International Standards for Radiation Sterilization of

Medical Devices

ArnArnee

MillerMillerRisRisøø

National LaboratoryNational Laboratory

Technical University of DenmarkTechnical University of DenmarkDK 4000 DK 4000 RoskildeRoskildeDenmarkDenmark

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Sterilization of Medical DevicesSterilization of Medical Devices

Medical Device Directive Medical Device Directive 93/42/EEC93/42/EECHas been implemented for CE marking in national legislation Has been implemented for CE marking in national legislation since 1998. since 1998. A new Medical Device Directive was issuedA new Medical Device Directive was issued12 October 2007: 2007/47/EC12 October 2007: 2007/47/EC

It amends the old directive It amends the old directive It must be implemented in national laws by end of 2008It must be implemented in national laws by end of 2008Manufactures must comply by March 2010Manufactures must comply by March 2010

Nothing is changed with respect to sterilizationNothing is changed with respect to sterilization

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Sterilization of Medical DevicesSterilization of Medical Devices

Medical Device Directive Medical Device Directive 93/42/EEC 93/42/EEC -- 2007/47/EC2007/47/EC

Essential requirements must be fulfilled in order for CEEssential requirements must be fulfilled in order for CE--marking of products marking of products Annex 1: Essential requirementsAnnex 1: Essential requirements8.48.4::

““Devices delivered in a sterile state must have been Devices delivered in a sterile state must have been manufactured and sterilized by an appropriate, validated manufactured and sterilized by an appropriate, validated method.method.””

How to comply with essential requirements? How to comply with essential requirements?

Follow mandated standardsFollow mandated standards

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The old standardsThe old standardsEN 552:1995EN 552:1995 Sterilization of Medical devices Sterilization of Medical devices ––Validation and Process control of Sterilization by Validation and Process control of Sterilization by IrradiationIrradiation..

CEN/TC 204 Sterilization of Medical DevicesCEN/TC 204 Sterilization of Medical Devices

ISO 11137:1996ISO 11137:1996 Sterilization of Health Care Sterilization of Health Care Products Products –– Requirements for validation and routine Requirements for validation and routine control control –– Radiation sterilizationRadiation sterilization..

ISO/TC 198 Sterilization of Health Care ProductsISO/TC 198 Sterilization of Health Care Products

EN 556EN 556--1:2001 1:2001 Sterilization of medical devices Sterilization of medical devices --Requirements for medical devices to be designated Requirements for medical devices to be designated 'STERILE' 'STERILE' -- Part 1: Requirements for terminally Part 1: Requirements for terminally sterilized medical devicessterilized medical devices

CEN/TC 204 Sterilization of Medical DevicesCEN/TC 204 Sterilization of Medical Devices

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The new standardThe new standard

EN ISO 11137:2006 Sterilization of health care EN ISO 11137:2006 Sterilization of health care products products –– RadiationRadiation

-- has replaced the two old standardshas replaced the two old standards

When the standard is followed, compliance with EU When the standard is followed, compliance with EU Medical Device Directive is presumedMedical Device Directive is presumedThe standard is accepted as an American standardThe standard is accepted as an American standardThe standard is accepted worldwideThe standard is accepted worldwide

EN 556EN 556--1:2001 1:2001 Sterilization of medical devices Sterilization of medical devices -- Requirements for medical devices to be Requirements for medical devices to be

designated 'STERILE' designated 'STERILE' --

Part 1: Requirements for Part 1: Requirements for terminally sterilized medical devicesterminally sterilized medical devices

66

EN 556EN 556--11

EN 556EN 556--1:2001 1:2001 Sterilization of medical devices Sterilization of medical devices --

Requirements for Requirements for medical devices to be designated 'STERILE' medical devices to be designated 'STERILE' --

Part 1: Requirements for Part 1: Requirements for

terminally sterilized medical devicesterminally sterilized medical devices

Requirement:Requirement:

For a terminally sterilized medical device to be designated For a terminally sterilized medical device to be designated ””STERILESTERILE””, , the theoretical probability of there being a viable microthe theoretical probability of there being a viable micro--organism organism present on/in the device shall equal to or less than 1 x 10present on/in the device shall equal to or less than 1 x 10--66..

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Standards providing background for Standards providing background for new EN ISO standardnew EN ISO standard

ISO 9001:2000, ISO 9001:2000, Quality management systems Quality management systems ––RequirementsRequirements

ISO 13485ISO 13485 Medical devices Medical devices -- Quality Quality management systems management systems -- Requirements for Requirements for regulatory purposesregulatory purposes

ISO 14937 ISO 14937 Sterilization of medical devices Sterilization of medical devices --General requirements for characterization of a General requirements for characterization of a sterilizing agent and the development, validation sterilizing agent and the development, validation and routine control of a sterilization process for and routine control of a sterilization process for medical devicesmedical devices

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Other standards that are incorporated Other standards that are incorporated into the new ISO EN standardsinto the new ISO EN standards

ISO/TR 15843 Product families, ISO/TR 15843 Product families, dose audit frequency and dose dose audit frequency and dose audit sample sizesaudit sample sizes

ISO/TR 15844 Radiation ISO/TR 15844 Radiation sterilization of one batchsterilization of one batch

AAMI TIR 27 VDAAMI TIR 27 VDmaxmaxsubstantiationsubstantiation ofof 25 kGy25 kGy

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EN ISO 11137:2006EN ISO 11137:2006

Three Parts:Three Parts:

Part 1: Part 1: Requirements for the development, Requirements for the development, validation and routine control of a validation and routine control of a sterilization process for medical devicessterilization process for medical devices

Part 2: Establishing the sterilization dose Part 2: Establishing the sterilization dose

Part 3: Guidance on Part 3: Guidance on dosimetricdosimetric aspectsaspects

Covers gamma, electron beam and xCovers gamma, electron beam and x--rayray

It is in principle limited to medical devicesIt is in principle limited to medical devices-- but can be used for other productsbut can be used for other products

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EN ISO 11137EN ISO 11137--11

ContentContent1 Scope1 Scope2 References2 References3 Terms and definitions3 Terms and definitions4 Quality management system4 Quality management system5 Sterilizing agent characterization5 Sterilizing agent characterization6 Process and equipment characterization6 Process and equipment characterization7 Product definition7 Product definition8 Process definition8 Process definition9 Validation9 Validation10 Routine monitoring10 Routine monitoring11 Product release11 Product release12 Maintaining process effectiveness12 Maintaining process effectiveness

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EN ISO 11137EN ISO 11137--11

ValidationValidation

Definitions 3.37: Definitions 3.37: documented procedure for obtaining, documented procedure for obtaining, recording and interpreting the results recording and interpreting the results required to establish that a process will required to establish that a process will consistently yield product complying with consistently yield product complying with predetermined specifications. predetermined specifications.

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EN ISO 11137EN ISO 11137--11

ValidationValidation

Definitions 3.37: Definitions 3.37: documenteddocumented66

procedureprocedure55

for obtaining, for obtaining,

recording and interpreting the results recording and interpreting the results required to establish that a required to establish that a processprocess22

will will

consistentlyconsistently44

yield yield productproduct11

complying with complying with predetermined predetermined specificationsspecifications33. .

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EN ISO 11137EN ISO 11137--11

ValidationValidationInstallation Qualification Installation Qualification -- IQIQ

Agreement supplier Agreement supplier –– customercustomer

Operational Qualification Operational Qualification -- OQOQshow consistent operationshow consistent operation

Performance Qualification Performance Qualification -- PQPQspecify how product shall be irradiatedspecify how product shall be irradiated

Routine Process ControlRoutine Process Controlshow that the process runs within specificationsshow that the process runs within specifications

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EN ISO 11137EN ISO 11137--1 Requirements1 Requirements

Documentation is in all steps based on Documentation is in all steps based on ability to measure doseability to measure doseSect. 4.3.4:Sect. 4.3.4:

““Dosimetry used in the development, Dosimetry used in the development, validation and routine control of the validation and routine control of the sterilization process shall have sterilization process shall have measurement traceability to national or measurement traceability to national or international standards and shall have a international standards and shall have a known level of uncertainty.known level of uncertainty.””

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EN ISO 11137EN ISO 11137--1 Requirements1 Requirements

Documentation in all steps based on Documentation in all steps based on ability to measure doseability to measure doseSect. 4.3.4:Sect. 4.3.4:

““Dosimetry used in the development, Dosimetry used in the development, validation and routine control of the validation and routine control of the sterilization process sterilization process shallshall have have measurement traceability to national or measurement traceability to national or international standards and international standards and shallshall have a have a known level of uncertainty.known level of uncertainty.””

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ISO 11137ISO 11137--1 Requirements1 Requirements Revision issues 1Revision issues 1

The use of Biological IndicatorsThe use of Biological Indicators••

and Tests and Tests forfor Sterility are not requiredSterility are not required

Sterilizing agent characterizationSterilizing agent characterization•• Radiation energy levels are Radiation energy levels are not restrictednot restricted. .

--

but assessment is but assessment is required required for potentially for potentially induced radioactivity at energy levelsinduced radioactivity at energy levels

higher higher

than 5 than 5 MeVMeV

xx--rays and 10 rays and 10 MeVMeV

electronselectrons

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ISO 11137ISO 11137--1 Requirements1 Requirements Revision issues 2Revision issues 2

Process and equipment characterizationProcess and equipment characterization

Product definitionProduct definitionProcessing categoriesProcessing categoriesGrouping for processingGrouping for processing

Process definitionProcess definitionEstablishing the maximum acceptable doseEstablishing the maximum acceptable doseEstablishing the sterilization doseEstablishing the sterilization dose

detailed in 11137detailed in 11137--22

Transference of established dosesTransference of established dosesbetween between ““similarsimilar”” facilities: No additional testingfacilities: No additional testing

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ISO 11137ISO 11137--1 Requirements1 Requirements Revision issues 3Revision issues 3

Product release Product release taking into account the uncertainty of the taking into account the uncertainty of the measurement systemmeasurement system

Maintaining process effectivenessMaintaining process effectivenessFrequency of bioburden determinationFrequency of bioburden determination

Quarterly (generally)Quarterly (generally)

Frequency of sterilization dose auditsFrequency of sterilization dose auditsQuarterly Quarterly →→ bibi--annually annually →→ annuallyannually

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ISO 11137ISO 11137--1 Requirements1 Requirements Revision issues 4Revision issues 4

GuidanceGuidanceFormat of EN 552 followed with guidance Format of EN 552 followed with guidance

for each sectionfor each sectionAnnex AAnnex A

Includes tables on recommended IQ / Includes tables on recommended IQ / OQ actions for facilities OQ actions for facilities

2020

ISO 11137ISO 11137--2 2 Establishing the Sterilization DoseEstablishing the Sterilization DoseRevision Issues 1Revision Issues 1

1.1. Product FamiliesProduct Familiesdefinition and maintenancedefinition and maintenancegrouping for bioburden, dose establishment grouping for bioburden, dose establishment and dose auditsand dose audits

2.2. Designation of product to Designation of product to represent familyrepresent family

master master equivalentequivalentsimulatedsimulated

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Revision Issues 2Revision Issues 23.3. Method 1 Method 1

change in table to reflect whole bioburden change in table to reflect whole bioburden numbersnumbersincluded table for bioburden 0.1 to 1.0 included table for bioburden 0.1 to 1.0 cfucfusingle batch proceduresingle batch procedure

4.4. Method 2 Method 2 remains essentially unchangedremains essentially unchanged

ISO 11137ISO 11137--2 2 Establishing the Sterilization DoseEstablishing the Sterilization Dose

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Revision Issues 3Revision Issues 35.5.

VDVDmaxmax

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Substantiation of 25 kGySubstantiation of 25 kGymethodmethod is based upon VDis based upon VDmaxmax

bioburden bioburden ≤≤ 1,000 1,000 cfucfu/product/product

single batchsingle batch procedureprocedure

6.6.

VDVDmaxmax

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Substantiation of 15 kGySubstantiation of 15 kGymethodmethod is based upon VDis based upon VDmaxmax

bioburden bioburden ≤≤ 1.5 1.5 cfucfu/product/productsingle batch proceduresingle batch procedure

ISO 11137ISO 11137--2 2 Establishing the Sterilization DoseEstablishing the Sterilization Dose

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Revision Issues 4Revision Issues 4Dose auditDose audit

audit procedures expanded and clarifiedaudit procedures expanded and clarifieddose augmentation expandeddose augmentation expanded

allow processing to continue in case of dose audit allow processing to continue in case of dose audit failurefailure

ISO 11137ISO 11137--2 2 Establishing the Sterilization DoseEstablishing the Sterilization Dose

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ISO 11137ISO 11137--3 3 Guidance on Guidance on DosimetricDosimetric

AspectsAspects

Specific guidance on dosimetry as Specific guidance on dosimetry as used in parts 1 and 2used in parts 1 and 2

ReferenceReference

to ISO/ASTM standards to ISO/ASTM standards onon

Dosimetry for Radiation Dosimetry for Radiation

ProcessingProcessing

AnnexAnnex

A:A:

MathematicalMathematical

modellingmodellingPoint Point KernelKernelMonteMonte

CarloCarlo

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ISO 11137ISO 11137--3 3 Guidance on Guidance on DosimetricDosimetric

AspectsAspectsISO/ASTMISO/ASTM

standards standards onon

Dosimetry for Radiation Dosimetry for Radiation

ProcessingProcessing

Presently 31 standards and guides Presently 31 standards and guides Dosimetry systemsDosimetry systems

AlanineAlanineCalorimetersCalorimetersetcetc

Dosimetry methodsDosimetry methodsCharacterization of gamma plantsCharacterization of gamma plantsCharacterization of electron acceleratorsCharacterization of electron acceleratorsDose mappingDose mappingetcetc

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ISO 11137ISO 11137--3 3 Guidance on Guidance on DosimetricDosimetric

AspectsAspectsIssues:Issues:

Dosimeter calibrationDosimeter calibration

Guidance on practical use of dosimetryGuidance on practical use of dosimetry

Application of measurement uncertainties.Application of measurement uncertainties.

Use of statistical evaluation of PQ dose Use of statistical evaluation of PQ dose map data.map data.

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Present statusPresent status

ISO standards published April ISO standards published April 20062006EN standards parts 1 and 3 EN standards parts 1 and 3 published April 2006published April 2006

Errors discovered in part 2Errors discovered in part 2

Revised ISO 11137Revised ISO 11137--2:20062:2006EN ISO 11137EN ISO 11137--2:20072:2007