1. Irradiator Specification Installation Qualification (IQ) + Software validation Operational Qualification (OQ) Performance Qualification (PQ) Demonstrate irradiator specifications are met (installation in accordance with agreed upon specifications between vendor and operator of the irradiator) Gamma No dosimetry Examples: sources installed, Source rack moves properly, conveyance E-beam Characterisation of beam Characterize dose delivery of the Irradiator under baseline conditions: Dose magnitude, distribution and reproducibility Gamma 1)Fully loaded irradiator with single density 2)Mixed densities in the irradiator 3)Incomplete load configurations 4)Process interruptions E-beam 1)Surface dose profile 2)Dose distribution (3 dimensions) 3)Dose versus process parameters 4)Process interruptions Establish process for irradiation of product within predescribed limits Process specification

2. Installation Qualification of electron beam irradiator Characterisation of the electron beam  Position and shape of the beam spot (ensure product surface is covered) Position and shape of the beam spot  Electron energy Electron energy  Scan width and uniformity Scan width and uniformity  Beam current Involve dosimetry Methods in ISO/ASTM 51649 Note: beam profile needs to be characterised at multiple distances from the conveyor

3. electrons EXAMPLE: Beam width characterisation; Setpoint 60 cm 77 cm 59 cm 32 cm Mark with pen at distance 25 cm (so peak not related to dose delivery)

4. electrons 77 cm 32 cm EXAMPLE: Beam spot characterisation Mark with pen (so peak not related to dose delivery)

5. EXAMPLE E-Beam energy measurement electrons Based on descending slope energy can be calculated (ASTM51649) Al

6. Operational Qualification of Gamma irradiator 1)“Standard operating conditions” i.e. Irradiator filled to design capacity with a single product density 2) “At or beyond Standard operating conditions” of the irradiator  At least 2 different runs, each with a different density (“low” and “high”)  At least 3 irradiation containers in each run  3-dimensional dosimeter grid DUR as function of density (compare with specification) Min and Max dose zone identified as function of density Dose distribution study Dose magnitude study (scalability with timer setting) Variability of dose delivery Impact of density mixing on Dose magnitude and distribution Incompletely filled irradiation containers Process interruptions Compare results With those of 1) Dose rate as function of density (throughput, compare with specification) In the same run or even in the same irradiation container

7. Transition Dose Map:  Low density (or empty) followed by high density loads  1st and last dose map  Compare to homogeneous map Partial Load Map:  May use compensating dummy to center load product  Map at maximum dose locations and compare to fully loaded adjacent containers. Transition Dose Map:  Low density (or empty) followed by high density loads  1st and last dose map  Compare to homogeneous map Partial Load Map:  May use compensating dummy to center load product  Map at maximum dose locations and compare to fully loaded adjacent containers. Low density (or empty as worst case) followed by high density Dose map at least their interfase

8. Partially filled irradiation container Dose map their interfase

9. Process interruption  Cycle source between fully up and fully down (multiple times)  Single material  Irradiation container adjacent to the source plane  Response of dosimeter might be influenced by fractionated exposure

10. Operational Qualification of electron beam irradiator 1)“Standard operating conditions” i.e. Irradiator filled to design capacity with a single product density 2) “At or beyond Standard operating conditions” of the irradiator  At least 1 run  At least 3 irradiation containers in each run  3-dimensional dosimeter grid DUR (as function of density) Min and Max dose zone identified as function of density Dose distribution study Dose magnitude study (scalability with process parameters) Variability of dose delivery Surface dose mapDemonstrate whole surface is effectively irradiated Process interruption study All scenarios for interruption need to be included in the test program For all pathways (single – double sided exposure, different beam energy) Edge effectsEdge effectsProduct irradiated as a single entity

11. EXAMPLE: Dose versus process parameters at an electron beam facility

12. EXAMPLE: Dose distribution in reference product (double sided exposure) 40cm high 0.15 g/cc stack of homogeneous material 10 MeV electron beam

13. EXAMPLE: Dose distribution in reference product (single sided exposure) 0.15 g/cc stack of homogeneous material 10 MeV electron beam

14. Process interruption study  Location closest to the scanhorn  1-dimensional dosimeter strip in direction of product conveyance  Response of dosimeter might be influenced by fractionated exposure  Test all possible sources of interruptions e.g. Accelerator, conveyor, safety, electrical  Parameters at the extremes of operating conditions EXAMPLE: Accelerator interruption at maximum of conveyor speed

15. Performance Qualification, GOAL Determining dose delivery characteristics to product in a defined load configuration and for a specified process flow  Minimum and maximum dose zone determined  Variation of dose delivery characterized  Process capability for meeting specified dose range is assessed  Process monitoring practice established Acceptance criteria

16. Select a Product Load Configuration and a Process Flow Select a Performance Qualification dosimeter grid Product Dose Requirements Irradiator Operational Qualification Processing Efficiency Operational Qualification Dose Distribution Characteristics Additional Locations to Account for Product Heterogeneity Product Load Configuration / Orientation (partial fill of irradiation container) Consider Routine Monitoring Practices Performance Qualification, METHOD Write protocol and get it approved by all parties Execute Analyse data Write report and get it approved by all parties

17. Process specification includes  Description of packaged product (dimensions, weight, orientation in shipper) and acceptable variations  Loading pattern in the irradiation container  Conveyor path, process flow including lead / trail product if required  Setpoints and tolerances on irradiator parameters  Dose range of the product  Temperature restrictions  Restrictions on time between end of manufacturing and completion of irradiaiton  Process monitoring position, frequency and acceptance criteria  Any required re-orientation for multiple exposure

18. Questions: -Do you have a signed record on file stating all the characteristics of the irradiator? -Have you during IQ / OQ verified characteristics of the irradiator as they are mentioned in that signed record with specifications? -Did PQ cover all scenarios of processing the product (partially filled cartons, partially filled irradiation containers,...) ? -Is the outcome of PQ detailed in a process specification? Is it sufficiently detailed and signed by contract irradiator and product manufacturer?

19. References: -IAEA Guidelines for development, validation and routine control of industrial radiation processes -ASTM 51649:2005 Practice for dosimetry in an electron beam facility for radiation processing at energies between 300 keV and 25 MeV -ASTM 2303:2003 Standard guide for absorbed dose mapping in radiation processing facilities -AAMI TIR 29:2012 Guide for process characterization and control in radiation sterilization of medical devices - ISO 11137 series