1、Designation: F3320 18Standard Guide forCoating Characterization of Drug Coated Balloons1This standard is issued under the fixed designation F3320; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of last revision. A number
2、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 acute in-vitro char-acterization methods for drug coated balloon (DCB) coatings.These methods include: coatin
3、g integrity, coating thickness,drug coating uniformity, and released particulates. Specifically,this guide details:1.1.1 Characterization of integrity by inspection of thecoated balloon surface.1.1.2 Measurement of coating thickness.1.1.3 Quantitation of drug coating uniformity (uniformity ofdrug di
4、stribution over the balloon surface) longitudinally andcircumferentially.1.1.4 Quantitation of the number of particulates released, invarious size ranges, during simulated use testing (insertion,tracking, deployment, retraction, and withdrawal) along withchemical and crystallinity characterization o
5、f particulates.1.2 This document does not address:1.2.1 Mechanical testing of drug coated balloons (DCBs).1.2.2 Drug substance evaluation (e.g., assay, relatedsubstances, uniformity of dosage units) of DCBs.1.2.3 Production release and stability testing, although somesections may be applicable in wh
6、ole or in part.1.2.4 Standard analytical testing (e.g., drug content, drugrelated substances, drug uniformity of dosage).1.3 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.4 This standard does not purport to address all of th
7、esafety concerns, if any, associated with its use. It is theresponsibility of the user of this standard to establish appro-priate safety, health, and environmental practices and deter-mine the applicability of regulatory limitations prior to use.1.5 This international standard was developed in accor
8、-dance with internationally recognized principles on standard-ization established in the Decision on Principles for theDevelopment of International Standards, Guides and Recom-mendations issued by the World Trade Organization TechnicalBarriers to Trade (TBT) Committee.2. Referenced Documents2.1 ASTM
9、 Standards:2F2743 Guide for Coating Inspection and Acute ParticulateCharacterization of Coated Drug-Eluting Vascular StentSystems2.2 AAMI Standard:3AAMI TIR 42 Evaluation of Particulates Associated withVascular Medical Devices2.3 USP Standards:4USP Particulate Matter in InjectionsUSP Uniformity of D
10、osage Units3. Terminology3.1 Definitions:3.1.1 tracking, nnavigation of a guide wire, guide catheteror introducer sheath, and/or balloon system through actual orsimulated vascular anatomy.3.1.2 vascular model, na model that simulates or repli-cates the geometry of a clinically relevant, sufficiently
11、 chal-lenging anatomical vasculature for the intended anatomythrough which the system will be placed. There should be adeployment site within the model or mock vessel attached tothe model for balloon deployment.3.2 Definitions of Terms Specific to This Standard:3.2.1 acute, nthe timeframe including
12、accessory and bal-loon delivery, deployment, and withdrawal.3.2.2 background assessment, na test measuring thenumber/size of particulates within the Particulate test systemwithout accessories or test articles.3.2.3 drug coated balloon (DCB), nmedical device com-prised of a drug coating over the surf
13、ace of vascular dilatationballoon.1This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.30 on Cardiovascular Standards.Current edition approved June 1, 2018. Published July 2018. DOI: 10.1520/F3320
14、18.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from Association for the Advancement of Medical
15、 Instrumentation(AAMI), 4301 N. Fairfax Dr., Suite 301, Arlington, VA 22203-1633, http:/www.aami.org.4Available from U.S. Pharmacopeial Convention (USP), 12601 TwinbrookPkwy., Rockville, MD 20852-1790, http:/www.usp.org.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohoc
16、ken, PA 19428-2959. United StatesThis international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for theDevelopment of International Standards, Guides and Recommendations issued by the World Trade Organiz
17、ation Technical Barriers to Trade (TBT) Committee.13.2.4 drug coating uniformity, na measure of drug distri-bution over the surface of the balloon intended to be coated.This evaluation is separate from uniformity of dosage units asdescribed in USP.3.2.5 expected segment content, nthe sum of the Mea-
18、sured Content from all segments divided by the number ofsegments, yielding a calculated expected segment content(typically measured in mass), assuming all segments are thesame size.3.2.6 longitudinal axis, nmajor axis of the balloon, paral-lel to the effective length.3.2.7 measured content, nthe amo
19、unt (typically measuredin mass) of the Active Pharmaceutical Ingredient (drug)determined for each DCB test article segment during thecoating uniformity assessment.3.2.8 mock vessel, nsimulation of the vasculature thatreplicates the geometry, mechanical properties, and/or chemi-cal properties at the
20、intended clinical deployment site.3.2.9 particulate test system, na combination of the vas-cular model, containing a deployment site or mock vessel, andan in-line particle counter or collection in a beaker or on a filterwith an off-line particle counter, microscope, or other particle-counting means.
21、3.2.10 simulated use, na simulation of DCB clinical use inaccordance with the instructions for use (IFU), includinginsertion, tracking, deployment, and withdrawal in a controlledaqueous environment through a vascular model using clinicalaccessories.3.2.11 spike documenting theappearance and location
22、 of any coating attributes, anomalies,or artifacts. Attributes or surface anomalies observed undercoarse inspection should be further examined under high (100 200) magnification. Higher magnification may be helpful toestimate the size and depth of the attribute using appropriatemeans (e.g., image an
23、alysis software). Coating integrity char-acterization may be performed by visualization methods ad-equate to fully depict the surface appearance of the coating.Methods such as scanning electron microscopy (SEM), optical(light) microscopy, profilometry, fluorescence microscopy, orspectroscopy can be
24、used with appropriate resolution.8.4 Coating ThicknessThe thickness of the as-manufactured drug coating should be characterized in order toF3320 185determine the range of the coating thickness throughout thedevice. Methods to determine the coating thickness includecross-section imaging with direct m
25、easurement or profilom-etry. Imaging methods such as scanning electron microscopy(SEM), optical (light) microscopy, interferometry, micro/nanocomputed tomography (CT), or fluorescence microscopy canbe utilized as long as the method provides an acceptableresolution and the thickness can be accurately
26、 measured. Theevaluation method used should be justified. Test articles maybe embedded (e.g., with resin) before cross-sectioning, so as toavoid compromising the coating during the sectioning process.The number and location of measurements, both around thecircumference and along the effective length
27、 of the balloon,should be recorded. A sufficient number of sections should beanalyzed to fully characterize the coating. Coating integrityand coating uniformity results may be used to support thenumber of sections analyzed for coating thickness. Measure-ments every 10mm - 40mm are generally suggeste
28、d, dependingon length and distribution of coating.Aminimum of two pointsaround the circumference per cross-section should be made,preferably opposite one another. If the coating is irregular dueto the manufacturing process, such as pooling of coatingmaterial at certain spots, and/or the design of th
29、e device (e.g.,scoring or other specialty balloons) additional measurementsshould be made at or near these features.8.5 Drug Coating UniformityDrug coated balloons shouldbe characterized for drug coating uniformity along the effectivelength (longitudinal uniformity) and around the circumference(circ
30、umferential uniformity) of the balloon. Longitudinal uni-formity and circumferential uniformity should be performed asseparate tests with independent samples unless an adequaterationale is provided explaining why this is not necessary. Therecommended method for balloon uniformity assessment is tocut
31、 the drug coated portion of the DCB into segments followedby a drug assay of each segment. Any appropriate method forsegmentation can be utilized with description and justification.8.5.1 Drug Coating Longitudinal Uniformity compares theamount of drug on balloon segments to the average amount ofdrug
32、per segment. The balloon is to be divided along theeffective length, making cuts orthogonal to the longitudinalaxis. Segment lengths of 10mm - 30mm are generallysuggested, depending on the balloon length, with a recom-mended minimum of three segments, or appropriate rationale.The number and length o
33、f segments per balloon length shouldbe supported by an appropriate rationale. Content results canbe normalized to a justified measured segment characteristic(e.g., length, surface area, mass).8.5.2 Drug Coating Circumferential Uniformity comparesthe amount of drug on balloon segments to the average
34、amountof drug per segment. The balloon is to be divided around thecircumference, cut along the length. The number of segmentsshould be supported by an appropriate rationale, with asuggested minimum of two segments to be analyzed. Contentresults can be normalized to a justified measured segmentcharac
35、teristic (e.g., length, surface area, mass).8.6 Particulate Characterization:8.6.1 Vascular Model and Mock Vessel (if applicable) Back-ground AssessmentPerform test in an environment that doesnot contribute any significant amount of additional particulatematter. The particulate test system must be c
36、leaned to theextent that any level of extraneous particles added has anegligible effect on the outcome of the test. Use cleaningprocedures and test environment considerations in generalaccordance with appropriate sections of USP . Analyzetest fluid (e.g., particle-free water) passed through the clea
37、nedtest system to verify that the test system is sufficiently clean toallow an accurate assessment of particulates shed from theDCB and accessories. Unless otherwise justified, the flushingflowrate and volume used for the background assessmentshould be the same as that used for the spike and recover
38、yvalidation and the particulation test. Background data shouldbe recorded. It is up to the user to reduce backgroundparticulates since they will affect the reported total cumulativecounts if their subtraction is not appropriately justified.8.6.2 Simulated Use Deployment:8.6.2.1 Prepare the DCB and a
39、ccessories in accordance withIFU.8.6.2.2 TrackingTrack the accessories and DCB throughthe appropriate water-filled, vascular model, in accordancewith IFU. If applicable, repeat the procedure using the numberof steps appropriate for the clinical indication and/or IFU. Useaccessory devices as appropri
40、ate. Unless otherwise justified,the entire portion of the DCB that is intended to enter the bodyshould be tracked through the vascular model in an aqueousenvironment that is thermally controlled at 37 6 2C.8.6.2.3 DeploymentDeploy the DCB in accordance withthe IFU. Unless otherwise justified, inflat
41、e to the rated burstpressure within a suitably sized lumen resulting in good wallapposition for the recommended time, and then completelydeflate the DCB. Unless otherwise justified, if multiple infla-tions of the DCB are permitted in the IFU, repeat the inflationand deflation for the maximum number
42、of times permitted inthe IFU. Completely withdraw the DCB per IFU and/or clinicalpractice.8.6.2.4 Rinse/FlushUnless otherwise justified, remove theaccessories per the IFU and/or clinical practice from the mockvessel, if applicable, and vascular model. Flush the vascularmodel and mock vessel, if appl
43、icable, with enough particle-freewater to capture released particles, as was done in the spike andrecovery testing. The flow rate and volume used should beidentical to those used in the spike and recovery testing. Sinceall particulates released during the simulated use evaluationcan be considered as
44、 a single bolus, it may be collected andanalyzed as a single sample. There may be advantages tocollecting separate samples at different phases (e.g., afterinsertion of accessories, after tracking but before inflation ofthe DCB, after each inflation of DCB).8.6.2.5 Particulate AccumulationIf necessar
45、y, transfer thecollection beaker contents to the container used for particulateanalysis. If transfer is necessary, the particulate sample shouldbe stirred or otherwise agitated to maintain a uniform suspen-sion of particulates prior to transfer and during analysis inaccordance with the spiking and r
46、ecovery testing. Continuousparticulate counting is one means to eliminate the need totransfer the sample for particulate analysis.F3320 1868.6.2.6 Particulate Sizing and CountingDetermine thetotal cumulative number of particulates released during acces-sory and DCB insertion, tracking, deployment, r
47、etraction, andwithdrawal through a vascular model, using procedures ingeneral accordance with the particulate characterization meth-ods outlined in USP and AAMI TIR 42. Determine thenumber of particulates in appropriate size ranges, as used forspike and recovery testing (see section 7.7.1). Evaluate
48、 addi-tional size ranges as appropriate. Separation may occur beforeor after particle sizing and counting (see section 8.6.2.7).8.6.2.7 Particulate SeparationSeparate particulate matterfrom the flushing water for additional analyses described insection 8.6.3. Any justified method, such as filtration
49、 usingappropriate pore size (e.g., 10m) or centrifugation, can beutilized. Separation may occur before or after particle sizingand counting (see section 8.6.2.6).8.6.3 Particulate Chemical and Crystallinity Characteriza-tion:8.6.3.1 Chemical CharacterizationIdentify and reportpercentage of known and unknown chemicals, with a justifi-cation for the total amount analyzed, and for excluding anytypes of particulates, as discussed in section 7.7.6.1. A briefsummary of possible analytical method advantages and disad-vantages for identification is provided in
