1、2023 Bio-Process Systems Alliance|bpsalliance.orgX X-ray ray SterilizationSterilization UpdateUpdateWednesday July 12,11:15-12:152023 Bio-Process Systems Alliance|bpsalliance.orgAgenda Part II White Paper Related Industry Activities Implementation Timelines Regulatory Perceptions&Feedback Leveraging

2、 Prior Knowledge,Physics Language,Communication Workshop Feedback Q&A2023 Bio-Process Systems Alliance|bpsalliance.orgX-Ray:Representative Qualification Data Part II X-ray paper now available Authors and Reviewers bpsalliance.org/resources/technical-guides/Please share the link,not the guide2023 Bio

3、-Process Systems Alliance|bpsalliance.orgX-Ray:Representative Qualification DataTemperature and ActivationAssessment(45 polymer formulations)Component Test Data&AssessmentMaterial Test Data&AssessmentsAssembly IntegrityNext Steps2023 Bio-Process Systems Alliance|bpsalliance.org https:/doi.org/10.101

4、6/B978-1-4831-9776-0.50007-3(1960!)Arthur Charlesbyhttps:/doi.org/10.1016/j.radphyschem.2022.110702(2023)Fermilab2023 Bio-Process Systems Alliance|bpsalliance.orgASTM E55/E61 Irradiation Workshop The objective of this workshop is to enhance the knowledge and understanding of the radiation process an

5、d critical requirements needed for the sterilization of components and finished products using radiation technologies Radiation Processing for the Pharmaceutical and BioPharmaceutical Industries Training Workshop()This workshop is powered by the ASTM E61 International Workshop on Radiation Processin

6、g but focused on and tailored for the individuals supporting the pharmaceutical and biopharmaceutical industriesRadiation Processing for the Pharmaceutical and BioPharmaceutical Industries Training Workshop,May 8-9,20232023 Bio-Process Systems Alliance|bpsalliance.orgBioPhorum Activities Physical,ch

7、emical,and biological impacts of the two irradiation methods are expected to be very similar&data exists to demonstrate equivalency based on physics and material compatibility with Gamma There is a risk of individual companies interpreting and approaching the change and submitting filing changes in

8、diverse ways No standardized industry guidance to inform evaluation,qualification/validation and documentation of the change2023 Bio-Process Systems Alliance|bpsalliance.orgBioPhorum ActivitiesAlternative to GammaSupply PartnerIntroduction of X-Ray Risk EvaluationDrug SubstanceDS Holding ContainerRe

9、g-XPerformed a Technical Risk Assessment on the Change of Sterilization(from Gamma to X-Ray Radiation)of the Drug Substance Holding BagThe output will be published as Appendix 3 to the Raw Material paper Developed Guidance to define the BioPhorum approach to risk evaluation of X-Ray irradiation for

10、sterilization of SUS defining key concepts and providing tools/templates to simplify proceduralizing the BPSA approach and which can be adapted to reflect each organizations own local quality system procedures Supply chain focus:developing an industry-wide validation package and change notification

11、process to introduce X-ray sterilization for SUS,alongside gamma irradiation,acceptable to regulators and customers.It is leveraging BioPhorum and BPSA best practice around change notification and regulatory QbD to support best practice across the industry.Pending publication:industry position state

12、ment to influence other reg authorities to follow FDA/EMA/PDMA standpoint on the introduction of x-ray.Work as part of a program of 3 cross-Phorum teams addressing different aspects of implementation of X-Ray 2023 Bio-Process Systems Alliance|bpsalliance.org Defining key concepts and providing tools

13、/templates to simplify proceduralizing the BPSA approach and which can be adapted to reflect each organizations own local quality system procedures TEAM DEVELOPED A METHOD FOR GLOBAL ASSESSMENT OF THE IMPLEMENTATIONBioPhorum Activities Harmonized industry approach mitigating risk of different approa

14、ches being reported to regulatory authorities Guidance on how to evaluate and categorize risk for SUS subject to the change from Gamma to X-Ray plus a spreadsheet with flexible,adaptable tools for documenting the evaluation and subsequent mitigations.2023 Bio-Process Systems Alliance|bpsalliance.org

15、CategoryTestReferencesAll Impact LevelsEquivalency Assessment Vendor Equivalency StatementVendor DocumentationPressure BurstManufacturer Defined,ISO 7241,ASTM D1599,EN 12266,ISO 1402IntegrityManufacturer defined,ASTM E515,ASTM D4991,ASTM 1003Tensile PullManufacturer definedTear ResistanceASTM D624,I

16、SO 34,ASTM D1938-14O2 and CO2 PermeabilityWVTR(water vapor transmission)ASTM F1249,ISO 15106Compression SetASTM D395,ISO 815HardnessASTM D2240,ISO 868ElongationASTM D412Tensile StrengthASTM D882,ISO 527Material ColorManufacturer definedGlass Transition TemperatureASTM D3418,ISO 11357-2Material by FT

17、IR-ATR(identification)Manufacturer definedISO 7241-2,ISO 3968,Manufacturer definedIEC60534-2-3.DIN EN 1267Accelerated Aging(Shelf Life)Manufacturer defined,ASTM F1980Particulate MatterUSP,ANSI/AAMI BF7,BPSA,EP2.9.19Kink Resistance/Bend RadiusManufacturer definedFilter IntegrityManufacturer definedBa

18、cterial RetentionASTM F838Bacterial Challenge/SoilingManufacturer defined,ANSI/AAMI BF7Sterilization Process CompatibilityManufacturer definedIrradiation ValidationANSI/AAMI/ISO 11137,AAMI TR33,CEN ISO/TS 13004Biological Reactivity-In VitroUSP,ISO 10993-5Biological Reactivity-In VivoUSP,ISO 10993-1,

19、6,10,11Cell Culture Toxicity/ComparabilityPGS/BRD definedChemical Process CompatibilityManufacturer defined,ASTM D543-14Extractables Manufacturer defined,USP moderate&high risk,BPOGPhysiochemical ContainerUSP EP/PhysiochemicalEP 3.1.xConductivityUSP pH ShiftUSP Total Organic Carbon(TOC)USP Animal Or

20、igin FreeEMA 410/01TSE BSE StatementEMA 410/01,EC 1774REACHEC/1907/2006RoHS2002/95/ECFood Contact21 CFR 177(2600,2400,1550,2510)System IntegrityManufacturer definedPackaging IntegrityASTM D4169,ASTM D4725,DIN ISO 2872,ISTA 2ATransportation ValidationASTM D4169,ASTM D4725,DIN ISO 2872,ISTA 2AImpact L

21、evels 2&3 OnlyBiologicalChemicalNo XI ImpactRegulatorySUSImpact Levels 1,2&3PhysicalASTM D3985,ASTM F1927,ISO 15105-2FunctionalWater Flow Rate and Pressure DropSterility&ProcessEstablished implementation cycleEstablished flowchart/decision treeDeveloped tools&templatesGUIDANCE FOR RISK EVALUATION OF

22、 X-RAY IRRADIATION OF SINGLE USE SYSTEMSDevelopment of Guidance&Tools2023 Bio-Process Systems Alliance|bpsalliance.orgX-ray Capacity for Pallet-Scale Irradiation Country Site TechnologyOpening dateSwitzerlandDanikenX G Eb2010NetherlandsVenloX-G2022ThailandChonburiX-G2023(Summer)USALibertyvilleX-G202

23、3(Sept/Oct)USAChesterX G Eb2024USAOntarioX G Eb2024GermanyRadebergX(2025)ChinaSuzhouX(2025)2023 Bio-Process Systems Alliance|bpsalliance.orgDemand,Capacity&Implementation12Contract Irradiation Capacity Bottle-Neck for Single-Use*2021 BPSA White Paper.X-ray Sterilization of Single-Use Bioprocess Equi

24、pment:Part I Industry Need,Requirements,and Risk Evaluation.Industry workgroups createdTimelines Integrators Pre-change Notification Issued Change Notifications Issued Pandemic changed SUS landscapeWe are hereImplementation Targets2023 Bio-Process Systems Alliance|bpsalliance.org WHO.Cross Industry

25、Team including BPSA members,BioPhorum members,BARDA,and SMEsFDA ETT(CDER led including active observers from CBER and EMA)EMA QIG(including observers from FDA)PMDA(Japan)WHAT.Engagement with Regulators to Align Expectations for X-ray Implementation Advocate for the tenets published in the 1st BPSA p

26、aper Share examples of representative data Risk assessment&implementation strategy for post-approval changes Understand any additional regulatory concernsRegulatory Perspectives&Feedback2023 Bio-Process Systems Alliance|bpsalliance.orgPost-Approval Change Reporting Categories2023 Bio-Process Systems

27、 Alliance|bpsalliance.org Specific Topics Addressed:Sterility assurance may be addressed via ISO 11137 Categorization of Changes.Post approval changes deemed to be low risk per the biomanufacturers,assessment may be seen as low risk on qualityWhat if gamma is mentioned in filing USP Moderate level t

28、esting may be acceptable to verify equivalence No outstanding concerns Annex 12(EMA specific):wording not impeding implementation Debriefs,Executive Summary,and Minutes Shared Key Alignment with Agencies&Industry 2023 Bio-Process Systems Alliance|bpsalliance.orgPrior Knowledge,Language&Communication

29、 Prior Knowledge Language Modality vs“Technology”Gamma vs“Ionizing radiation”Communication Radiation physics Materials Impact SUS Impact DS/DP Quality ImpactICH Q10“Photons deliver the dose”“there is no energy dependent difference between gamma,e-beam,and X-ray for radiation sterilization”“Electrons

30、 get the job done!”2023 Bio-Process Systems Alliance|bpsalliance.orgPrior Knowledge,Language&CommunicationThomas KrocApplications Physicist for Technology Development at Fermilab IARC Medical Device Sterilization Workshop Organizer Technical reviewer and Consultant for BPSA paper and regulator engag

31、ements Author of key publication on physics of gamma and X-rayThe Physics of Sterilization by RadiationThomas K.Kroc,PhD 10th BPSA International Single-Use Summit12 July 2023This work was produced by Fermi Research Alliance,LLC under Contract No.DE-AC02-07CH11359 with the U.S.Department of Energy.FE

32、RMILAB-SLIDES-23-162-ETD7/12/2023Kroc|10th BPSA Summit19An Electron-Ion PairIonization=Dose(Energy/Mass)7/12/2023Kroc|10th BPSA Summit20Why is ionization important?ChemistryChemical(molecular)bonds are made by the electronsIn living organisms,we want to disrupt cellular processesDestroy DNA,disrupt

33、membranes and signaling pathways All these can lead to cell death7/12/2023Kroc|10th BPSA Summit21How does Ionization lead to Sterilization?Ionizing radiation is a form of energy that acts by removing electrons from atoms and molecules of materials that include air,water,and living tissue.(def from C

34、DC website)What is Ionizing Radiation?7/12/2023Kroc|10th BPSA Summit22Ionizing Radiation7/12/2023Kroc|10th BPSA Summit23Wavelength(m)Energy(eV)10-1-1-6110-410-210-210--8 AlphaHe2+Very Shallow BetaElectronsPenetration depends on energy10 MeV,5 cm in H20(Photons)G

35、ammaX-ray10s of cm in H20(UV light)ElectronsBut how do we get from gamma and x-rays to electrons?OutlinePhoton Creation Gamma Rays&X-raysGoing from Photons to ElectronsHow equivalent are electrons from Gamma Rays&X-rays?7/12/2023Kroc|10th BPSA Summit24How do we create Ionization?Cobalt-59Cobalt 59Co

36、balt 60Nickel 601.33 MeV1.17 MeV7/12/2023Kroc|10th BPSA Summit25Or Days,or Months,Or Years All natural cobalt is Cobalt-59 Produced in reactors 18 36 months,converts 5%of Co-59 to Co-60 5.27 year half-life 12%loss per year Needs to be replaced at some regular intervalCobalt-607/12/2023Kroc|10th BPSA

37、 Summit267/12/2023Kroc|10th BPSA Summit27X-rays7/12/2023Kroc|10th BPSA Summit28Energy Spectra for each0.00010.00100.01000.10001.000010.00000.0100.1001.00010.000Energy(MeV)Energy Spectra7.5 MeV X-rayCo-60 GammaIonizing Radiation7/12/2023Kroc|10th BPSA Summit29Wavelength(m)Energy(eV)10-1

38、-1-6110-410-210-210--8 AlphaHe2+Very Shallow BetaElectronsPenetration depends on energy10 MeV,5 cm in H20(Photons)GammaX-ray10s of cm in H20(UV light)Gamma&X-raysPhoton Interactions with Atoms7/12/2023Kroc|10th BPSA Summit30Compton electron 0.5 MeV 500,000 eVe-e+e-e-e-e-e-e-e

39、-e-e-Spur:0-100 eV,65%Blob:100 500 eV,15%Short track:500 5000 eV,20%A-Positron Annihilation,B-Bremsstrahlung,C-Compton Scattering,PE-Photoelectric Effect,PP-Pair ProductionBCPEPEPEPEPPACBe-PE7/12/2023Kroc|10th BPSA Summit31Photon Interactions with AtomsThe Photon-Electron Cascade7/12/2023Presenter|P

40、resentation Title or Meeting Title32 Photons Produce ElectronsCompton ScatteringPhoto-electric EffectPair ProductionPhoton Auger Electrons Produce PhotonsBremsstrahlungPositron AnnihilationElectron X-raysFluorescence Electrons Produce Electrons Electron Auger Delta Rays(Knock-on)7/12/2023Kroc|10th B

41、PSA Summit33Simulated Geometry7/12/2023Kroc|10th BPSA Summit34ElectronsIn Tote 1CobaltX-ray0.000010.000100.001000.010000.010.10Electrons per emitted source photon/MeVElectron Energy(MeV)0.000010.000100.001000.010000.010.10Electrons per emitted beam Electron/MeV(before Brems.)Electron Energy(MeV)1-12

42、0.3 cm2-125.4 cm3-130.5 cm4-135.6 cm5-140.6 cm6-145.7 cm7-150.8 cm8-155.9 cm9-161.0 cm10-166.0 cm11-171.1 cm12-176.2 cmDOI:10.1016/j.radphyschem.2022.110702Fundamentally,A Photon is A Photon is A Photon7/12/2023Kroc|10th BPSA Summit35=7/12/2023Kroc|10th BPSA Summit362023 Bio-Process Systems Alliance

43、|bpsalliance.orgBPSA X-ray Workshop Feedback2023 Bio-Process Systems Alliance|bpsalliance.orgHave you finalized your supporting qualification datasets for X-ray?2023 Bio-Process Systems Alliance|bpsalliance.orgI feel confident current datasets,coupled with the irradiation physics understanding,demon

44、strate X-ray and gamma exhibit equivalent impact?2023 Bio-Process Systems Alliance|bpsalliance.orgI feel confident in understanding the types of supplier testing needed to support X-ray qualification?2023 Bio-Process Systems Alliance|bpsalliance.orgI feel confident that regulators will accept X-ray?

45、Initial feedback is positive,but it is still largely unknown what data/justification/filing updates that might be required for ROW I feel like we have done our due diligence and followed the guidelines of the BPSA.However,I am not familiar enough with regulators to gauge their responseStill unsure o

46、n this one.I do think regulators are slowly coming around on this thoughThe science is pretty compelling 2023 Bio-Process Systems Alliance|bpsalliance.orgI have a clear understanding of what supplier components and SUS are being qualified for X-ray?I find it straight forward knowing how and where to

47、 access qualification data?2023 Bio-Process Systems Alliance|bpsalliance.orgWhat should be the ongoing meeting cadence for the BPSA working team?2023 Bio-Process Systems Alliance|bpsalliance.orgIs there a specific topic we need to revisit/discuss during the workshop?Feed-back on first registration.M

48、issing data.What level of qualification testing is required for gamma and X-ray for anynew materials launched?2023 Bio-Process Systems Alliance|bpsalliance.orgI or someone from my company would attend an ASTM E55/E61 irradiation training workshop?2023 Bio-Process Systems Alliance|bpsalliance.orgThank you!Thank you!