ASTM F2743-11(2018)

This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the
Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
Designation: F2743 − 11 (Reapproved 2018)
Standard Guide for
Coating Inspection and Acute Particulate Characterization of
Coated Drug-Eluting Vascular Stent Systems
This standard is issued under the fixed designation F2743; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope 2. Referenced Documents
1.1 This guide describes recommended in vitro test proce-
2.1 Other Standards:
dures for coating inspection and acute particulate characteriza-
USP <788> Particulate Matter in Injections
tion of coated drug-eluting vascular (balloon-expandable and FDA Guidance for Industry and FDA StaffNon-Clinical
self-expanding) stent systems. Engineering Tests and Recommended Labeling for Intra-
vascular Stents and Associated Delivery Systems, April
1.2 Recommended practices for coating inspection and 3
18, 2010
acute particulate characterization include baseline (deploy-
AAMITIR42:2010Evaluation of Particulates Associated
ment) testing and simulated use testing. This guide describes 4
with Vascular Medical Devices
the capture and analysis of particulates. This guide describes
the inspection of the coated stent surface. This guide was
3. Terminology
developed for characterization and not intended for production
3.1 Definitions:
release testing of coated drug-eluting vascular stent systems
3.1.1 mock vessel—physicalsimulationofthevasculatureat
although some sections may be appropriate.
the intended clinical deployment site.
1.3 Chronic particulate characterization and coating inspec-
3.1.2 stent system—a system comprised of a vascular stent
tion are not included herein.
and its delivery system.
3.1.3 tracking—navigation of a guide wire, guide catheter,
1.4 Coating systems specifically designed to degrade or
and/or stent system through either actual or simulated vascular
otherwise intentionally separate themselves from the perma-
anatomy.
nent stent structure may not be fully addressed herein.
3.1.4 tracking fixture—a model that simulates or replicates
1.5 The values stated in SI units are to be regarded as
thegeometryofarepresentativevasculaturethroughwhichthe
standard. No other units of measurement are included in this
stent system will be passed.
standard.
3.2 Definitions of Terms Specific to This Standard:
1.6 The values stated in inch-pound units are to be regarded
3.2.1 acute—a test timeframe intended to include stent
as standard. The values given in parentheses are mathematical
delivery and deployment beginning with the initial insertion of
conversions to SI units that are provided for information only
stent system until full removal of the delivery system and its
and are not considered standard.
accessory devices.
1.7 This international standard was developed in accor- 3.2.2 baseline—coating inspection and acute particulate
characterizationafterstentexpansiontothedesireddiameterin
dance with internationally recognized principles on standard-
an unconstrained environment and without tracking.
ization established in the Decision on Principles for the
Development of International Standards, Guides and Recom-
3.2.3 chronic—a test timeframe intended to mimic the
mendations issued by the World Trade Organization Technical
implantation time after full removal of the delivery system and
Barriers to Trade (TBT) Committee.
its accessory devices.
1 2
This guide is under the jurisdiction of ASTM Committee F04 on Medical and Available from U.S. Pharmacopeia (USP), 12601Twinbrook Pkwy., Rockville,
Surgical Materials and Devices and is the direct responsibility of Subcommittee MD 20852-1790, http://www.usp.org.
F04.30 on Cardiovascular Standards. Available from Food and DrugAdministration (FDA), 10903 New Hampshire
Current edition approved Nov. 1, 2018. Published November 2018. Originally Ave., Silver Spring, MD 20993-0002, http://www.fda.gov.
approved in 2011. Last previous edition approved in 2011 as F2743–11. DOI: Available from Association for the Advancement of Medical Instrumentation
10.1520/F2743-11R18. (AAMI), 4301 North Fairfax Dr., Suite 301, Arlington, VA 22203-1633.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F2743 − 11 (2018)
3.2.4 constrained environment—a deployment site in which 4.3.1 Particles released may be captured in a collection
the stent is deployed into a mock vessel. beaker and sampled for count/size using light obscuration or
filtration/microscopy.Theneedforpost-dilatation,overlapping
3.2.5 simulated use—coating inspection and acute particu-
or to limit self-expansion may require deployment into a mock
late characterization after tracking in simulated anatomy and
vessel, or
aqueous environment. It may also include deployment in bent
4.3.2 Particles released may be acquired and continuously
configuration, deployment in overlapped configuration, post-
counted in an apparatus (for example, tube) for facilitating
dilatation,orotherscenariosthatcanreasonablybeexpectedin
flow.
clinical use.
3.2.6 unconstrained environment—a deployment site in
5. Significance and Use
which the stent is not constrained by a mock vessel. Compare
to “Constrained Environment”.
5.1 The shedding of the coating from a vascular stent can
alter its clinical safety and/or therapeutic benefit. Clinical
4. Summary of Practice
performance (for example, drug elution) may be affected by
4.1 Test Sequence and Samples—Baseline and Simulated
particulategenerationfromthecoatedstentsystemandcoating
Use Testing are conducted as two separate tests. Coating
defects. This document provides guidance for coating inspec-
inspection and acute particulate characterization may be per-
tion and acute particulate characterization of drug eluting
formed as two separate tests with independent samples.
vascular stents. Information about the potential for shedding
4.2 Baseline Testing—Asingle stent is deployed to nominal can be gained during bench testing. The general guidelines
or maximum labeled diameter. The stent is expanded in an
presented here may be used for writing detailed protocols for
unconstrained environment so as to characterize the stent only. specific products at the various stages of the product develop-
Baseline testing includes coating inspection and acute particu-
ment process. Such testing may be performed during device
late characterization of the stent. Baseline coating inspection development, design validation testing, lot-release testing,
may be conducted after deployment in air or in an aqueous
and/or stability testing although different requirements may
unconstrained environment. Baseline acute particulate charac- apply at each stage. These suggested methods may represent a
terization should be conducted in an aqueous unconstrained
reasonable simulation of clinical usage. When establishing the
environment.Thesurfacesofthestentcoatingareinspectedfor coatinginspectionandacuteparticulatecharacterizationtesting
defects or other adverse attributes caused by this procedure.
conditions, the current clinical usage/practice (for example,
Cumulative particulates released are captured or continuously post-dilation, overlapping stents) and the instructions for use
monitored, counted and classified according to size ranges. (IFU), as applicable, should be considered. While methods for
4.2.1 Particles released may be captured in a receptacle and chronic particulate characterization and coating inspection
sampled for count/size using light obscuration or filtration/ have not been established, these suggested methods may be
microscopy, or helpful in the development of chronic methods. Testing in
4.2.2 Particles released may be acquired and continuously accordance with recommendations in this guide will generate
counted in an apparatus (for example, tube) for facilitating data that may lead to further improvements in the method and
flow. its validation, as well as possible advancements in device
design and performance. See also FDA Guidance for Industry
4.3 Simulated Use Testing—The stent system is tracked in
and FDA Staff and AAMITIR42:2010.
an aqueous environment, through an appropriately clean, in
vitromodelsimulatingthevascularanatomytobenavigatedto
6. Suggested Materials and Reagents
access the targeted clinical deployment site.Accessory devices
(for example, guidewires, guide catheters, and so forth) are
6.1 Baseline Testing:
utilized as indicated in the IFU. The stent is deployed either
6.1.1 Beaker.
singly or overlapped with another stent and bent configuration
6.1.2 Filtered (for example, 1.2 µm or finer), de-ionized or
to represent worst-case clinical condition, as appropriate. A
distilled water, in general accordance with USP<788>. Other
constrained environment should be used as the deployment
solutions may be used if justified.
location. Stents should be expanded in accordance with the
6.1.3 Heating system, capable of maintaining fluid tempera-
IFU, including expansion to post-dilatation limits, as appropri-
ture at 37 6 2ºC.
ate. Cumulative particulates released from the stent(s), stent
6.1.4 Particulate filter, 1.2 µm or finer, with appropriate
coating(s), stent system(s) and accessory devices (if used)
holder
during the procedure are captured or continuously monitored,
6.1.5 Particulate analyzer, capable of detecting and count-
counted and classified according to size ranges. Particulate
ing particulates in appropriate size ranges (for example,
characterization may be necessary to aid in classifying poten-
≥10µm).
tial particulate sources, and the test developer should under-
6.1.6 Calibration standards, for particulate sizing and
stand the constituents of the coated stent system. The surfaces
counting.
ofthestentcoating(s)areinspectedfordefectsorotheradverse
attributes caused by this procedure. Analysis of particulates 6.1.7 Analytical instrumentation for particulate character-
and surface inspection may be accomplished using the same ization [for example FTIR (Fourier transform infrared)
test articles subjected to tracking and deployment, if appropri- spectroscopy, Raman Spectroscopy, Scanning Electron Micro-
ate. scope (SEM) with Energy Dispersive Spectroscopy (EDAX),
F2743 − 11 (2018)
X-ray photoelectron spectroscopy (XPS) or Time-of-flight whichwillnotaffecttheintegrityofthestudy).Themeaningful
secondary ionization mass spectroscopy (TOF-SIMS)] (if uti- characterization of size and quantity of small particulates shed
lized). by the coated stent can be significantly impacted by environ-
6.1.8 Continuous flow particulate counting system (if uti- mental contamination. Likewise, contamination on the stent
lized): surface may be misinterpreted as coating defects or may mask
6.1.8.1 Apparatus (for example, tube) for facilitating flow actual defects. Poor experimental technique and handling of
and housing the test article in an unconstrained environment. accessory devices may also be significant sources of non
6.1.8.2 Pump for controlling fluid flow. coating particulates. Physical and chemical contamination, in
6.1.8.3 Continuous flow particulate counter. addition to particulates, may impact the results of this charac-
terization.
6.2 Simulated Use:
6.2.1 Filtered (for example, 1.2 µm or finer), de-ionized or 7.2 Stent Surface Inspection—For complete
distilled water, in general accordance with USP<788>. Other
characterization, inspection of the surface of the stent may be
solutions may be used if justified. performed at different time points (for example, before
6.2.2 Tracking fixture, (see 3.1 and 7.3).
expansion,afterexpansiontothenominalormaximumlabeled
6.2.3 Heating system, capable of maintaining fluid tempera- diameter, and after simulated use). Representative photos
ture at 37 6 2ºC.
should be provided for each step and region, as described
6.2.4 Mock vessel, (see 3.1 and 7.4). further in Section 8. The location of the photographed regions
6.2.5 Continuous flow particulate counting system: should be predetermined.Alower magnification photograph(s)
6.2.5.1 Apparatus (for example, tube) for facilitating flow of the stent that includes and identifies the pre-specified
and housing the test article in a constrained environment. locations should also be provided. The “before expansion”
6.2.5.2 Pump for controlling fluid flow. inspection of the stent may be performed prior to or after the
6.2.5.3 Continuous flow particulate counter. stent is mounted on a delivery system; however, stent surface
6.2.6 Collection Beaker, (optional). inspections made prior to stent system assembly (for example,
6.2.7 Particulate filter 1.2 µm or finer, with appropriate crimping/loading) can make identifying the source of damage
holder (if utilized). (for example, crimping/loading or tracking and deployment)
6.2.8 Particulate analyzer, capable of detecting and count- difficult. Handling during the initial inspection may introduce
ing particulates in appropriate size ranges (for example, particulatesandcontamination.Inspectionofthestentmounted
≥10µm). on/in the delivery system may be useful for assessing initial
6.2.9 Calibration standards for particulate sizing and count- manufacturing quality and/or for establishing a baseline for
ing. determining when during the subsequent tracking/deployment
6.2.10 Accessory devices per IFU (for example, guide
process coating damage or particulate shedding may be occur-
catheter, guidewire, post-dilatation balloon catheter, and so ring. Individual defects may be assessed throughout usage, if
forth).
appropriate (for example, for investigative purposes). A stent
6.2.11 Analytical instrumentation for particulate character- may be inspected on all surfaces prior to loading onto the
ization [for example FTIR (Fourier transform infrared)
delivery system. Self-expanding stents are usually covered by
spectroscopy, Raman Spectroscopy, Scanning Electron Micro- an opaque sheath and may not be amenable to inspection after
scope (SEM) with Energy Dispersive Spectroscopy (EDAX),
loading onto the delivery system.
X-ray photoelectron spectroscopy (XPS) or Time-of-flight 7.2.1 Summary of inspection steps which may be per-
secondary ionization mass spectroscopy (TOF-SIMS)] (if uti-
formed:
lized). 7.2.1.1 Before stent loading (if applicable).
7.2.1.2 Before expansion.
6.3 Coating Inspection (Baseline and Simulated Use), Op-
7.2.1.3 After baseline expansion to nominal or maximum
tical microscope with appropriate lighting and camera and/or
diameter.
SEM.
7.2.1.4 After simulated use.
6.4 Test Articles—Unless otherwise justified, all samples
7.2.2 Inspections of stent surfaces may be performed by
selected for testing should be clinical or commercial quality
optical (light) microscopy, scanning electron microscopy
products(forexample,completestentsystems).Environmental
(SEM), fluorescence microscopy, Raman spectroscopy, and so
conditions(forexample,aging,shipping,storage,andsoforth)
forth. Each technique offers advantages and disadvantages:
may affect the stent system and should be considered when
7.2.2.1 Optical (Light) Microscopy—See Table 1.
assessingcoatinginspectionandacuteparticulatecharacteriza-
7.2.2.2 Scanning Electron Microscopy—See Table 2.
tion. Post-coating activities (for example, crimping,
7.2.2.3 Fluorescence Microscopy—See Table 3.
sterilization, balloon expansion) are critical for coating inspec-
7.2.2.4 Raman Spectroscopy—See Table 4.
tion and acute particulate characterization.Asufficient number
7.2.3 Examples of commonly observed surface anomalies
ofspecimensshouldbetestedtosupportanyclaimstobemade
and defects are shown in Appendix X1. See also
based on the test results.
AAMITIR42:2010.
7. Test Method Considerations
7.3 Simulated Use Tracking—Tracking during simulated
7.1 Environment—It is extremely important that all proce- use should be through a model tortuous path that simulates the
dures be performed in a controlled environment (that is, one geometry of a typical severe anatomic path through which the
F2743 − 11 (2018)
TABLE 1 Advantages and Disadvantages of Optical (Light) Microscopy
Advantages Disadvantages
A. Lower magnification (typically <200×) speeds coarse inspection A. Limited resolution
B. May allow inspection of stent system B. Smaller depth of field (focus depth) as compared to SEM
C. No stent size limitations C. Light reflections may mask features
D. Non-destructive
E. Color differentiation (if applicable)
TABLE 2 Advantages and Disadvantages of Scanning Electron Microscopy
Advantages Disadvantages
A. Greater depth of field (focus depth) compared to Optical Microscopy A. May be a destructive test
B. Higher magnification (up to 10 000× magnification) enhances view of small features B. May require sputter coating (except for environmental SEM),
precluding the use of a single test article for multi-time point
inspections
C. Slower manipulation compared to Optical Microscopy
D. Inspection of the full length stent may not be possible within the
chamber
E. Grey scale only
TABLE 3 Advantages and Disadvantages of Fluorescence Microscopy
Advantages Disadvantages
A. Signal-to-noise ratio can help discern different types of product in mixture A. High cost of capital equipment (that is, fluorescence microscope)
B. Non-destructive B. Not many materials have intrinsic fluorescence
TABLE 4 Advantages and Disadvantages of Raman Spectroscopy
Advantages Disadvantages
A. Can obtain spectroscopic data using aqueous solutions A. High cost of capital equipment (that is, Raman spectrometer or attachment)
B. Non-destructive B. Requires high sample concentration
C. Provides both chemical and structural information
stent system will be passed during clinical use. The tracking vessel.Ifusedthemockvesselshouldreasonablyrepresentthe
fixtureshouldincludeboththeportionofanatomyinwhichthe intended clinical deployment site. Critical features to be
stent system would be passed through the guide catheter and considered in selecting the appropriate mock vessel include
the portion through which it would be passed after exit from geometry (for example, inside diameter, length), mechanical
theguidecatheter,ifapplicable.Theappropriategeometrymay properties, ability to remove stent without coating damage,
be different for different intended deployment sites (for coefficient of friction of the material (for example,
example, coronary, carotid, or femoral arteries) or for different polyurethane, silicone, latex and native vessel). Any particu-
access points (for example, femoral or radial artery). Critical lates from the mock vessel will contribute to the total cumu-
features to be considered in selecting the appropriate tracking lative count unless their composition is characterized in order
fixture include lumen diameter, bend radii, bend reversals, to exclude them from the total count but should be included in
ability to clean and coefficient of friction of the tracking the test report. Means for extracting the deployed stent from
material (for example, polyurethane, silicone, Teflon, glass, the mock vessel without imposing additional damage to the
latex or native vessel). The tracking lumen for the guide coating will be necessary for the post-deployment inspection.
catheter path may be constructed of glass or other durable
7.5 Particulate Capture and Characterization:
materialswhichminimizebackgroundnoiseparticulatecounts.
7.5.1 Spiking and Recovery:
Ifjustifiable,surrogateancillarydevices(forexample,mandrel
7.5.1.1 Anappropriatespikingandrecoverystudyshouldbe
for guidewire) may be used to aid in minimizing background
performed on each test system for baseline and simu
...