1、Designation: F2743 11Standard Guide forCoating Inspection and Acute Particulate Characterization ofCoated Drug-Eluting Vascular Stent Systems1This standard is issued under the fixed designation F2743; the number immediately following the designation indicates the year oforiginal adoption or, in the
2、case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide describes recommended in vitro test proce-dures for coating inspection and ac
3、ute particulate characteriza-tion of coated drug-eluting vascular (balloon-expandable andself-expanding) stent systems.1.2 Recommended practices for coating inspection andacute particulate characterization include baseline (deploy-ment) testing and simulated use testing. This guide describesthe capt
4、ure and analysis of particulates. This guide describesthe inspection of the coated stent surface. This guide wasdeveloped for characterization and not intended for productionrelease testing of coated drug-eluting vascular stent systemsalthough some sections may be appropriate.1.3 Chronic particulate
5、 characterization and coating inspec-tion are not included herein.1.4 Coating systems specifically designed to degrade orotherwise intentionally separate themselves from the perma-nent stent structure may not be fully addressed herein.1.5 The values stated in SI units are to be regarded asstandard.
6、No other units of measurement are included in thisstandard.1.6 The values stated in inch-pound units are to be regardedas standard. The values given in parentheses are mathematicalconversions to SI units that are provided for information onlyand are not considered standard.2. Referenced Documents2.1
7、 Other Standards:USP Particulate Matter in Injections2FDA Guidance for Industry and FDA Staff Non-ClinicalEngineering Tests and Recommended Labeling for Intra-vascular Stents and Associated Delivery Systems, April18, 20103AAMI TIR42:2010 Evaluation of Particulates Associatedwith Vascular Medical Dev
8、ices43. Terminology3.1 Definitions:3.1.1 mock vesselphysical simulation of the vasculature atthe intended clinical deployment site.3.1.2 stent systema system comprised of a vascular stentand its delivery system.3.1.3 trackingnavigation of a guide wire, guide catheter,and/or stent system through eith
9、er actual or simulated vascularanatomy.3.1.4 tracking fixturea model that simulates or replicatesthe geometry of a representative vasculature through which thestent system will be passed.3.2 Definitions of Terms Specific to This Standard:3.2.1 acutea test timeframe intended to include stentdelivery
10、and deployment beginning with the initial insertion ofstent system until full removal of the delivery system and itsaccessory devices.3.2.2 baselinecoating inspection and acute particulatecharacterization after stent expansion to the desired diameter inan unconstrained environment and without tracki
11、ng.3.2.3 chronica test timeframe intended to mimic theimplantation time after full removal of the delivery system andits accessory devices.3.2.4 constrained environmenta deployment site in whichthe stent is deployed into a mock vessel.3.2.5 simulated usecoating inspection and acute particu-late char
12、acterization after tracking in simulated anatomy andaqueous environment. It may also include deployment in bentconfiguration, deployment in overlapped configuration, post-dilatation, or other scenarios that can reasonably be expected inclinical use.3.2.6 unconstrained environmenta deployment site in
13、which the stent is not constrained by a mock vessel. Compareto “Constrained Environment”.4. Summary of Practice4.1 Test Sequence and SamplesBaseline and SimulatedUse Testing are conducted as two separate tests. Coating1This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical
14、 Materials and Devices and is the direct responsibility of SubcommitteeF04.30 on Cardiovascular Standards.Current edition approved Oct. 1, 2011. Published November 2011. DOI:10.1520/F2743-11.2Available from U.S. Pharmacopeia (USP), 12601 Twinbrook Pkwy., Rockville,MD 20852-1790, http:/www.usp.org.3A
15、vailable from Food and Drug Administration (FDA), 10903 New HampshireAve., Silver Spring, MD 20993-0002, http:/www.fda.gov.4Available from Association for the Advancement of Medical Instrumentation(AAMI), 4301 North Fairfax Dr., Suite 301, Arlington, VA 22203-1633.1Copyright ASTM International, 100
16、Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.inspection and acute particulate characterization may be per-formed as two separate tests with independent samples.4.2 Baseline TestingA single stent is deployed to nominalor maximum labeled diameter. The stent is expand
17、ed in anunconstrained environment so as to characterize the stent only.Baseline testing includes coating inspection and acute particu-late characterization of the stent. Baseline coating inspectionmay be conducted after deployment in air or in an aqueousunconstrained environment. Baseline acute part
18、iculate charac-terization should be conducted in an aqueous unconstrainedenvironment. The surfaces of the stent coating are inspected fordefects or other adverse attributes caused by this procedure.Cumulative particulates released are captured or continuouslymonitored, counted and classified accordi
19、ng to size ranges.4.2.1 Particles released may be captured in a receptacle andsampled for count/size using light obscuration or filtration/microscopy, or4.2.2 Particles released may be acquired and continuouslycounted in an apparatus (for example, tube) for facilitatingflow.4.3 Simulated Use Testing
20、The stent system is tracked inan aqueous environment, through an appropriately clean, invitro model simulating the vascular anatomy to be navigated toaccess the targeted clinical deployment site. Accessory devices(for example, guidewires, guide catheters, and so forth) areutilized as indicated in th
21、e IFU. The stent is deployed eithersingly or overlapped with another stent and bent configurationto represent worst-case clinical condition, as appropriate. Aconstrained environment should be used as the deploymentlocation. Stents should be expanded in accordance with theIFU, including expansion to
22、post-dilatation limits, as appropri-ate. Cumulative particulates released from the stent(s), stentcoating(s), stent system(s) and accessory devices (if used)during the procedure are captured or continuously monitored,counted and classified according to size ranges. Particulatecharacterization may be
23、 necessary to aid in classifying poten-tial particulate sources, and the test developer should under-stand the constituents of the coated stent system. The surfacesof the stent coating(s) are inspected for defects or other adverseattributes caused by this procedure. Analysis of particulatesand surfa
24、ce inspection may be accomplished using the sametest articles subjected to tracking and deployment, if appropri-ate.4.3.1 Particles released may be captured in a collectionbeaker and sampled for count/size using light obscuration orfiltration/microscopy. The need for post-dilatation, overlappingor t
25、o limit self-expansion may require deployment into a mockvessel, or4.3.2 Particles released may be acquired and continuouslycounted in an apparatus (for example, tube) for facilitatingflow.5. Significance and Use5.1 The shedding of the coating from a vascular stent canalter its clinical safety and/o
26、r therapeutic benefit. Clinicalperformance (for example, drug elution) may be affected byparticulate generation from the coated stent system and coatingdefects. This document provides guidance for coating inspec-tion and acute particulate characterization of drug elutingvascular stents. Information
27、about the potential for sheddingcan be gained during bench testing. The general guidelinespresented here may be used for writing detailed protocols forspecific products at the various stages of the product develop-ment process. Such testing may be performed during devicedevelopment, design validatio
28、n testing, lot-release testing,and/or stability testing although different requirements mayapply at each stage. These suggested methods may represent areasonable simulation of clinical usage. When establishing thecoating inspection and acute particulate characterization testingconditions, the curren
29、t clinical usage/practice (for example,post-dilation, overlapping stents) and the instructions for use(IFU), as applicable, should be considered. While methods forchronic particulate characterization and coating inspectionhave not been established, these suggested methods may behelpful in the develo
30、pment of chronic methods. Testing inaccordance with recommendations in this guide will generatedata that may lead to further improvements in the method andits validation, as well as possible advancements in devicedesign and performance. See also FDA Guidance for Industryand FDA Staff and AAMI TIR42:
31、2010.6. Suggested Materials and Reagents6.1 Baseline Testing:6.1.1 Beaker.6.1.2 Filtered (for example, 1.2 m or finer), de-ionized ordistilled water, in general accordance with USP . Othersolutions may be used if justified.6.1.3 Heating system, capable of maintaining fluid tempera-ture at 37 6 2C.6.
32、1.4 Particulate filter, 1.2 m or finer, with appropriateholder6.1.5 Particulate analyzer, capable of detecting and count-ing particulates in appropriate size ranges (for example,$10 m).6.1.6 Calibration standards for particulate sizing andcounting.6.1.7 Analytical instrumentation for particulate cha
33、racter-ization for example FTIR (Fourier transform infrared) spec-troscopy, Raman Spectroscopy, Scanning Electron Microscope(SEM) with Energy Dispersive Spectroscopy (EDAX), X-rayphotoelectron spectroscopy (XPS) or Time-of-flight secondaryionization mass spectroscopy (TOF-SIMS) (if utilized).6.1.8 C
34、ontinuous flow particulate counting system (if uti-lized):6.1.8.1 Apparatus (for example, tube) for facilitating flowand housing the test article in an unconstrained environment.6.1.8.2 Pump for controlling fluid flow.6.1.8.3 Continuous flow particulate counter.6.2 Simulated Use:6.2.1 Filtered (for
35、example, 1.2 m or finer), de-ionized ordistilled water, in general accordance with USP . Othersolutions may be used if justified.6.2.2 Tracking fixture, (see 3.1 and 7.3).6.2.3 Heating system, capable of maintaining fluid tempera-ture at 37 6 2C.6.2.4 Mock vessel, (see 3.1 and 7.4).6.2.5 Continuous
36、flow particulate counting system:F2743 1126.2.5.1 Apparatus (for example, tube) for facilitating flowand housing the test article in a constrained environment.6.2.5.2 Pump for controlling fluid flow.6.2.5.3 Continuous flow particulate counter.6.2.6 Collection Beaker, (optional).6.2.7 Particulate fil
37、ter 1.2 m or finer, with appropriateholder (if utilized).6.2.8 Particulate analyzer, capable of detecting and count-ing particulates in appropriate size ranges (for example,$10 m).6.2.9 Calibration standards for particulate sizing and count-ing.6.2.10 Accessory devices per IFU (for example, guidecat
38、heter, guidewire, post-dilatation balloon catheter, and soforth).6.2.11 Analytical instrumentation for particulate character-ization for example FTIR (Fourier transform infrared) spec-troscopy, Raman Spectroscopy, Scanning Electron Microscope(SEM) with Energy Dispersive Spectroscopy (EDAX), X-raypho
39、toelectron spectroscopy (XPS) or Time-of-flight secondaryionization mass spectroscopy (TOF-SIMS) (if utilized).6.3 Coating Inspection (Baseline and Simulated Use), Op-tical microscope with appropriate lighting and camera and/orSEM.6.4 Test ArticlesUnless otherwise justified, all samplesselected for
40、testing should be clinical or commercial qualityproducts (for example, complete stent systems). Environmentalconditions (for example, aging, shipping, storage, and so forth)may affect the stent system and should be considered whenassessing coating inspection and acute particulate characteriza-tion.
41、Post-coating activities (for example, crimping, steriliza-tion, balloon expansion) are critical for coating inspection andacute particulate characterization.Asufficient number of speci-mens should be tested to support any claims to be made basedon the test results.7. Test Method Considerations7.1 En
42、vironmentIt is extremely important that all proce-dures be performed in a controlled environment (that is, onewhich will not affect the integrity of the study). The meaningfulcharacterization of size and quantity of small particulates shedby the coated stent can be significantly impacted by environ-
43、mental contamination. Likewise, contamination on the stentsurface may be misinterpreted as coating defects or may maskactual defects. Poor experimental technique and handling ofaccessory devices may also be significant sources of noncoating particulates. Physical and chemical contamination, inadditi
44、on to particulates, may impact the results of this charac-terization.7.2 Stent Surface InspectionFor complete characteriza-tion, inspection of the surface of the stent may be performed atdifferent time points (for example, before expansion, afterexpansion to the nominal or maximum labeled diameter,
45、andafter simulated use). Representative photos should be providedfor each step and region, as described further in Section 8. Thelocation of the photographed regions should be predetermined.A lower magnification photograph(s) of the stent that includesand identifies the pre-specified locations shoul
46、d also be pro-vided. The “before expansion” inspection of the stent may beperformed prior to or after the stent is mounted on a deliverysystem; however, stent surface inspections made prior to stentsystem assembly (for example, crimping/loading) can makeidentifying the source of damage (for example,
47、 crimping/loading or tracking and deployment) difficult. Handling duringthe initial inspection may introduce particulates and contami-nation. Inspection of the stent mounted on/in the deliverysystem may be useful for assessing initial manufacturingquality and/or for establishing a baseline for deter
48、mining whenduring the subsequent tracking/deployment process coatingdamage or particulate shedding may be occurring. Individualdefects may be assessed throughout usage, if appropriate (forexample, for investigative purposes). A stent may be inspectedon all surfaces prior to loading onto the delivery
49、 system.Self-expanding stents are usually covered by an opaque sheathand may not be amenable to inspection after loading onto thedelivery system.7.2.1 Summary of inspection steps which may be per-formed:7.2.1.1 Before stent loading (if applicable).7.2.1.2 Before expansion.7.2.1.3 After baseline expansion to nominal or maximumdiameter.7.2.1.4 After simulated use.7.2.2 Inspections of stent surfaces may be performed byoptical (light) microscopy, scanning electron microscopy(SEM), fluorescence microscopy, Raman spectroscopy, and soforth. Each technique offers a
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