ISO/TS 37137-1:2021
(Main)Biological evaluation of absorbable medical devices — Part 1: General requirements
Biological evaluation of absorbable medical devices — Part 1: General requirements
This document specifies the requirements for the evaluation of absorbable medical devices during a biological risk assessment based on ISO 10993-1, including a clarification of the terms "absorb", "degrade" and other related terms (see Annex A).
Évaluation biologique des dispositifs médicaux résorbables — Partie 1: Exigences générales
General Information
Standards Content (Sample)
TECHNICAL ISO/TS
SPECIFICATION 37137-1
First edition
2021-03
Biological evaluation of absorbable
medical devices —
Part 1:
General requirements
Évaluation biologique des dispositifs médicaux résorbables —
Partie 1: Exigences générales
Reference number
©
ISO 2021
© ISO 2021
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Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 2
5 Test article considerations . 4
6 Sterilization considerations . 4
7 Drug-device combination product considerations . 4
8 E valuation of absorbable medical devices in the context of the ISO 10993 series .4
8.1 General . 4
8.2 ISO 10993-1, evaluation and testing within a risk management process . 5
8.3 ISO 10993-2, animal welfare requirements . 5
8.4 ISO 10993-3, tests for genotoxicity, carcinogenicity, and reproductive toxicity . 5
8.5 ISO 10993-4, selection of tests for interactions with blood . 6
8.6 ISO 10993-5, tests for in vitro cytotoxicity . 6
8.7 ISO 10993-6, Tests for local effects after implantation . 6
8.8 ISO 10993-7, ethylene oxide sterilization residuals . 7
8.9 ISO 10993-9, framework for identification and quantification of potential
degradation products . 7
8.10 ISO 10993-10, tests for skin sensitization. 7
8.11 ISO 10993-11, tests for systemic toxicity . 7
8.12 ISO 10993-12, sample preparation and reference materials . 8
8.13 ISO 10993-13, identification and quantification of degradation products from
polymeric medical devices . 8
8.14 ISO 10993-14, identification and quantification of degradation products from ceramics . 8
8.15 ISO 10993-15, identification and quantification of degradation products from
metals and alloys . 9
8.16 ISO 10993-16, toxicokinetic study design for degradation products and leachables . 9
8.17 ISO 10993-17, establishment of allowable limits for leachable substances . 9
8.18 ISO 10993-18, chemical characterization of materials . 9
8.19 ISO/TS 10993-19, physico-chemical, morphological and topographical
characterization of materials . 9
8.20 ISO/TS 10993-20, principles and methods for immunotoxicology testing of
medical devices .10
8.21 ISO/TR 10993-22, guidance on nanomaterials .10
8.22 ISO 10993-23, tests for irritation .10
8.22.1 General.10
8.22.2 Tests for irritation .10
Annex A (informative) Nomenclature of absorb, degrade and related terms .11
Bibliography .12
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
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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 (see 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 (see www .iso .org/ patents).
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expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/
iso/ foreword .html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices.
A list of all parts in the ISO 37137 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/ members .html.
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Introduction
Absorbable implants are intentionally designed to degrade and therefore release degradation products
into the patient, a feature making these products fundamentally different from other medical devices
that are not intended to be absorbed by the patient’s body.
The provided content is intended to describe potential approaches to perform biological evaluation of
absorbable implants to support the safety of such absorbable medical devices.
TECHNICAL SPECIFICATION ISO/TS 37137-1:2021(E)
Biological evaluation of absorbable medical devices —
Part 1:
General requirements
1 Scope
This document specifies the requirements for the evaluation of absorbable medical devices during
a biological risk assessment based on ISO 10993-1, including a clarification of the terms "absorb",
"degrade" and other related terms (see Annex A).
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. 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
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
NOTE For further discussion of utilized terminology and for a list of potential terms to be included in a
literature search see Annex A.
3.1
absorb
absorption
action of a non-endogenous (foreign) material or substance, or its decomposition
products passing through or being assimilated by either cells or tissue, or both over time
[SOURCE: ISO 10993-6:2016, 3.1]
3.2
degradation product
intermediate or final substance which results from the physical, metabolic, and/or chemical
decomposition of a material or agent
3.3
degrade
physically, metabolically, and/or chemically decompose a material or substance
3.4
leachable
substance that can be released from a medical device or material during clinical use or simulated
clinical use
Note 1 to entry: In absorbable medical devices, leachables can be substances released from the as-manufactured
product or substances generated and released as a consequence of its degradation (i.e. degradation products).
[SOURCE: ISO 10993-12:2020, 3.9 modified — Note 1 to entry has been added.]
3.5
final product
medical device or medical device component that has been subjected to all manufacturing processes for
the “to be marketed” medical device including packaging and if applicable, sterilization
Note 1 to entry: The final medical device or sterilized finished medical device has the same meaning as the final
product in this document.
[SOURCE: ISO 10993-1:2018, 3.8 modified — Note 1 to entry has been added.]
4 General considerations
Biological evaluation is the assessment of a medical device, medical device component, or a material
to determine if either the medical device material or the medical device design, or both is likely to
result in an unacceptable adverse systemic and/or local effect on the surrounding cells and/or tissues.
Biological evaluation of an absorbable material shall be conducted in accordance with ISO 10993-1, and
other relevant parts of ISO 10993. Any modifications to the methods specified in the ISO 10993 series of
standards shall be justified in a written biological risk assessment.
Degradation products can be released into either the extraction media or tissue, or both or remain in
the degrading implant. Released degradation products that are generated either prior to product use
(i.e. during manufacturing, processing or shelf-life) or during product use should be characterized (e.g.
chemical identity, quantity, toxicity, and particulates (see 8.19) as applicable).
Identification of the degradation products may be derived from chemical and physical analyses of the
implant or through a theoretical judgement. Literature data for implants manufactured from absorbable
materials with an established history of safe clinical use (at the intended anatomical location) can be
helpful in identifying expected degradation products and potential toxicities if there is an adequate
scientific rationale for the applicability of the referenced data.
Differences in processing might impact the biocompatibility of the final product. Simply demonstrating
identical composition is not sufficient since many other factors (e.g. sequence distribution of copolymers,
crystallinity, degree of purity, grain size and crystal structure for metals, oxidation level of cellulose
derivatives, molecular weight, mode of sterilization) can influence absorbable material performance
and biocompatibility. A finished device biological risk assessment using information from chemical
analyses of the absorbable material(s) and its(their) degradation products, in conjunction with toxicity
data from the literature, can support some of the biological end points described in ISO 10993-1 if a
scientifically sound justification can be provided for their clinical relevance.
Additionally, standard extraction conditions and biocompatibility tests are not designed to assess
biological responses to absorbable devices throughout degradation. Testing at different stages of device
degradation can be needed to demonstrate safety, as absorbable devices are constantly changing in the
physiological environment and may present different adverse biological responses at different stages of
degradation.
By design, most polymeric, ceramic, or metallic absorbable materials inherently produce relatively
low molar mass degradation products in vivo. Since the presence of these degradation products within
the extraction media can potentially impact the results of some biocompatibility tests and since
standard extraction methods were originally intended for non-degradable materials, interpretation of
these results often cannot be distilled to simple pass/fail criteria. For example, in some cases, if the
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degradation rate of an absorbable material is sufficiently rapid, elevated concentrations of one or more
of the intended degradation products could alter the pH and/or osmolality of an in vitro biological test
system. Since the in vivo condition can provide the combined presence of perfusion and carbonate
equilibria, such in vitro results might not reflect the in vivo response.
If under standard test conditions an adverse result occurs in an in vitro assay, one can consider the test
system and degradation products when deciding if repeat testing may be useful in the context of the
overall biological risk assessment. Extract adjustments (e.g. dilution, pH, osmolality) can be used as
part of the overall biological risk assessment strategy to determine the cause of the test failure which
may inform the overall interpretation of results. Testing of multiple extract dilutions can be used to
determine the point at which the extract passes the in vitro assay which may allow for the adverse
response to be viewed in the context of other currently marketed absorbable devices (e.g. similar
materials, intended use, and biocompatibility observations, such as cytotoxicity). As described above,
testing extracts after pH and/or osmolality adjustment can be useful; however, any extract adjustment
shall be justified in the biological risk assessment, as pH and osmolality changes can result in adverse
local and/or system effects that are clinically relevant. A justification for extract adjustment shall
include scientific evidence (e.g. clinically-relevant animal study, chemical characterization, literature
references) to support the relevance of the adjusted extract for the overall biological risk assessment
evaluation.
A justification shall include the potential impact of the extract adjustment on extract chemistry to
support that the adjusted extract is representative of the device. Any extract adjustments shall be
well-described, including the initial pH or osmolality measurements, extract adjustment procedure
(e.g. chemical, chemical concentration, volume added), and final pH or osmolality measurements.
Appropriate control group(s), per ISO 10993-12, shall be included to address the potential impact of any
extract adjustments on the in vitro results.
If particulates form during sample preparation, the particulates shall neither be filtered, centrifuged
or allowed to settle prior to introducing the sample to the in vitro test system. If particulates cause
interference in the original testing, repeat testing with particulate removal can be considered if justified
in the biological risk assessment. For in vivo testing, particulates shall neither be filtered, centrifuged
or allowed to settle prior to introducing the sample, except in cases where animal welfare concerns
preclude intravascular injection of extracts containing particulates.
Ultimately the biological risk assessment shall consider all pertinent data from, e.g., testing, prior
experience, literature; and present a coherent scientific justification explaining how the data interrelate
and demonstrate the safety of the absorbable device with a reasonable level of scientific evidence (see
ISO 10993-1:2018, Clause 7).
Degradation products from some intentionally absorbable materials can be chemical components
(which could include active pharmaceutical ingredients [APIs] in drug-device combination products)
that have previously been identified, characterized, and had biological evaluation performed. For these
materials, the biological evaluation can be performed in accordance with ISO 10993-17. The evaluation
of local effects can require additional data.
Since absorbable materials are intended to degrade, transient particulate matter may be present as the
medical device breaks down. The particle size, morphology, generation rate, and mobility can all affect
biological response and should be considered in the biological risk assessment.
Rate of absorption through the device lifetime needs to be understood to accurately assess the
biological safety. Different rates of absorption need to be identified and the conditions that could
potentially impact the rate need to be considered (e.g. change in pH, temperature, tissue environment,
material phase change). An understanding of the potential clinical impact of degradation is needed and
the effect of degradation on the potential for adverse effects (systemic and local) shall be discussed in
the biological risk assessment.
NOTE 1 Guidance regarding the identification and assessment of chemical degradation products and leachables
can be found in ISO 10993-9, ISO 10993-13, ISO 10993-14, ISO 10993-15, ISO 10993-17 and ISO 10993-18. Guidance
regarding aspects of the biological evaluation of particulate nanomaterials can be found in ISO 10993-22.
NOTE 2 pH adjustment can change the osmolality, depending on the extract contents and what is used
for adjustment. If it can be justified that the dilution will reduce the osmolality without affecting the pH, pH
adjustments can be done prior to osmolality adjustments.
5 Test article considerations
Final product evaluation should be conducted on sterilized finished medical devices or test samples
that are representative of the final medical device.
If the final product is not used for testing, a rationale shall be provided that includes:
— a description of all differences between the test article and the final product;
— data that demonstrate that all differences between the test article and the final product do not
impact their chemistry or degradation kinetics.
6 Sterilization considerations
The sterilization methods and conditions should be carefully considered and justified prior to biological
testing. For irradiation sterilization, caution should be undertaken when medical devices are sterilized
using a higher radiation dose. With an increased dose, different chemical degradation products can be
produced in substantial amounts, or non-toxic chemicals can be degraded into toxic species. Conversely
for other sterilization methods, toxicity might increase with increased exposure time/duration (e.g.
penetration of ethylene oxide [EO] residuals).
7 Drug-device combination product considerations
For medical devices that include an API, the presence of a pharmaceutical can affect the response in a
biocompatibility assay. As such, separate testing of the medical device both with and without the API
should be considered, but might not be necessary. In addition, available information on the API alone,
as well as any potential interaction between the pharmaceutical ingredient(s) and the as-manufactured
absorbable materials or degradation product(s) should be evaluated for their impact on medical device
biocompatibility and degradation.
APIs can potentially impact the results of biocompatibility assays with drug-induced positives when
extracted at the recommended extraction ratio(s) detailed in ISO 10993-12. Use of a range of dilutions
of the sample or a partition of the overall medical device evaluation may be considered as part of the
overall risk management process if the API is expected to be toxic for the particular end point being
studied. Use of a range of dilutions may not allow medical device biocompatibility to be adequately
assessed if the API mode of action directly impacts the specific biocompatibility test (e.g. when
performing cytotoxicity testing on a medical device that includes a cytotoxic API). In these instances,
additional testing of a finished medical device constructed without the API is recommended.
NOTE 1 For vascular device-drug combination products, additional guidance can be obtained in ISO 12417-1.
NOTE 2 Additional tests can be appropriate to study the chemical and biological interaction with the drug, in
vivo drug migration, toxicological profile, degradation products, and controlled release of the drug (therapeutic
dose) to determine toxicological profile and pharmacological safety and efficacy.
8 E valuation of absorbable medical devices in the context of the ISO 10993 series
8.1 General
Clause 8 provides clarification on the biological evaluation of absorbable medical devices and is
intended to be used in conjunction with the respective part of the ISO 10993 series.
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8.2 ISO 10993-1, evaluation and testing within a risk management process
Degradation information (e.g. rate, duration, chemical changes, mechanisms, degradation products) of
the absorbable device, component(s), or material(s) shall be provided in the biological risk assessment
documentation, including parameters that could affect the degradation process. Expected mechanical
changes (under in vitro or in vivo degradation testing conditions) also need to be understood. A general
framework for degradation characterization is provided in ISO 10993-9, with guidance for hydrolysable
polymers provided in ISO 13781. Guidance for in vitro degradation characterization of absorbable
metals can be found in ASTM F3268.
The biological risk assessment of absorbable medical devices shall include all the relevant end points
identified in ISO 10993-1:2018, Annex A, with consideration of 8.2 to 8.22, as relevant. In addition,
degradation and toxicokinetics are typically required end points. Reproductive and developmental
toxicity should be considered and discussed for any absorbable medical devices used in the reproductive
system or with potential for systemic distribution in paediatric patients or those of reproductive age.
The bi
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