ASTM F3320-18

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: F3320 − 18
Standard Guide for
Coating Characterization of Drug Coated Balloons
This standard is issued under the fixed designation F3320; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision.Anumber in parentheses indicates the year of last reapproval.A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope mendations issued by the World Trade Organization Technical
Barriers to Trade (TBT) Committee.
1.1 This guide describes recommended acute in-vitro char-
acterization methods for drug coated balloon (DCB) coatings.
2. Referenced Documents
These methods include: coating integrity, coating thickness,
2.1 ASTM Standards:
drugcoatinguniformity,andreleasedparticulates.Specifically,
F2743Guide for Coating Inspection and Acute Particulate
this guide details:
Characterization of Coated Drug-Eluting Vascular Stent
1.1.1 Characterization of integrity by inspection of the
Systems
coated balloon surface.
2.2 AAMI Standard:
1.1.2 Measurement of coating thickness.
AAMI TIR 42Evaluation of Particulates Associated with
1.1.3 Quantitationofdrugcoatinguniformity(uniformityof
Vascular Medical Devices
drug distribution over the balloon surface) longitudinally and
2.3 USP Standards:
circumferentially.
USP <788>Particulate Matter in Injections
1.1.4 Quantitation of the number of particulates released, in
USP <905>Uniformity of Dosage Units
various size ranges, during simulated use testing (insertion,
3. Terminology
tracking, deployment, retraction, and withdrawal) along with
chemical and crystallinity characterization of particulates.
3.1 Definitions:
3.1.1 tracking, n—navigationofaguidewire,guidecatheter
1.2 This document does not address:
or introducer sheath, and/or balloon system through actual or
1.2.1 Mechanical testing of drug coated balloons (DCBs).
simulated vascular anatomy.
1.2.2 Drug substance evaluation (e.g., assay, related
substances, uniformity of dosage units) of DCBs.
3.1.2 vascular model, n—a model that simulates or repli-
1.2.3 Productionreleaseandstabilitytesting,althoughsome
cates the geometry of a clinically relevant, sufficiently chal-
sections may be applicable in whole or in part.
lenging anatomical vasculature for the intended anatomy
1.2.4 Standard analytical testing (e.g., drug content, drug through which the system will be placed. There should be a
related substances, drug uniformity of dosage).
deployment site within the model or mock vessel attached to
the model for balloon deployment.
1.3 The values stated in SI units are to be regarded as
standard. No other units of measurement are included in this 3.2 Definitions of Terms Specific to This Standard:
standard. 3.2.1 acute, n—the timeframe including accessory and bal-
loon delivery, deployment, and withdrawal.
1.4 This standard does not purport to address all of the
3.2.2 background assessment, n—a test measuring the
safety concerns, if any, associated with its use. It is the
number/size of particulates within the Particulate test system
responsibility of the user of this standard to establish appro-
without accessories or test articles.
priate safety, health, and environmental practices and deter-
mine the applicability of regulatory limitations prior to use.
3.2.3 drug coated balloon (DCB), n—medical device com-
1.5 This international standard was developed in accor-
prised of a drug coating over the surface of vascular dilatation
dance with internationally recognized principles on standard-
balloon.
ization established in the Decision on Principles for the
Development of International Standards, Guides and Recom-
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Standards volume information, refer to the standard’s Document Summary page on
the ASTM website.
1 3
This guide is under the jurisdiction ofASTM Committee F04 on Medical and Available from Association for the Advancement of Medical Instrumentation
Surgical Materials and Devices and is the direct responsibility of Subcommittee (AAMI), 4301 N. Fairfax Dr., Suite 301, Arlington, VA 22203-1633, http://
F04.30 on Cardiovascular Standards. www.aami.org.
Current edition approved June 1, 2018. Published July 2018. DOI: 10.1520/ Available from U.S. Pharmacopeial Convention (USP), 12601 Twinbrook
F3320–18. Pkwy., Rockville, MD 20852-1790, http://www.usp.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F3320 − 18
3.2.4 drug coating uniformity, n—a measure of drug distri- cable. Thickness measurements may be obtained by cross-
bution over the surface of the balloon intended to be coated. sectioning of the DCB, measuring the thickness, and reporting
This evaluation is separate from uniformity of dosage units as the range and average thicknesses. Other means of measure-
described in USP<905>. ment may be used if appropriately justified.
3.2.5 expected segment content, n—the sum of the Mea-
4.4 Drug Coating Uniformity—The quantitative character-
sured Content from all segments divided by the number of
ization of drug coating uniformity is intended to compare
segments, yielding a calculated expected segment content
actual regional drug content to the expected segment content.
(typically measured in mass), assuming all segments are the
The drug content on specified segments along the effective
same size.
length and around the circumference of the device is analyti-
callydeterminedandreportedrelativetotheexpectedsegment
3.2.6 longitudinal axis, n—major axis of the balloon, paral-
content.
lel to the effective length.
3.2.7 measured content, n—the amount (typically measured 4.5 Particulate Testing—Particulate characterization is in-
in mass) of the Active Pharmaceutical Ingredient (drug) tended to determine the number of particulates released from
determined for each DCB test article segment during the
the device and accessories in pre-specified size ranges during
coating uniformity assessment. insertion, tracking, deployment, retraction, and withdrawal
through a vascular model. Particulates released might include
3.2.8 mock vessel, n—simulation of the vasculature that
material from the balloon drug coating, balloon catheter
replicates the geometry, mechanical properties, and/or chemi-
system, other device coatings, accessory devices used during
cal properties at the intended clinical deployment site.
the procedure, and trace environmental contaminants. The
3.2.9 particulate test system, n—a combination of the vas-
chemical identity and probable source of particulate material
cular model, containing a deployment site or mock vessel, and
should be determined by chemical characterization of repre-
anin-lineparticlecounterorcollectioninabeakeroronafilter
sentative samples of particulates. The scope of the chemical
with an off-line particle counter, microscope, or other particle-
identification is based on multiple considerations that are
counting means.
device-specific. The percent crystallinity of the particulate
3.2.10 simulateduse,n—asimulationofDCBclinicalusein
samples should also be assessed and reported.
accordance with the instructions for use (IFU), including
4.5.1 Remaining Drug (optional)—The amount of drug
insertion,tracking,deployment,andwithdrawalinacontrolled
remaining on the balloon surface after simulated use may be
aqueous environment through a vascular model using clinical
determined analytically.
accessories.
4.6 When establishing the drug coating integrity, drug
3.2.11 spike & recovery, n—an evaluation of particle cap-
coating thickness, drug coating uniformity, and particulate
ture efficiency of the vascular model. Particle standards repre-
characterization testing conditions, the current clinical usage/
sentative of the sizes being investigated should be evaluated
practice and the instructions for use should be considered and
using the same collection and counting technique to be used
incorporated.
during testing. Recovery should meet pre-specified levels.
4.7 Alternative means for evaluating the DCB attributes
covered in this guide should be appropriately justified.
4. Summary of Guide
4.8 See also ASTM F2743-11 and AAMI TIR 42:2010.
4.1 Test Samples—Drug coating integrity, drug coating
thickness, drug coating uniformity and particulate testing
5. Significance and Use
should be performed as separate tests with independent
samples, unless an adequate rationale is provided explaining
5.1 The methods described herein allow for in-vitro charac-
why this is not necessary.Additionally, the samples of particu-
terization of DCB drug coating attributes that, along with
lates used for chemical identification and percent crystallinity
pre-clinical and clinical safety and effectiveness data, establish
determination might need to be separate samples.
that the DCBs, with the characterized coating attributes, are
safe and effective. Clinical safety and therapeutic benefit may
4.2 Drug Coating Integrity—The coating integrity charac-
terization is a qualitative assessment of the DCB drug coating be affected by non-uniform distribution of the active pharma-
ceutical ingredient, coating anomalies on the device, and
appearance over the surface intended to be coated. Coating
integrity visually characterizes coating attributes and coverage particulate release. Variability in drug coating may result in
insufficient or excessive drug availability and inconsistent
anomalies at various magnifications. Representative images of
the drug coating (e.g., light microscope, electron microscope, device performance.
profilometer and/or spectroscope) allow for evaluation of the
5.2 Individual characterization tests may not have direct
coating attributes which may not be detectable during other
clinical relevance, although bench-based characterization re-
quantitative evaluations or macroscopic inspection.
sults can be combined with other data to provide insight to
4.3 Drug Coating Thickness—Coating thickness is a quan- characteristics that influence clinical safety and effectiveness.
titative characterization meant to describe the local drug Bench testing is performed under repeatable and controlled
coating thickness at multiple, representative points along the conditions, providing information about drug coating integrity,
DCB surface. The representative areas should include local thickness,uniformity,particulateshedding,particulateidentity,
attributes, e.g., scoring/cutting features or drug wells, if appli- and particulate crystallinity.
F3320 − 18
5.3 Distribution of the drug coating is characterized by 6.4.4 If applicable, a continuous flow particulate counting
coating integrity, thickness, and uniformity. Particulate counts system:
canprovideameasureofmanufacturingrepeatability,andmay
6.4.4.1 Pump for controlling fluid flow.
provide an indication of in vivo safety if simulated use 6.4.4.2 Continuous flow particle counter capable of detect-
particulates and in vivo particulates are shown to be similar, or
ing and counting particles in appropriate size ranges (e.g.,
if particulate testing results are correlated to in vivo safety. ≥10µm, ≥25µm).
Chemical identity of particulates and crystallinity may further
6.4.5 If applicable, collection vessel.
advise the kinetics related to the potential for particulate
6.4.6 If applicable, particulate filter with appropriate pore
persistence, dissolution or other characteristics which may
size (e.g., 10µm) to capture pre-specified particulate sizes.
relate to in vivo safety. Conducting this testing and gathering
6.4.7 Particulate analyzer or microscope system capable of
the data further allows for the potential comparison of devices
detecting and counting particles in appropriate size ranges
(e.g., demonstrating equivalence between pre-clinical and
(e.g., ≥10µm, ≥25µm).
clinical devices for these coating attributes).
6.4.8 Reference standards for particulate sizing and count-
ing.
5.4 The methods described in this guide are for character-
6.4.9 Accessory devices per Instructions for Use (IFU).
ization purposes and are not intended for production release
6.4.10 Analytical instrumentation for chemical identifica-
testing of drug coated balloon catheters. However, some
tion of particulates. See section 7.7.6 for more information.
content may be applicable to generating release data. The
6.4.11 Analyticalinstrumentationforcrystallinitycharacter-
general guidelines presented here may be used for product
ization of particulates. See section 7.7.6 for more information.
control at various stages of the product development process.
6.4.12 Analytical instrumentation for determining the re-
maining drug content after simulated use (optional).
6. Suggested Reagents and Materials
6.4.13 Test Articles—Unless otherwise justified, all samples
6.1 Coating Integrity—Equipment for visual assessment of
selected for testing should be representative of final, sterile
the DCB drug coating appearance, capable of 25× - 200×
clinical products. A sufficient number of specimens should be
magnification. Depending on the coating surface, higher mag-
testedtoadequatelycharacterizethedevice.Testingofdevices
nification may be needed in order to fully characterize the
from multiple lots should be considered. If the DCB is offered
coating integrity. Instruments such as scanning electron micro-
inmultiplesizes,appropriatesizesshouldbeselectedtoensure
scopes (SEM), optical (light) microscopes, profilometers, fluo-
that the DCB size matrix is adequately characterized for the
rescence microscopes, or Raman spectroscopes can be used if
attributes covered in this guide.
appropriate.
6.2 Coating Thickness: 7. Test Method Considerations
6.2.1 Instruments for cross-sectioning the DCB or the DCB
7.1 Environment—Environmental conditions may affect the
coating (e.g., cryostat, ion mill, scalpel) if applicable.
balloonsystemandshouldbeconsideredwhenassessingDCB
6.2.2 Means (e.g. material) to keep the coating in place
characteristics.Itisimportantthatallproceduresbeperformed
while cutting, if applicable.
in an environment (e.g., room with filtered air) that does not
6.2.3 System for measuring DCB drug coating thickness
impacttheintegrityofthestudy.Contaminationontheballoon
orthogonaltotheballoonsurface(e.g.,SEMoropticalmicros-
surface may be misinterpreted as coating anomalies or may
copy with measurement capability or in conjunction with
mask actual defects.
quantitative image analysis software, quantitative micro or
7.2 Handling—DCBsaretobehandledappropriatelysothat
nano computed tomography (CT) machine, or profilometer).
theintegrityofthestudyisnotcompromised.Poorexperimen-
6.3 Drug Coating Uniformity:
tal techniques and handling may be significant sources of
6.3.1 Means for dividing the DCB into circumferential and artifacts or non-representative results. Excessive manipulation
longitudinal segments. When selecting the instrument and/or
can result in loss of material resulting in changes in drug
means of DCB or DCB drug coating segmentation, consider- coating uniformity, local effects to coating integrity, thickness
ation should be given to minimizing drug coating loss.
variability, and variation in particulate count.
6.3.2 Analytical instrumentation for quantitative determina-
7.3 Sterilization—Unless otherwise justified, all samples
tion of drug content per segment.
selected for testing should be representative of final, sterile
6.3.3 Equipment for measuring segment size characteristics
clinicalproducts.Ifcharacterizationtestarticlesarenotsubject
(e.g., dimensions, surface area, or mass), if applicable.
to the number of sterilization cycles to be used for marketed
product, a rationale should be provided to support this condi-
6.4 Simulated Use and Particulates:
tion being worst case for all assessments.Additional steriliza-
6.4.1 Particle-free (0.22µm filtered) water, in general accor-
tion cycles should not automatically be considered worst case.
dance with USP<788>. Other solutions may be used if justi-
fied.
7.4 Coating Integrity—Evaluation of coating integrity
6.4.2 Apparatus for facilitating flow and vascular model
should be performed over areas representative of the entire
(see 3.1.2 and 7.7.1).
coated balloon surface to allow for complete visualization of
6.4.3 Heatingsystem,capableofmaintainingfluidtempera- thecoatedsurfaceofthedevice,unlessotherwisejustified.The
ture at 37 6 2°C. device should not be in the folded state, but may be in the
F3320 − 18
inflated, partially inflated, or non-inflated state with a rationale this represents the worst case for particle capture efficiency.
provided for the configuration evaluated. Simulated physi- Uniform distribution of particles within the standard used for
ological conditions (e.g., body temperature, mock vessel) may spiking as well as accurate volume for injection are critical to
be used during balloon inflation. If applicable, both regions of the success of the spiking and recovery study. The amount of
high stress/strain and low stress/strain should be evaluated.
particulates recovered during this test should meet a pre-
specified level prior to test article evaluation. It is recom-
7.5 Coating Thickness—Measurement of the drug coating
mended that recovered particulates meet≥90% recovery in the
thickness should be performed at appropriate locations to
≥10µmand≥25µmsizeranges.Thelargestparticulatesizethat
adequatelydeterminethethicknessofthedrugcoatingoverthe
isquantifiedshouldbebasedonthesizeforwhichtherecovery
entire coated balloon surface, with a justification for the
study yields ≥75%. The largest size is suggested to be, at a
number and type of sampled areas.Arationale for the configu-
minimum, ≥50µm.
rationusedformeasurement(e.g.,inflated,partiallyinflated,or
7.7.3 Simulated Use Tracking Within Anatomical Model—
non-inflated state) should be provided. Assessment at or near
Tracking for particulate testing should be through a vascular
any specific characteristics or landmarks of the balloon (folds,
model that simulates a sufficiently challenging, tortuous ana-
metallic structures, etc.) should be included. Simulated physi-
tomical path geometry, including vascular access, through
ological conditions (e.g., body temperature, mock vessel) may
which the balloon catheter will be passed during clinical use.
be used during balloon inflation. Thickness values and varia-
The vascular model should include the portion of the anatomy
tion should be explained to support performance based on
in which the DCB would be passed through the guide catheter
device design. Regulatory bodies have a preference for thick-
orintroducersheathandtheportionthroughwhichitwouldbe
ness determined by direct measurement, but may accept
passed after exit from the guide catheter or introducer sheath,
alternative methods with appropriate justification.
if applicable. The appropriate geometry may be different for
7.6 Drug Coating Uniformity—Testing may be performed
different intended deployment sites (e.g., carotid, coronary, or
on the inflated, partially-inflated, or non-inflated device, with
femoral arteries) or for different access points (e.g., femoral or
appropriate justification. The inflation state of the balloon
radial arteries). Vascular access angulation should be consid-
should not impact drug evaluation. The amount of drug
ered. Critical features for selection of the appropriate vascular
measured per balloon segment using analytical techniques
model include lumen diameter, bend radii, bend reversals,
(measured amount) should be compared to the expected
rigidity, ability to clean, ability to recover particles, and
segmentamount,whichisthefractionalpercentageofthetotal
coefficient of friction of the tracking material (e.g.,
assay based on length, surface area, or mass. The drug per
polyurethane, silicone, Teflon, glass, latex, and native vessel).
segmentmaybecomparedtotheaverageballoonsegmentdrug
The vascular model may be constructed of glass or other
content.Thiscanbereportedinperlength,persurfacearea,per
durable materials which minimize background particulate
mass, or equivalent units. The size (length, area or mass) of
counts.
each segment and the number of segments for each balloon
7.7.4 Simulated Use Deployment Within Anatomical
tested should be justified. Certain regulatory bodies recom-
Model—Simulatedusedeploymentshouldbeintoanappropri-
mend an acceptance criterion for drug coating uniformity. If
ately justified vascular model that reasonably represents the
needed, scientifically valid rationale describing the established
intended clinical deployment site. Critical features to be
acceptance criteria adopted should be provided. If the device
considered for the integral deployment site or mock vessel
design (e.g., balloon fold) impacts drug uniformity, a rationale
includegeometry(e.g.,referencevesselinternaldiameter(ID),
foruniformityincludingthesefeaturesshouldbeprovided.Itis
radius of curvature (if applicable), taper (if applicable)),
up to the manufacturer to determine the validation require-
mechanical properties (e.g., radial compliance, flexibility, co-
ments for any test method with acceptance criteria.
efficient of friction), chemical properties (e.g., presence of
7.7 Particulate Characterization: lubricant, other manufacturing aids, material, interaction with
thedrugcoating).TheDCBshouldbeinflatedtotheratedburst
7.7.1 An appropriate spiking and recovery study should be
pressure (RBP) within a suitably sized lumen, resulting in
performed on the test system. Spiking and recovery should be
complete wall apposition. The inflation duration, within the
performed in the test system, including the vascular model,
mockvesselormodel(asappropriate),shouldbeinaccordance
mockvessel(ifapplicable)andparticulatecollectionbeaker(if
with the IFU. If used, any effect of the mock vessel on
applicable) without the presence of a DCB. Unless otherwise
particulates (coating adhesion to the mock vessel, particulate
justified, accessories should not be in the test system during
release from the mock vessel) will impact the total cumulative
spike and recovery testing. The same procedural steps (e.g.,
count and should be discussed in the report.
flow rate, particle collection method, sample transfer, particu-
late counting method) used during the spiking and recovery 7.7.5 Particulate Collection and Analysis:
study should be used for subsequent particulate testing.
7.7.5.1 Particulate Collection—Particulatemattershouldbe
7.7.2 Particulate standards representative of the sizes to be captured for later analysis or continuously monitored and
investigatedshouldbeusedforspikeandrecoverystudies.The analyzed.Unlessotherwisejustified,particulatesreleasedfrom
numberandsizeofparticulatesstandardsshouldbecertifiedby accessoriesandtheDCB,beginningwhenthefirstaccessoryis
the manufacturer or verified with a different method. One or introduced into the vascular model and ending when the DCB
more injections at the location where the DCB would be and accessories are completely withdrawn, should be counted
introduced into the test fixture should be performed because and sized. Since particulates released can be considered a
F3320 − 18
single bolus, they may be collected and analyzed as a single platform, discussions regarding potential interactions of the
sample. However, there may be advantages to collecting drugcoatingcomponentswiththeballooncathetercomponents
separate samples at different phases of the test or to continu- (e.g. materials), representative colored images of the particu-
ously monitor particulates. In the event that coating compo- lates captured on the filter with tabular description of the
particulate appearance to help classify and identify particles,
nents are water-soluble (e.g., excipient), a constant particulate
testtimethatisnolongerthannecessaryisrecommended.The performing a risk assessment related to potential contaminants
and the coating chemical compositions, and discussions re-
collection method and materials used (e.g., filter effective pore
size, diameter, material, solvent compatibility, crystallinity, garding any available animal and/or clinical data related to
downstream or embolic events. This approach may not be
color, flatness, and roughness) should be appropriate for
practical if: the device is made of novel materials, there is a
subsequent imaging and analysis steps.
hydrophilic coating present, high amounts of particulates are
7.7.5.2 Sizing and Counting—The sizing and counting of
observed in the quantification studies, there are concerning
particulates can be accomplished by light obscuration or by
events in animal/clinical data, etc. Various regulatory agencies
filtrationandmicroscopicanalysis.Eachmethodhasitsadvan-
may have different recommendations for this analysis and
tages and disadvantages. A brief summary of methods is
should be consulted prior to commencing testing. Unless
provided in Annex A1. Additional information on particulate
otherwise justified, results should be reported as a percentage
sizing and counting may be found in USP<788> and AAMI
of total material analyzed.
TIR 42.The user is encouraged to consider all options prior to
7.7.6.2 Particulate Crystalline Characterization—The per-
testing.
centcrystallinityoftheparticulatesamplesshouldbereported.
7.7.6 Analytical Methods—Chemical characterization of
Peaks not associated with the active pharmaceutical ingredient
captured particulates for identity and crystallinity can be
(API) should be reported and discussed or their omission
accomplished through a variety of methods including energy-
appropriate justified. A justification for the samples analyzed
dispersive x-ray spectroscopy (EDX), Fourier transform infra-
should be provided. If necessary and justified, samples from
red (FTIR) spectroscopy, Raman spectroscopy, mass
multiple devices can be combined to conduct this analysis or
spectroscopy, differential scanning calorimetry (DSC), or dif-
particles smaller than 10 µm may be included in the analysis.
fraction techniques. A combination of two or more methods
7.7.7 Retained Material Content (optional)—If desired,
might be needed to fully characterize the crystallinity.Analyti-
drug content analysis of the drug coating rem
...