ISO/TS 17137:2014

TECHNICAL ISO/TS
SPECIFICATION 17137
First edition
2014-05-15
Cardiovascular implants and
extracorporeal systems —
Cardiovascular absorbable implants
Implants cardiovasculaires et systèmes extracorporels — Implants
cardiovasculaires absorbables
Reference number
©
ISO 2014
© ISO 2014
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Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Implant considerations . 2
4.1 Classification . 2
4.2 Intended clinical performance . 3
4.3 Intended clinical use . 3
4.4 Materials . 3
4.5 Packaging, labelling, and sterilization . 3
4.6 Risk management . 6
5 Design verification and validation — Testing and analysis . 7
5.1 Overview . 7
5.2 Considerations in the characterization and assessment of material and
implant properties . 9
5.3 in vitro procedural assessment .12
5.4 in vitro degradation assessment (post procedure) .13
5.5 in vitro-in vivo correlation (IVIVC) .15
5.6 Biocompatibility .16
5.7 Pre-clinical in vivo evaluation .17
5.8 Clinical considerations specific to absorbable implants .19
5.9 Shelf life considerations .21
Annex A (informative) Nomenclature of absorb, degrade and related terms .23
Bibliography .24
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2. www.iso.org/directives
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any
patent rights identified during the development of the document will be in the Introduction and/or on
the ISO list of patent declarations received. www.iso.org/patents
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
The committee responsible for this document is ISO/TC 150, Implants for surgery, sous-comité SC 2,
Cardiovascular implants and extracorporeal systems.
The following definitions apply in understanding how to implement an ISO International Standard and
other normative ISO deliverables (TS, PAS, IWA):
— “shall” indicates a requirement;
— “should” indicates a recommendation;
— “may” is used to indicate that something is permitted;
— “can” is used to indicate that something is possible, for example, that an organization or individual
is able to do something.
3.3.1 of the ISO/IEC Directives, Part 2 (sixth edition, 2011) defines a requirement as an “expression in
the content of a document conveying criteria to be fulfilled if compliance with the document is to be
claimed and from which no deviation is permitted.”
3.3.2 of the ISO/IEC Directives, Part 2 (sixth edition, 2011) defines a recommendation as an “expression in
the content of a document conveying that among several possibilities one is recommended as particularly
suitable, without mentioning or excluding others, or that a certain course of action is preferred but not
necessarily required, or that (in the negative form) a certain possibility or course of action is deprecated
but not prohibited.”
iv © ISO 2014 – All rights reserved

Introduction
Absorbable cardiovascular implants are medical devices with various clinical indications for use in the
human cardiovascular blood system. An absorbable cardiovascular implant, or at least a portion thereof,
is designed to intentionally degrade over time into products that are absorbed by the body through
metabolism, assimilation, and/or excretion (elimination). Such implants can be either surgically or
interventionally introduced to the site of treatment.
This Technical Specification outlines requirements for intended performance, design attributes,
materials, design evaluation, manufacturing, sterilization, packaging, and information supplied by the
manufacturer. This Technical Specification should be considered as a supplement to ISO 14630, which
specifies general requirements for the performance of non-active surgical implants. This Technical
Specification should also be considered as a supplement to relevant device-specific standards such as the
ISO 25539 series specifying requirements for endovascular devices, which do not address degradation
and other time dependent aspects of absorbable implants and coatings.
This Technical Specification is not comprehensive with respect to the pharmacological evaluation
of cardiovascular absorbable implants. More detailed safety and performance requirements for
pharmacological agents included in the absorbable cardiovascular implant are described in ISO/TS 12417.
Only issues related to absorption combined with the cardiovascular implant are covered by this
Technical Specification.
NOTE For issues related to the common mechanical function of the cardiovascular implant, the reader might
find it useful to consider a number of other International Standards (see Bibliography).
TECHNICAL SPECIFICATION ISO/TS 17137:2014(E)
Cardiovascular implants and extracorporeal systems —
Cardiovascular absorbable implants
1 Scope
This Technical Specification outlines design verification and validation considerations for absorbable
cardiovascular implants.
NOTE Due to the variations in the design of implants covered by this Technical Specification and in some
cases due to the relatively recent development of some of these implants (e.g. absorbable stents), acceptable
standardized in vitro tests and clinical results are not always available. As further scientific and clinical data
become available, appropriate revision of this Technical Specification will be necessary.
For the purpose of this Technical Specification the terms “vessel and/or vascular space” refer to the
entire circulatory system, including the heart and all vasculature.
This Technical Specification is applicable to implants in direct contact with the cardiovascular system,
where the intended action is upon the circulatory system. This technical specification does not address
the specific evaluation of issues associated with viable tissues, viable cells, and/or implants with non-
viable biological materials and their derivatives. Additionally, procedures and devices used prior to and
following the introduction of the absorbable cardiovascular implant (e.g. balloon angioplasty devices)
are excluded from the scope of this Technical Specification if they do not affect the absorption aspects of
the implant. A cardiovascular absorbable implant may incorporate substance(s) which, if used separately,
can be considered to be a medicinal product (drug product) but the action of the medicinal substance is
ancillary to that of the implant and supports the primary mode of action of the implant.
NOTE Some aspects of absorbable components of cardiovascular device-drug combination products (e.g.
coatings) in their connection with drug-related aspects of the device are addressed in ISO/TS 12417.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993 (all parts), Biological evaluation of medical devices
ISO 11135-1, Sterilization of health care products — Ethylene oxide — Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices
ISO 11137 (all parts), Sterilization of health care products — Radiation
ISO/TS 12417, Cardiovascular implants and extracorporeal systems—Vascular device-drug combination
products
ISO 14155:2011, Clinical Investigation of Medical Devices for Human Subjects — Good Clinical Practice
ISO 14630:2012, Non-active surgical implants — General requirements
ISO 14937, Sterilization of health care products — General requirements for characterization of a sterilizing
agent and the development, validation and routine control of a sterilization process for medical devices
ISO 14971:2007, Medical devices — Application of risk management to medical devices
ISO/TR 15499, Biological evaluation of medical devices — Guidance on the conduct of biological evaluation
within a risk management process
ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development,
validation and routine control of a sterilization process for medical devices
ISO 25539-2:2008, Cardiovascular implants — Endovascular devices — Part 2: Vascular stents
ISO 5840 (all parts), Cardiovascular implants — Cardiac valve prostheses
ISO 11607-1:2006, Packaging for terminally sterilized medical devices — Part 1: Requirements for materials,
sterile barrier systems and packaging systems
IEC 62366, Medical devices — Application of usability engineering to medical devices
ASTM F2394-07(2013), Standard Guide for Measuring Securement of Balloon Expandable Vascular Stent
Mounted on Delivery System
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1
absorb
action of a non-endogenous (foreign) material or substance passing through or being
assimilated by cells and/or tissue over time
3.2
degradation product (noun)
byproduct (noun)
any intermediate or final result from the physical, metabolic, and/or chemical decomposition of a
material or substance
3.3
degrade (verb)
to physically, metabolically, and/or chemically decompose a material or substance
3.4
leachable (adjective)
substances that can be released from a medical device or material during clinical use
Note 1 to entry: In absorbable devices, leachables may be substances released from the as-manufactured product
or substances generated and released as a consequence of its degradation (i.e. degradation products).
4 Implant considerations
4.1 Classification
A cardiovascular absorbable implant is a product that is considered to be a medical device that
accomplishes its intended clinical use and performance over a defined time period. A cardiovascular
absorbable implant accomplishes its intended clinical use and is then absorbed by the body over a finite
period of time. The implant’s temporary nature is provided by its ability to degrade and the resulting
products’ ability to be metabolized, assimilated, and/or excreted (eliminated) over time.
An absorbable cardiovascular implant may also incorporate a medicinal substance. However, for the
purposes of this Technical Specification, if the action of the medicinal substance is ancillary to a device’s
primary mode of action, the product is considered to be a surgical implant.
The manufacturer shall determine the acceptability of the product for clinical use at all stages of the
product life cycle.
2 © ISO 2014 – All rights reserved

4.2 Intended clinical performance
The intended performance of an absorbable implant shall be described and documented by addressing
at least the following, with particular regard to patient’s safety:
a) intended purpose(s);
b) intended lifetime.
4.3 Intended clinical use
The intended clinical location shall be identified as one or more of the following:
a) abdominal aorta;
b) arterio-venous shunt for vascular access;
c) carotid artery;
d) coronary artery;
e) coronary heart chambers;
f) femoral artery;
g) iliac artery;
h) popliteal artery;
i) intra-cerebral artery;
j) renal artery;
k) thoracic aorta;
l) thoraco-abdominal aorta;
m) tibial artery;
n) other arterial or venous vessels to be specified.
4.4 Materials
The requirements of ISO 14630:2012, Clause 6, shall apply.
Additional testing appropriate to specific material types (e.g. metals, polymers, drugs) shall be
performed to determine material acceptability for use in the design. For example, a general guide for
assessing absorbable polymeric implants can be found in ASTM F2902. In a more specific example,
absorbable materials dependent on shape memory properties should be subjected to testing that
assesses transformation properties. For drug-eluting absorbable implants, drug identity testing shall
be performed, including the identification of impurities and degradants. Electro-chemical potentials of
differing metals (stents, guidewires, other accessory devices) might require additional types of testing.
4.5 Packaging, labelling, and sterilization
4.5.1 Packaging
4.5.1.1 General
The requirements of ISO 11607-1:2006 and ISO 14630:2012, Clause 10 shall apply.
Each device shall be packaged in a unit container with a sterile barrier, or a combination of unit container
and an outer container. The unit container (within its outer container if applicable) may be packaged in a
shipping container during transit and storage.
The device packaging configuration should be designed to protect the implant during normal conditions
of handling, storage and transport such that device specifications are maintained.
For devices that are supplied sterile, the sterile barrier shall be maintained to permit the contents to be
presented for use in an aseptic manner.
4.5.1.2 Considerations for absorbable product
For absorbable products, non-standard packaging attributes may be needed to mitigate or eliminate
the effects of environmental factors in order to maintain the physical, chemical and/or mechanical
specifications of the implant. Where the absorbable product is susceptible to hydrolytic or corrosive
degradation, consideration should be given toward the control and/or removal of moisture from the
package interior (e.g. through the use of moisture resistant packaging materials and/or desiccants).
In addition, absorbable products may also be susceptible to physical, chemical, and/or mechanical
degradation under extreme temperature conditions. For example, storage at temperatures that approach
or exceed the glass transition temperature of absorbable polymeric products might adversely affect the
physical and chemical state of the implant. Therefore, storage conditions should be specified that limit
the temperature range and time limit of implant exposure.
4.5.2 Labelling
4.5.2.1 Label(s)
Each device shall be accompanied by one or more labels, one on each of the containers.
The requirements of ISO 14630:2012, Clause 11, shall apply, with the following information to be
supplied as part of the label(s):
NOTE Items with particular relevance to absorbable implants are italicised.
a) name or trade name of the device;
b) recommendations for storage; the actual modelled storage range determined to be acceptable for the
packaged device, taking into consideration the absorbable properties of the device or components
thereof;
c) description and/or list of the package contents;
d) size and device type (if applicable);
e) dimensions applicable for clinical use;
f) sterilization method and the notification ‘STERILE’ if applicable;
g) for implants supplied sterile, a warning against the use of the device if the package is damaged;
h) reference to consult Instructions for Use for user information;
i) chemical nature of any storage medium in the unit container, with appropriate hazard warning.
4.5.2.2 Instructions for use (IFU)
The requirements of ISO 14630:2012, Clause 11, shall apply together with the following information to
be included, if applicable:
a) name or trade name of the device;
4 © ISO 2014 – All rights reserved

b) recommendations for storage; the actual modelled storage range determined to be acceptable for the
packaged device, taking into consideration the absorbable properties of the implant or components
there-of;
c) statement that the device can or cannot be re-sterilized, including the statements ‘STERILE’, ‘DO
NOT RESTERILIZE’ in prominent form, if applicable;
d) the statement ‘SINGLE USE ONLY’ in prominent form, if applicable;
e) description and/or list of the package contents;
f) available models and sizes applicable for intended clinical use;
g) identification and description of the absorbable device or components thereof;
h) location of the absorbable part of the device, if only a portion of the implant is absorbable;
i) a general description of the principle of degradation along with both the expected time frame for
loss of mechanical properties and in vivo absorption of the implant;
j) intended use/indications for use;
k) contraindications, warnings and precautions;
l) the potential for interaction of the absorbable material with other materials used in the handling,
preparation and implantation of the implant, considering direct contact and the effect of procedural
fluids;
m) potential adverse events, including known adverse events associated with implant (or portion
thereof) degradation and/or in vivo absorption process;
n) recommended methods for the aseptic presentation and preparation of the implant considering the
potential for interaction of the absorbable material with the environment or materials used;
o) recommended methods for preparation of the implantation site if applicable;
p) recommendations for visualization if applicable;
q) if the implant is metallic, electrically conductive, or contains metallic or electrically conductive
components, MRI safety information shall be provided, including any potential impact that an
accompanying radio frequency (RF)-induced temperature rise may have on the absorbable
properties of the implant or components thereof. Provided information may also include a post-
implantation time period after which safety MRI precautions are no longer relevant or needed;
r) date of or reference relating to the publication of the text, indicating if the text has been revised.
4.5.3 Sterilization
4.5.3.1 General
The requirements of ISO 14630:2012, Clause 9, shall apply.
The entirety of the device and packaging shall be compatible with the chosen sterilization method. The
following provides a list of typical sterilization methods and a brief description of their applicability to
absorbable implants or components thereof.
4.5.3.2 Radiation sterilization
If devices are to be sterilized by gamma, electron beam or X-ray radiation sterilization, ISO 11137 Parts
1, 2 and 3 shall apply, including the Part 1 provision that the product meet its performance specifications
throughout its intended lifetime at its maximum acceptable dose.
NOTE Radiation sterilization (of polymers) commonly results in a residual presence of free radicals and an
increase in the rate of degradation.
4.5.3.3 Ethylene oxide sterilization
If devices are to be sterilized by ethylene oxide, ISO 11135-1 shall apply, including the provision that
the product meet its performance specifications at the most challenging parameters. Ethylene oxide
sterilization processes involve exposure to heat and humidity parameters that may impact absorbable
material properties that could in turn impact product performance specifications.
4.5.3.4 Steam sterilization
If devices are to be sterilized by steam, ISO 17665-1 shall apply. Steam may not be a viable sterilization
option since hydrolysable polymers are highly susceptible to uncontrollable damage under autoclave
conditions.
4.5.3.5 Alternative sterilization
If devices are to be sterilized by use of any other sterilization method, such as dry heat sterilization,
hydrogen peroxide sterilization, ozone or nitrogen dioxide sterilization, ISO 14937 shall apply.
4.6 Risk management
4.6.1 General
The manufacturer shall define and implement a risk management system in accordance with ISO 14971.
The entire system shall provide intended users the ability to safely and effectively perform all required
preoperative, intra-operative, and post-operative procedural tasks and achieve all desired objectives.
This shall include all other tools and accessories that intended users will use to complete the procedure.
NOTE For guidance on how to determine and establish design attributes pertaining to the use of the system
to conduct the implant procedure, see ANSI/AAMI HE74 and IEC 62366.
4.6.2 Failure modes
There exist three groups of failure modes. Examples of possible failure within each group specific to
absorbable cardiovascular implants include the following:
Design related: One or more implant design deficiencies (e.g. materials, dimensions, construction)
can result in unintended functional failure (e.g. selection of an absorbable material that degrades
prematurely). In addition, implant design should provide a safety margin adequate to provide functional
integrity in all clinical indications (e.g. force differences in the coronary vs tibial artery).
Manufacturing related: Inappropriate manufacturing conditions (e.g. excess moisture), storage (e.g.
defective packaging) and/or transport (e.g. excess thermal exposure) can potentially result in functional
compromise or failure.
Application/User Interface related: Unintended (abnormal) use errors (e.g. over-expansion resulting
in excessive particulate/fragment generation at implantation) as described in IEC 62366. Intended
6 © ISO 2014 – All rights reserved

(correct) use errors (e.g. unable to deliver device past tortuous anatomy that was not excluded in the
IFU).
NOTE ISO 25539-2:2008, Annex C and ISO 5840-3:2013, Annex G. contain lists of potential cardiovascular
hazards that can provide basis for a risk analysis of an absorbable implant.
4.6.3 Risk mitigation
These risks can be mitigated by three mechanisms (see also ISO 14971:2007, A.2.6.2):
a) inherent safety by design;
b) protective measures in the medical device itself or in the manufacturing process;
c) information for safety.
4.6.4 Specific aspects for absorbable implants
Absorbable implants exhibit time dependent sensitivities to temperature and moisture due to the
degradable/corrosive nature of these implant materials. Therefore, the whole life cycle of the implant
from the raw material up to the complete absorption of the implant should be analysed carefully to
identify the potential for risk related to premature degradation during processing, distribution, and
implantation (see Figure 1). Potential means for mitigating such risks is discussed at various locations
throughout this Technical Specification.
Design Validation:
Process Validation:
(Distribution &
(Manufacturing Process)
Implantation)
Scaffold
Rawmat.
Implantation
SBS-
Inter-
Assembled Outer Box Shipping Period/
Packaging, Transport
Device Packaging Container vention
Absorption
Sterilization
Storage
Storage at
Rawmat.
distribution
Site / Hospital
Rawmat.
tLabel=0
Start Shelf Life
Time Axis:
Shipment
Life Cycle of one single device
Figure 1 — Life cycle of one single device/implant
5 Design verification and validation — Testing and analysis
5.1 Overview
A general characterization of the implant’s composition, structural features, and degradation properties
needs to be included in a design verification or validation. The relevant material and mechanical
properties of the as-manufactured implant should be characterized from its initial pre-implanted
state until measurement of the degraded implant becomes impractical. An overview of the assessment
guidance provided herein is as follows:
— Clause 5.2 Summarizes the in vitro evaluation steps and describes general considerations and
relevant pre-test characterizations and treatments.
— Clause 5.3 guides product assessment from opening of the package through simulated vessel closure,
which includes the delivery, placement, and initial function of the device (depicted as Procedural
Stage in Figure 2).
— Clause 5.4 addresses appropriate characterization of the post-procedure mechanical, dimensional,
mass, and chemical changes that occur as the implant (and any included coating) adjust to the
physiological environment and encounter degradation over time (depicted as the Intermediate
Stage in Figure 2).
— Clause 5.5 discusses some of the issues and potential barriers to successful generation of a correlation
between in vitro and in vivo results.
— Clause 5.6 describes biocompatibility testing of absorbable implants, including reference to specific
guidance for testing in accordance with the various parts of ISO 10993.
— Clause 5.7 covers both cardiovascular and absorbable specific concerns when conducting a pre-
clinical in vivo evaluation.
— Clause 5.8 covers absorbable-specific concerns when conducting a clinical evaluation
— Clause 5.9 covers shelf-life and product aging considerations.
8 © ISO 2014 – All rights reserved

Figure 2 — Schematic representation of stages in the degradation of an absorbable implant
In this example figure, the decline in mechanical attributes is schematically represented through time
(“Intermediate Stage”) in comparison with the time frame for implantation (“Procedural Stage”) and
the period between loss of mechanical integrity and final in vivo resolution of the implant (“Advanced
Stage”). The degradation profile for some materials may exhibit alternate trends but generally will
include a decay to measurement limits. Relevant non-mechanical attributes should also be monitored
at pertinent evaluation intervals, potentially throughout both the Intermediate and Advanced stages
of degradation. Also, note that the graphically depicted Measurement Limit and Acceptance Criteria
are hypothetical values that will vary dependent on measurement methods and the specific product’s
characteristics and performance requirements.
5.2 Considerations in the characterization and assessment of material and implant
properties
5.2.1 General considerations
A non-exhaustive listing of material and implant characteristics that should be considered for inclusion
and subsequent assessment are:
a) composition/chemical/purity properties (e.g. molecular weight, inherent viscosity), thermal
properties (e.g. polymeric Tg, melting point), and microstructure [e.g. degree of crystallinity (in
polymers), grain size (in metals), pore characterization (in porous constructs)];
b) corrosion/degradation mechanism and rate profiling, including consideration of potential variations
and/or material interactions in different applicable environments (e.g. extreme storage or in vivo
service conditions);
c) changes that occur over the lifetime of the implant with respect to its chemical, thermal, and/or
physical properties (e.g. molecular weight, mass), as well as the implant’s mechanical behaviour and
degradation products.
NOTE 1 Degradation products may be released into the media/tissue or reside in the degrading implant.
Released degradation products that are generated either prior to product use (i.e. during processing or shelf-
life) or during degradation should be characterized (e.g. chemical identity, quantity, and toxicity). Identification
of the degradation products may be derived from chemical analyses of the implant or a theoretical analysis.
Literature data for implants manufactured from absorbable materials with an established history of safe
clinical use (e.g. PGA) at the intended location may be helpful in identifying expected degradation products
and potential toxicities - if one can demonstrate that equivalent manufacturing processes were used. A
toxicological risk assessment of degradation products over time in conjunction with toxicity data from the
literature may be sufficient to support an omission of biocompatibility testing from various stages of material
degradation (either during device storage or in clinical use).
NOTE 2 Guidance regarding the identification and assessment of chemical degradation products and
leachables may be found in ISO 10993, parts 9 and 17.
d) integrity of the implant under both normal and extreme handling and in vivo service expectations.
e) anticipated impact of clinically utilized visibility methods (for example, X-ray, MRI, ultrasound,
OCT) on the material and/or implant (e.g. effects of magnetic fields). Consideration should also be
made regarding potential for interaction with other commonly used implants.
The requirements of ISO 14630:2012, Clause 7, regarding general requirements for non-active surgical
implants shall apply.
A justification or rationale shall be provided for the partial or full omission of testing regarding potentially
relevant chemical, mechanical, or structural attributes. For example a rationale is not needed to justify
omission of stent securement testing during in vitro degradation since the attribute is only relevant
during the Procedural Stage (can ignore or designate as “not applicable”). Conversely, a rationale may be
required for radial force characterization during only a portion of the Intermediate Stage.
Since it is impossible to take into consideration all current and future technologies, absorbable
cardiovascular implants evaluated following the basic requirements of this specification can also need
additional testing to adequately characterize a device system. When deciding on the type of testing
that is needed, consideration should be given to the device’s failure mode(s) and the related effects they
may have on the performance of the implant and/or implant component. In addition, the applicability
of standards such as ISO/TS 12417 regarding drug-device combination products and ISO 25539-2
regarding endovascular devices need to be considered. Whenever changes are made in materials,
construction, configuration, application or processing methods, appropriate analyses need to be
undertaken regarding the potential impact the change may have on the failure modes and performance
of the absorbable implant or component. The use of a control device for comparison should be considered
when evaluating performance of the implant’s design attributes.
All test samples shall be complete final sterilized devices. If the evaluated samples are comprised of
implant components/subcomponents that are not sterilized or otherwise differ from final devices, a
justification shall be provided.
Establishment of product shelf life shall be through evaluation of one or more appropriate implant
performance tests conducted on the final product (see 5.9), with justification for the selection of tests
provided. Refer to ASTM F2914 for guidance in selecting appropriate tests for the determination of
shelf life in endovascular devices. If different finished-product manufacturing sites are used, generation
of appropriate batch release/stability data including appropriate performance specifications to ensure
the consistency and equivalency of the finished product across manufacturing sites should also be
considered.
10 © ISO 2014 – All rights reserved

5.2.2 Drug-substrate Interaction considerations
In drug-device combination products, potential exists for an absorbable component (coating
and/or structure) to interact with any accompanying pharmaceutical ingredient(s), possibly affecting
degradation rate and/or drug strength (potency), stability, and/or purity. While this standard provides
guidance toward the direct assessment of absorbable component(s) and their degradation properties
in the presence of a pharmaceutical, it does not address their impact on a pharmaceutical or its rate of
release. General guidance regarding the assessment of pharmaceutical components contained within
cardiovascular drug-device combination products is detailed in ISO/TS 12417.
5.2.3 Summary of in vitro evaluation steps
The following provides an outline of implant characterizations described within this section.
— Section 5.3 – In vitro procedural assessment
— Section 5.3.1 – Conditioning of test samples
— Unpacking;
— Preparation of device per IFU.
— Section 5.3.2 - Assessment of delivery and placement
— Insertion through sheath or guide catheter, if interventionally placed;
— Advancement to target lesion;
— Utilizing vascular tracking model;
— Implantation/deployment.
— Section 5.3.3 Assessment of initial function post-deployment
— Includes assurance that the device fulfills design requirements through placement and
closure (e.g provides adequate radial crush resistance).
— Section 5.4 - In vitro degradation assessment (post procedure)
NOTE While degradation can occur at any stage, even during manufacture and before opening of the
package, this section refers to the period post-placement where exposure to the physiological environment leads
to intentional degradation of the implant.
Briefly, this section describes how relevant properties of the as-manufactured implant are characterized
from its initial pre-implanted state until monitoring of the relevant attribute in the partially degraded
implant becomes impractical due to measurement limitations. The following provides a description of
the progression of degradation for absorbable implants following procedural placement (as depicted
in Figure 2). Characterization of degradation shall be completed as relevant for the attribute and time
frame being evaluated.
— Equilibrium
— Equilibrium encompasses changes driven by implant adaptation to the physical environment
and not changes that occur as a result of degradation of the absorbable material. The actual
duration of this equilibrium process can be considered as implant dependent, ranging from
immediate (i.e. upon deployment), as could be expected with metallic implants, to days, as
could be the case for a full hydration of some polymers. Equilibrium duration is also dependent
on the mechanical property being measured.
— Other than experimentally approximating the time point where equilibration occurs (Equilibrium
Point) for the system being evaluated and the relevant characteristic (e.g. strength), no further
direct characterization is needed.
— Intermediate Stage
— This stage of degradation spans from the end of the Procedural Stage to where integrity of the
implant is no longer detectable.
— The acquired evaluation time point frequency needs to be sufficient to allow at least an
extrapolated understanding of the approximate time at which the mechanical attribute of the
implant is unable to be measured.
— Advanced Stage
— This stage of degradation spans from the time point when the mechanical attribute is unable to
be measured to the full absorption of the implant, as determined by the substantial absence of
fragmentation particles, gels, or other physical degradation products - regardless of whether the
implant is evaluated in an in vitro or an in vivo context. While mechanical characterization of the
degrading implant will be inherently limited to the Intermediate Stage, material characterization
may continue through the Advanced Stage until evaluation becomes impractical or the acquired
data are below the quantification limit or is no longer meaningful.
5.3 in vitro procedural assessment
5.3.1 Conditioning of test samples
Pre-treatment/conditioning of the samples should simulate relevant procedural steps described in the
instructions for use (IFU) and exercised prior to insertion of the device. This includes all preparation
activities from opening of the package up to, but not including, introduction into the vasculature.
Introduction or post-insertion activities, such as tracking through a simulated vasculature, and device
deployment are described in the following procedural-related subsections.
5.3.2 Assessment of delivery and placement
An assessment of the device’s ability to be reliably implanted (via either percutaneous access or surgical
placement) needs to be included in a design verification or validation. The design attributes necessary
to meet the intended performance of a delivery system can be summarized by the following:
a) the ability of the delivery system to permit consistent, accurate and safe access to the intended
location;
b) the ability of the delivery system to permit consistent, accurate and safe deployment and placement
of the absorbable implant;
c) the ability of the delivery system to permit consistent and safe withdrawal of all necessary auxiliary
devices;
d) the ability of the delivery system to be adequately visualized under fluoroscopy or other relevant
imaging technologies.
For additional general guidance regarding the assessment of intravascular implant delivery systems,
see:
— Guidance for Industry and FDA Staff - Non-Clinical Engineering Tests and Recommended Labelling
for Intravascular Stents and Associated Delivery Systems (issued: April 18, 2010)
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/
ucm071863.htm
— ISO 25539-2 Cardiovascular implants – Endovascular devices, Part 2 – Vascular stents
12 © ISO 2014 – All rights reserved

— ASTM F2394-07(2013) Standard Guide for Measuring Securement of Balloon Expandable Vascular
Stent Mounted on Delivery System
5.3.3 Assessment of initial function post-deployment
The ability of the absorbable implant to meet its initial functional design performance specification
should be assessed immediately after placement. The ability of the implant to be reliably deployed,
placed, and then remain in its initially targeted position is essential for clinical success, regardless of
any subsequent enhancement or decline in mechanical properties. Structural characterization of the
implant immediately post-placement is conducted on devices that have been fully pre-conditioned as
described in 5.3.1. Considerations for inclusion in the initial functional performance specification and
the characterization of the deployed implant can be summarized as follows:
a) confirmation of adequate mechanical (structural) integrity post-deployment (e.g. absence of any
unintended loss of strength);
b) identification of any strut fractures or de-laminations of the coating(s);
c) absence of degradation or release of degradation/corrosion product(s), including particles, in excess
of design expectations;
d) absence of shrinkage/swelling of product in excess of design expectations (e.g from fluid uptake or
physical factors such
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