Select Updates for Non-Clinical 
Engineering Tests and 
Recommended Labeling for 
Intravascular Stents and Associated 
Delivery Systems 
 
Guidance for Industry and Food and 
Drug Administration Staff  
Document issued on: August 18, 2015. 
 
The draft of this document was issued on August 30, 2013. 
 
This document updates and augments (but does not replace) Non-Clinical 
Engineering Tests and Recommended Labeling for Intravascular Stents and 
Associated Delivery Systems guidance, issued April 18, 2010.  
 
For questions regarding this document, contact the Interventional Cardiology Devices Branch at or 
the Peripheral Interventional Devices Branch at (301) 796-7000.  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
Office of Device Evaluation 
Division of Cardiovascular Devices 
 
Office of Science and Engineering Laboratories  Preface 
Public Comment 
You may submit electronic comments and suggestions at any time for Agency consideration to 
http://www.regulations.gov.  Submit written comments to the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. 
Identify all comments with the docket number FDA-2013-D-0920.  Comments may not be acted 
 
upon by the Agency until the document is next revised or updated.
Additional Copies 
Additional copies are available from the Internet.  You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance.  Please use the document 
number 1826 to identify the guidance you are requesting. 
  Select Updates for Non-Clinical Engineering 
Tests and Recommended Labeling for 
Intravascular Stents and Associated Delivery 
Systems
 
 
 
Guidance for Industry and  
Food and Drug Administration Staff  
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) current thinking on this topic.  It does not establish any rights for any person and is 
not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
contact the FDA staff responsible for this guidance as listed on the title page.  
 
I.  Introduction and Scope 
FDA has developed this guidance to inform the coronary and peripheral stent industry about 
selected updates to FDAs thinking regarding certain non-clinical testing for these devices.  
While FDA is in the process of making more substantial updates to the Non-Clinical Engineering 
Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems 
guidance 
(http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm0718
63.htm), we are issuing this guidance update on select sections in order to notify the industry in a 
timely manner of our revised recommendations.   
Section III of this guidance provides cross-reference and updates to the related sections of the 
existing Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents 
and Associated Delivery Systems guidance.   FDA will incorporate the elements of this final 
guidance into an anticipated revision of the entire Non-Clinical Engineering Tests and 
Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance. 
This guidance provides updates for the following topics: 
  Pitting corrosion potential; 
  Galvanic corrosion; 
  Surface characterization; and 
  Nickel ion release. 
1 
   
This guidance document addresses self-expanding and balloon expandable extracranial 
intravascular stents and their associated delivery systems. The scope includes extracranial 
intravascular stents placed in coronary or peripheral arteries and saphenous vein grafts but is not 
limited to stents used in these locations; other vascular indications outside of the intracranial 
vasculature are also included.  This guidance or parts of this guidance may not be applicable to 
stents with components intended to degrade. 
 
Intravascular stents, including balloon expandable and self-expanding stents, are class III devices 
whose product codes are given in the table below. 
Table 1: Product Codes for Stents Addressed in this Guidance 
Product Code  Device 
 
MAF  Stent, Coronary 
NIM  Stent, Carotid 
NIN  Stent, Renal 
NIO  Stent, Iliac 
NIP  Stent, Superficial Femoral Artery 
These devices require a premarket approval (PMA) application before marketing.  See sections 
513(a) and 515 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and 21 CFR Part 
814.   
II.  Background and Rationale 
FDA held a public workshop entitled Cardiovascular Metallic Implants: Corrosion, Surface 
Characterization, and Nickel Leaching on March 8-9, 2012 that provided information on 
current practices for performing these tests (see 
http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm287535.htm).  A 
pre-workshop assignment on test practices and outcomes completed by participants from 
industry, test houses, and academia served as a basis for moderated discussions at this workshop.  
Regarding corrosion testing, the general consensus was that no single corrosion assessment can 
be used to assess in vivo corrosion susceptibility.  However, nearly all respondents indicated that 
they performed pitting corrosion testing, and more than half of the respondents indicated that 
they performed galvanic corrosion testing.  Therefore, in the current guidance, we have updated 
a key aspect of sample conditioning for pitting corrosion testing that is less burdensome, and 
included additional information on when galvanic corrosion testing may be omitted with 
justification, based on information gained from the workshop. 
Corrosion of implant devices made of, or having components made of, nickel-rich alloys (e.g., 
nitinol, stainless steel, MP35N) results in the release of nickel ions, which may lead to various 
modes of toxicities.  However, there are no suitable standard test methods for measuring metal 
ion release from intravascular stents.  Therefore, based on currently available scientific evidence 
and industry practices discussed at the workshop, we have included information on test methods 
2 
   
for in vitro nickel ion release testing.  Furthermore, both nickel ion release and corrosion 
characteristics are dependent on surface finishing for nitinol and for some other nickel-rich 
alloys.  While there is insufficient information to quantitatively correlate surface oxide 
characteristics to device performance characteristics at this time, workshop participants indicated 
that surface characterization may be most useful as a tool to assess the root cause of poor device 
performance characteristics (e.g., corrosion susceptibility or nickel ion release).  We have 
therefore modified the recommendations for when surface characterization should be performed 
to consider outcomes from other characterization testing and surface finishing techniques used.   
 
Based on the information obtained from this workshop, FDA was able to refine existing 
recommendations on when certain tests should be performed or considered, such that industry 
can avoid performing additional tests that would add little valid scientific evidence regarding the 
safety and effectiveness of the device.  For example, corrosion testing post-accelerated durability 
testing has generally not provided value over evaluating corrosion on as-manufactured stents.  In 
addition, information on test methods for pitting and galvanic corrosion, as well as nickel ion 
release, has been updated, which we believe will aid in test protocol development.  While pitting 
corrosion potential, surface characterization, and in vitro nickel ion release testing are described 
in different sections of the Non-Clinical Engineering Tests and Recommended Labeling for 
Intravascular Stents and Associated Delivery Systems guidance, taken together, the results of 
these tests are interrelated and provide a global perspective on the corrosion and ion leach 
potential of the stent.  We recommend that you initially assess the pitting corrosion potential of 
your stent.  If the results do not meet the pre-specified acceptance criteria or an established 
surface finishing process is not used, we recommend that you perform further testing outlined in 
the specific test sections below and the flow chart in Appendix 1.  If available, data obtained 
from other assessments, such as animal or clinical studies, may supplement the analysis of the 
corrosion and ion leach potential of the device, and should be considered as part of the risk 
analysis for these potential failure modes.  
 
III.  Select Updates 
A. Material Characterization 
1.  Pitting Corrosion Potential 
The following recommendations update Section IV.A.3 of the Non-Clinical 
Engineering Tests and Recommended Labeling for Intravascular Stents and 
Associated Delivery Systems guidance regarding Pitting Corrosion Potential. 
We recommend that you characterize the corrosion potential of your as-manufactured 
(i.e., non-fatigued) stent according to the method described in the currently recognized 
version of ASTM F21291 or equivalent method.  The test setup should meet the criteria 
                                                 
1 ASTM F2129 Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to 
Determine the Corrosion Susceptibility of Small Implant Devices. Please see FDAs Recognized Consensus 
Standards database (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm) for the most current 
information on which editions are recognized by FDA. 
3 
   
outlined in ASTM G5-142 (figure 2, Table x2.1).  Testing should be performed after 
subjecting the device to simulated use testing, which includes crimping, tracking, and 
deployment of the device through an in vitro fixture that mimics in vivo anatomic 
conditions (See section C2. Delivery, Deployment, and Retraction in the Non-Clinical 
Engineering Tests and Recommended Labeling for Intravascular Stents and Associated 
Delivery Systems guidance).  Alternatively, the stent may be subjected to strains expected 
during simulated use (e.g. bending) without passing through a tracking fixture, with 
justification.  This device conditioning is intended to simulate the clinical conditions of 
the stent at the time of implantation.  You should test device sizes that are the worst-case 
in terms of corrosion susceptibility based on surface area, size, and/or geometry.  
Considerations should be given to factors such as geometry or size that may affect 
surface finishing such as adequate polishing of regions of high curvature.  Test devices 
should be representative of final sterilized devices and selected such that potential 
variations due to manufacturing can be assessed (e.g. by taking samples from multiple 
lots).  In addition, the number of samples tested and sampling scheme should be justified 
with consideration of variability in results.  If your worst case stent size cannot be 
accommodated in the test fixture, alternate device sizes or shortened samples may be 
used with justification.  We recommend that you discuss the variability of your results.   
Test reports for pitting corrosion potential testing should be consistent with ASTM F2129.  
For example, test reports should include corrosion/rest potentials, breakdown potentials, 
as well as polarization curves.  When practical, we recommend that you plot all 
polarization curves in one graph.  You should report whether your test setup met the 
criteria outlined in ASTM G5-14.  Results should be assessed against your acceptance 
criteria.  The acceptance criteria for the pitting corrosion testing should be determined by 
comparison to a legally marketed device with good clinical history of use (i.e. no history 
of corrosion-related fractures or adverse events associated with nickel release).  
Alternatively, while there is a lack of data directly linking in vitro corrosion testing to in 
vivo corrosion outcomes, conservative guidelines have been published by Rosenbloom 
and Corbett, which may also be used to establish the acceptance criteria3.  If breakdown 
occurred in any samples tested, you should include results of the visual inspection of your 
device before and after testing to assess evidence of pitting.  Images of sufficient 
magnification should be included to support these observations and identify pit locations.   
Literature or previous performance data may support the pitting susceptibility assessment of 
your stent.  However, the materials, design, and fabrication processes specific to your stent 
may reduce or eliminate the applicability of literature or previous experience with your 
device.  For example, the pitting corrosion resistance of nitinol is sensitive to processing 
variables such as heat treatment and surface finish, and therefore, literature would not be 
                                                 
2 ASTM G5-14 Standard Reference Test Method for Making Potentiostatic and Potentiodynamic Anodic 
Polarization Measurements 
3 Rosenbloom, S. N. and R. A. Corbett (2006). An Assessment of ASTM F 2129 Test Results Comparing Nitinol to 
Other Implant Alloys. Proceedings of the International Conference on Shape Memory and Superelastic 
Technologies (ASM International), Pacific Grove, CA. 
4 
   
applicable.  In cases where manufacturing changes that could impact surface finish are 
implemented, ASTM F2129 testing or surface characterization should be performed to 
demonstrate that the surface is not adversely altered. 
 
2.  Galvanic Corrosion 
The following recommendations update Section IV.A.3 of the Non-Clinical 
Engineering Tests and Recommended Labeling for Intravascular Stents and 
Associated Delivery Systems guidance regarding Galvanic Corrosion. 
 
We continue to recommend the Galvanic Corrosion testing recommendations as outlined 
in Section IV.A.3 of the Non-Clinical Engineering Tests and Recommended Labeling for 
Intravascular Stents and Associated Delivery Systems guidance.  As an alternative to 
using marketed stents for galvanic corrosion testing, coupons representing an expected 
worst-case galvanic coupling, that are subjected to identical manufacturing processes 
may be used.  In addition, a justification may be provided, in lieu of testing, if the 
expected worst-case galvanic coupling potentials are small and if the relative surface 
ratios of the cathodic to anodic materials are low (e.g., marker band to stent surface ratio). 
B. Material Composition 
1.  Surface Characterization 
The following recommendations update Section IV.A.1 of the Non-Clinical 
Engineering Tests and Recommended Labeling for Intravascular Stents and 
Associated Delivery Systems guidance to clarify when Surface Characterization 
should be considered. 
 
Intravascular metallic stents should have a polished, passive and clean surface unless a 
justification for an alternative surface is provided.  Surface finish is known to affect other 
material properties such as corrosion and metal ion release for certain alloys (e.g. nitinol, 
MP35N, stainless steel).  Therefore, if results from other characterization testing (e.g., 
pitting corrosion) do not meet pre-specified acceptance criteria, we recommend that you 
characterize the material surface of your finished product in terms of passivation layer 
chemical composition vs. depth and/or perform in vitro nickel leach testing (see 
Appendix 1).  However, if you do not have a final passivation step, or use the same 
surface finishing process as for a marketed stent with good clinical history, or if you do 
not use a commonly used surface finishing process, we recommend that you perform 
surface characterization of your device.  Commonly used surface finishing processes may 
include a process with any final passivation step such as electropolishing, chemical etch.  
Special attention should be paid to surfaces and geometries that may be affected by heat 
or finishing processes.  Surface characterization should be performed on multiple devices 
from multiple lots.  This characterization should include multiple assessments at various 
representative areas on the device surface including the locations that may be most 
difficult to polish.  Acceptance criteria for surface characterization should be pre-
specified based on oxide thickness and composition.  While there is limited information 
on the correlation between oxide thickness to nickel release, work by Fasching et al 
5 
   
indicates that nickel release increases substantially as the oxide thickness increases from 
20 to 200nm for nitinol4.  In addition, information gathered from prior submissions of 
nitinol devices indicate that an oxide layer of less than 50nm typically do not result in 
significant levels of nickel release.  If information on oxide thickness of other legally 
marketed nitinol implants with good clinical history of use is available, this information 
may also be used to set your acceptance criteria.  The oxide layer should consist primarily 
of TiO (for nitinol) and should not contain nickel-rich regions.  
2 
C. Biocompatibility 
1.  Nickel ion release 
The following recommendations update Section IV.E of the Non-Clinical 
Engineering Tests and Recommended Labeling for Intravascular Stents and 
Associated Delivery Systems guidance regarding Nickel Ion Release. 
 
For devices containing nickel-rich alloys, we recommend that you consider the potential 
for nickel ion release from your device.  Specifically, if the corrosion resistance and 
passivation layer characterization results do not meet pre-specified acceptance criteria for 
your device, we recommend that you quantify nickel ion release from your device over 
time by measuring concentrations of nickel leached from the device into a fluid at 
physiologic temperature and pH.  To avoid excursions in pH, we recommend using a 
buffered solution, such as phosphate buffered saline (PBS).  We recommend testing be 
conducted for at least 60 days.  Alternatively if the testing demonstrates that the surface is 
stable (i.e. the release rate falls below a predetermined level based on toxicological risk 
assessment), testing may be concluded earlier, with a minimum test duration of 30 days.  
A justification should be provided for reducing the test duration.  Solution sampling 
should be conducted at adequate intervals and over a sufficient duration to sufficiently 
characterize the nickel release profile of the device in vitro.  You should use a sampling 
regimen that will adequately capture any initial bolus release of nickel.  For example, 
sampling intervals for nitinol implants might include at least days 1, 2, 4, 7, 14, 21, and 
28 days for the first month of cumulative exposure time, and at least bi-weekly thereafter.  
Alternative sampling frequencies may be used with justification. 
Testing should be performed on as-manufactured devices after subjecting the device to 
simulated use testing, which includes tracking and deployment of the device through an 
in vitro fixture that mimics in vivo anatomic conditions (See section C2. Delivery, 
Deployment, and Retraction in the Non-Clinical Engineering Tests and Recommended 
Labeling for Intravascular Stents and Associated Delivery Systems guidance), or as 
outlined in section A1. Pitting Corrosion Potential in the current guidance update.  Test 
                                                 
4 Fasching, A., E. Kus, et al. (2009). The effects of heat treatment, surface condition and strain on nickel-leaching 
rates and corrosion performance in nitinol wires. Materials and Processes for Medical Devices, ASM International, 
Minneapolis MN. 
6 
   
devices should be representative of final sterilized devices and selected such that 
potential variations due to manufacturing can be assessed (e.g., by taking samples from 
multiple lots), with a justification for the number of samples tested and sampling scheme.  
Additional samples may be needed if there is wide variability in the test results.  The 
devices should be selected such that they represent the worst-case for nickel leaching 
(e.g., largest surface area).  A justification of sample selection should be provided (e.g. if 
largest sample does not fit testing apparatus). 
Validation testing should be performed and summarized in the test report.  This 
validation testing should include validation of the analytical instrumentation as well as an 
extended (>14 days) spike and recovery test to demonstrate that nickel is not lost out of 
solution, (e.g., due to adsorption onto the extraction container) during testing.  The 
extraction ratio, or the ratio of the surface area of the tested device to the volume of test 
solution, should be provided along with a rationale for why the ratio was selected.  Both 
the detection limit of the analytical instrumentation and nickel solubility in the test 
solution should be considered in your rationale. For example, a surface to volume ratio of 
0.1 to 1cm2/mL may be appropriate if the nickel released does not approach the nickel 
solubility limit in the test solution and is sufficiently above the detection limit.   
We recommend that you replace the entire test solution at each time point sampled, or an 
alternative method may be used with justification.  
Test results should be reported as total cumulative release per device in micrograms, as 
well as a per day release (g/day).  In addition, if release rates are compared between 
devices or samples with different geometries, results should also be normalized by device 
surface area.  
2.  Risk Assessment   
If in vitro nickel leach testing will be performed, a risk assessment should be performed 
prior to testing.  The risk assessment should establish acceptable limits for nickel released 
from the device based on potential toxicological risks.  The results of in vitro nickel leach 
testing should then be used as the basis for the exposure estimate.  If any in vivo nickel 
exposure data exists for your device, these values should be included in your risk 
assessment as well.  The risk assessment should consider route of exposure.  While much 
of the literature on nickel toxicity is from studies with oral or inhalation as routes of 
exposure, and not intravascular exposure, it is known that chemicals that are toxic via one 
route of exposure may also be toxic via a different route of exposure.   Standard route-to-
route extrapolation methods should be used to address toxicity from different routes of 
exposure in the absence of data from the relevant route of exposure.  The duration of 
exposure should be considered as well.  In addition to acute and chronic (30 days) non-
cancer endpoints, if your device releases nickel in a chronic fashion (30 days) based on 
in vitro testing, carcinogenicity (including genotoxicity) and reproductive toxicity should 
be considered.  In addition to systemic toxicity, local effects of nickel accumulation 
should also be discussed as part of your assessment of the device.  References used in the 
risk assessment, as well as a description of how the values used in the risk assessment 
calculations were derived, should be included in your risk assessment report. 
7 
   
Appendix 1  Testing Paradigm Flowchart 
 
 
 
Fasching, A., E. Kus, et al. (2009). The effects of heat treatment, surface condition and strain on 
nickel-leaching rates and corrosion performance in nitinol wires. Materials and Processes for 
Medical Devices, ASM International, Minneapolis MN. 
Rosenbloom, S. N. and R. A. Corbett (2006). An Assessment of ASTM F 2129 Test Results 
Comparing Nitinol to Other Implant Alloys. Proceedings of the International Conference on 
Shape Memory and Superelastic Technologies (ASM International), Pacific Grove, CA. 
8