2. Good management Processing record Qualified and experienced operators Quality Manual  A Radiation processing facility should have the following vital components

3. Processing record Should contain information of  Reception and inspection of product  Unique code identifying each product  Storage environment  Scheduling the irradiation  Loading the product onto the irradiator system  Unloading the irradiated product from the system  Inspection  checking of routine dosimetry, process parameters  Sign-off of any non-conformances  Approval for release and dispatch  Dispatch to the customer

4. Specifications of the process  The product covered by the specification  The product pattern and relationship between dose at the monitoring position and the dose at the maximum and minimum dose position  The routine dosimeter monitoring position(s)  For gamma irradiation, the relationship between product density, dose and source strength  For electron beam, the relationship between characteristics, conveyor speed, product configuration and dose

5. Description of the product  The dimensions and density of package  A description of the irradiation container  A description of the conveyor path

6. Process Control Receipt and inspection of the product Product Storage Product Processing Post irradiation Inspection Routine Dosimetry Product Release

7. Receipt and inspection of the product  Check for any obvious signs of damage.  Check that the identity of the product matches the description in the documentation  Check that the amount of material to be irradiated matches with the amount described in the paperwork (purchase orders or delivery note).  Check the product that has been sent for routine irradiation has been validated for that process.

8. Product Storage  Store unirradiated product in an area isolated from any irradiated product.  Physical separation such as barrier is most appropriate.  Keep storage conditions appropriate for the product being irradiated  Pest control if required  Record the storage environment as a part of the processing records for the product

9. Product Processing

10. Product processing-Documentation  Document should be maintained for each consignment of product and it should be signed off at each stage of processing through the irradiator for  Reception and inspection of product  Scheduling the irradiator  Loading the product onto the irradiator system  Unloading the irradiated product form the system  Final inspection including checking of routine dosimetry and other stored process parameters  Recording of any non-conformances  Approval for release and dispatch  Dispatch to the customer or their courier.

11. Product loading for irradiation  Use approved loading configurations specified in approved and documented procedures  Place controlled identification labels location date of processing, Unique codes identifying the irradiation conditions and batch/lot numbers.

12. Use of Radiation sensitive indicators  Radiation sensitive indicators may be used to show that the product containers have been irradiated.  Radiation sensitive indicators should be used as only qualitative indicators of irradiation.  Routine dosimetry of each and every run is essential in order to certify the dose to the product.

13. Placement of Routine dosimeters  Place routine dosimeters at predetermined routine monitoring position  Place routine dosimeters at least at the beginning, end of an irradiation lot, in order that it may be demonstrated that the irradiation process was under control  The frequency of dosimeter placement should be sufficient to verify that the process is in control.

14. For Gamma Irradiator  Dosimeters are typically placed at the beginning and at the end of each run of a particular processing category.  Additionally, dosimeters may be placed so at least one dosimeter is within the irradiator cell at all times.

15. For Electron beam irradiator  Dosimeters are typically placed at the beginning and at the end of each run of a particular category utilizing a specific set of processing parameters.

16. Bulk-flow irradiators  For fluids and grains continuously flow during irradiation, add several dosimeters to the product stream at the beginning and during the production run.  From the statistical distribution of the dose measurements, the absorbed dose is estimated with statistical confidence.

17. Product Processing  Process control  Process interruptions  Dose monitoring  Analysis

18. Process control For gamma irradiators,  Record date and time of processing  Set the operating parameters as established duringprocess qualification  Control and record the dwell time and conveyor speed of the product

19. Process control For Electron Beam irradiators,  Record date and time of processing  Set the operating parameters as established during process qualification  Measure and record machine variables beam current scan width conveyor speed Beam energy

20. Process interruptions  If the parameters deviate outside the processing limits prescribed from process qualification, interrupt the process to evaluate and correct the cause of the deviations  Effect on the quality of the product

21. Dose monitoring  The dose measurements at the routine monitoring position provides a measure of the process that is independent of any other control or measurement system of the irradiator.  The minimum frequency of dose measurement should be chosen based on the particular requirement of the irradiator or process

22. Separate location for irradiated product  The identification as irradiated may best be achieved by ensuring that product is unloaded from an irradiator to a separate location from the one which is used for unirradiated product. This, together with the use of unique identification labels, ensures a full trail of traceable records for the product.

23. Routine Dosimetry

24. Dosimetry  The key quantity that determines the process is the absorbed dose.  Dosimeters are the devices that are capable of providing a quantitative and reproducible measurement of dose.  Various dosimetry techniques are available for measuring absorbed dose in a quantitative manner.  Relevant ISO/ASTM standard practices and guides are available for dosimetry in radiation processing facilities

25. Dose Measurement It has to be demonstrated that  Dose measurement is traceable to a national or international standard.  The uncertainty of measurement is known.  The Influence of temperature, humidity and other environmental considerations on dosimeter response is known and taken into account

26. Dosimetry Standards – Measurement ASTM E2628 “Standard Practice for Dosimetry in Radiation Processing” ASTM E2701 “Standard Guide for Performance Characterization of Dosimeters and Dosimetry Systems for Use in Radiation Processing” ISO/ASTM 51261 “Standard Guide for Selection and Calibration of Dosimetry Systems for Radiation Processing” ISO/ASTM 51707 “Standard Guide for Estimating Uncertainties in Dosimetry for Radiation Processing”

27. Dosimetry Standards - Application ISO 11137-3:2006 “Sterilization of health care products – Radiation – Part 3:Guidance on dosimetric aspects” ASTM E2303 “Standard Guide for Absorbed Dose Mapping in Radiation Processing Facilities” ISO /ASTM 51608 “Standard Practice for Dosimetry in an X-ray (Bremsstrahlung) Facility for Radiation Processing” ISO/ASTM 51649 “Standard Practice for Dosimetry in an Electron BeamFacility for Radiation Processing at Energies Between 300 keV and 25MeV” ISO/ASTM 51702 “Standard Practice for Dosimetry in Gamma Irradiation Facilities for Radiation Processing”

28. Dosimetry Standards - individual dosimetry system ISO/ASTM 51205 Practice for Use of a Ceric-Cerous Sulfate Dosimetry System ISO/ASTM 51275 Practice for Use of a Radiochromic Film Dosimetry System ISO/ASTM 51276 Practice for Use of a Polymethylmethacrylate Dosimetry System ISO/ASTM 51310 Practice for Use of a Radiochromic Optical Waveguide Dosimetry System ISO/ASTM 51401 Practice for Use of a Dichromate Dosimetry System ISO/ASTM 51538 Practice for Use of the Ethanol- Chlorobenzene Dosimetry System

29. Dosimetry Standards - individual dosimetry system ISO/ASTM 51540 Practice for Use of a Radiochromic Liquid Dosimetry System ISO/ASTM 51607 Practice for Use of the Alanine-EPR Dosimetry System ISO/ASTM 51631 Practice for Use of Calorimetric Dosimetry Systems for Electron Beam Dose Measurements and Dosimeter Calibrations ISO/ASTM 51650 Practice for Use of Cellulose Acetate Dosimetry Systems ISO/ASTM 51956 Practice for thermoluminescence Dosimetry (TLD) Systems for Radiation Processing ASTM E1026 Practice for Using the Fricke Reference Standard Dosimetry System ASTM E2304 Practice for Use of a LiF Photo-Fluorescent Film Dosimetry System

30. Dosimetry Standards - any process deviation ISO/ASTM 51707 Guide for Estimating Uncertainties in Dosimetry for Radiation Processing ASTM E2232 Guide for Selection and Use of Mathematical Methods for Calculating Absorbed Dose in Radiation Processing Applications

31. Analysis of the dose measurement  Dosimetric measurements are subject to sizeable uncertainties  Calibration of the dosimetry system  Reproducibility of individual dosimeters  Reproducibility of the positions of dosimeters in dose mapping experiments, and of the product being irradiated near those dosimeters;  Stability of the irradiator (beam current, beam energy, scanning width, conveyor speed for electron beams; variations in tote properties for gamma irradiators, or in positioning of product within the totes, for gamma irradiators)  Effects of influence quantities such as temperature, humidity, dose rate, time between irradiation and measurement the dosimeters.

32. For a controlled process  For a process under control, the measured values of the routine dose will be distributed statistically about a target dose value.  Use statistical process control techniques to confirm that the process delivered to the product meets the conditions established during the validation exercise.

33. The irradiated product  The radiation process is mainly governed by the minimum absorbed dose achieved in the dose distribution within a given product.  If the required minimum is not applied, the intended effect may not be achieved.  There are also situations where high dose would damage the quality of the product

34. Post irradiation inspection

35.  Inspect if the product suffered any damage as a result of the process Irradiation damage (discoloring as a result of a significant overdose) Machine damage (tearing of the cartons on the irradiation conveyor system)  Examine and report routine dosimetry results  If any product cartons suspected of receiving a non-conforming process are stored in the segregated area, isolated from the rest of the product.

36. Post irradiation inspection  Any cartons identified from the irradiation records as having had a non-conforming irradiation (for example, with interruption to the process) should be held and only released once investigations have confirmed the process was under control.  Routine dosimetry obtained along with records of the machine variable during the irradiation process are compared with expected and validated range.

37. Non Conforming product As a result of  Routine dosimetry measurement indicating the process was not correct  Evident damage to the carton.

38. Product Release

39. PRODUCT RELEASE Once the product, irradiation process records including routine dosimetry, and other records from the manufacturing process have been approved as conforming to the requirements, the product may be released.

40. References  Guidelines for the Development, Validation and Routine Control of Industrial Radiation Process. IAEA Radiation Technology Series No.4 (2013)  Trends in radiation Sterilization of Health Care Products. IAEA, STI/PUB/1313 (2008)  ISO 11137:2006 “Sterilization of Healthcare Products – Radiation” Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices Part 2: Establishing the sterilization dose Part 3: Guidance on dosimetric aspects