Risk Mitigation And Regulatory Compliance With Gamma .
Risk Mitigation and RegulatoryCompliance with GammaSterilizationCarlo CoppolaDirector, Gamma Centre of ExcellenceJune 10, 2014www.nordion.com Nordion (Canada) Inc. All rights reserved 2014
Why are we here today? Ensure that products are safe and effective forpatients2
Section 1 – Assurance of Sterilitythrough Dose and Dosimetrywww.nordion.com
Gamma Sterilization Mechanism4
Minimum Dose for Sterility Verification testing Sterility Assurance Level (SAL) Microbiological Controls5
Maximum Dose for Functionality Radiation resistance of materials Product testing to determine or establishmaximum dose6
Risk Mitigation with Gamma Terminal sterilization process Provides overkill No residuals Process Reliability7
How does Gamma work?8
Dose Distribution Distribution of dosethrough the productstack Dose ratio (DUR)depends on stack size,density and irradiatordesign9
Dose DistributionDose from both passesDose from second passDose from first pass10
The role of dosimetry Dosimetry measures dose– Operational Qualification– Product mapping– Routine monitoring Dosimetry is the link between your gammaprocess and sterilization11
The role of dosimetry Dosimetry makes sure that minimum dose is metand maximum dose is not exceeded What happens if calibration is wrong? What happens if mapping incomplete?STERILEDAMAGE12
Section 2 – RegulatoryRequirementswww.nordion.com
ANSI/AAMI/ISO 11137-1 ANSI/AAMI/ISO 11137-1 describes therequirements for the development, validationand routine control of a sterilization processusing radiation14
Setting up a radiation process Dosimetry The role of dosimetry– ISO/ASTM 52628, Standard Practice for Dosimetry inRadiation Processing– ISO/ASTM 52701, Guide for PerformanceCharacterization of Dosimeters and DosimetrySystems for Use in Radiation Processing– ISO/ASTM51702, Standard Practice for Dosimetry ina Gamma Facility for Radiation Processing15
Calibration Applicable FDA recognized standard– ISO/ASTM 51261, Practice for Calibration of RoutineDosimeters for Radiation Processing Calibration of a dosimetry system can beachieved through in-plant or laboratorycalibrations16
Dose Mapping – OperationalQualification What is OQ?– Demonstrate range of operation– Determine distribution and variability of dose– Effect of process interruptions Applicable FDA recognized standard– ASTM E2303, Standard Guide for Absorbed-DoseMapping in Radiation Processing Facilities17
Dose Mapping – OperationalQualification18
OQ Continued How many dosimeters are enough?– 28 per tote? DUR Measured was 1.53 Actual DUR was 1.5719
OQ Continued How many dosimeters are enough?– 85 per pallet?A4B4C4D4A3B3C3D3MA2B2C2D2A1B1C1D12D view from above DUR Measured 1.48 Actual DUR was 1.5220
OQ Continued How many dosimeters are enough?– 225 per pallet? Better 21
Picking the right number For first map:–5 across–3 deep–Every 10cm or 4” vertically Use knowledge from previous maps Use mathematical modeling22
OQ continued Process Interruptions–Need to quantify effect–Will be additive to both minimum andmaximum dose–Magnitude will depend on number of transits,location, amount of activity in source, type ofirradiator23
Dose Mapping – PerformanceQualification What is PQ?– PQ performed with product in a specific loadingpattern– Determine location and magnitude of min and maxdose– Determine relationship between min and max androutine monitoring position24
PQ Continued Choice of reference location PQ used to determineprocessing categories When do you have to re-doPQ?25
Routine Monitoring and Control What does AAMI/ISO 11137 tell us?– A routine dosimeter shall be used, measured andanalyzed, sufficient quantities to demonstrate processis in control Product release from sterilization must take intoaccount the uncertainty of the measurementsystem26
Process Monitoring andUncertainty What are components of overall uncertainty?– Measurement components: calibration, dosimeterplacement, influence quantities, measurement equipment,response variability– Mapping Uncertainties– Process variability – ability of irradiator to deliver consistentdose (captured in dose mapping replicates) Given PQ data tied into reference dosimeter, what rangeof values is acceptable?– Process aims for minimum dose plus uncertainty– DUR must allow for maximum dose minus uncertainty27
Example Dmin 25 kGy, Dmax 40 kGy PQ measurement shows:– DUR 1.30– Ratio(min) 0.90– Ratio(max) 1.17 Overall Uncertainty 6% Set process– Process target minimum range 25*1.06 26.5 kGy– Process target maximum 40*0.94 37.6 kGy For perfect process, Dref 29.4 to 32.1, expect to seesome between 27.8 and 29.4 and some 32.1 to 34.228
Requalification/Assessment ofchange Changes that may affect dose or distributionshould be assessed. May mean IQ, OQ and/orPQ repeated. Change in product needsassessment and may require PQ. In the ABSENCE of OQ, PQ must be done withevery loading29
Understanding Risk Mitigation through use of standards As the medical device manufacturer, you areresponsible for demonstrating process validation Work with your contract sterilizer Document everything30
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Questions?Thank you!32
ANSI/AAMI/ISO 11137-1 ANSI/AAMI/ISO 11137-1 describes the requirements for the development, validation and routine control of a sterilization process using radiation . 15 Setting up a radiation process - Dosimetry The role of dosimetry –IS
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