation of a106 BI at a Half-cycle exposuretime. When exposure time isdoubled, a minimum 12 SLR isdelivered during a Full-cycle EOexposure.CONFIDENTIAL

AAMI TIR 16: 2009 section 5.1.1“A typical performance qualification requires three consecutivesuccessful validation cycles to demonstrate reproducibility the firsttime the cycle is validated. The first successful cycle indicates that theproposed cycle lethality is achievable. The second successful cycleindicates that the cycle can be repeated successfully, while the thirddemonstrates reproducibility.”CONFIDENTIAL

Half Cycles Preconditioning time should be less than routine (full cycle) time Chamber settings should be sub-nominal for at least one parameter (worst-case)oTemperatureoHumidityoPressure / Gas ConcentrationoTime (Gas Exposure)CONFIDENTIAL

Half Cycles Run Half Cycles using the parametersestablished during Cycle Development. Place BI samples and sensors according to theprotocol The number of Biological Indicators andtemperature/humidity sensors required isdefined in ISO 11135:2014CONFIDENTIAL

Full Cycles Run three Full Cycles using parameters which will represent routine processing Place samples and sensors according to the protocol Full Cycles will evaluate:oAeration/EO ResiduesoProduct functionality/package integrityoAt least 1 cycle should contain sensorsCONFIDENTIAL

Full Cycles Aeration Requirements/EO ResiduesoDevelop dissipation curve to establish release time Qualify release time based on three (3) separate cycles Allowable residue limits are based on intended use of productCONFIDENTIAL

Summary Regulatory overviewoMany Standards involved. Several have been recently updated. Ethylene Oxide SterilizationoHow the EO process works Process DefinitionoHow to define your sterilization process Performance QualificationoHow to validate your sterilization processoConfirmation of Steriliy Assurance LevelCONFIDENTIAL

Thanks for listening

ISO/TS11135-2:2008 –Sterilization of health care products –Ethylene Oxide Guidance on the application of ISO11135-1 ISO11135:2014 –Sterilization of health care products –Ethylene Oxide Requirements for development, validation and routine control of a sterilization process for medica

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