GUIDE

GUIDE

BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING
TO THE ISO 10993-1 STANDARD

OCTOBER 2021 EDITION

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO THE ISO 10993-1 STANDARD

CONTENTS
OCTOBER 2021 EDITION

A INTRODUCTION 3

B DEFINITIONS 4

C SUGGESTED METHODOLOGY 5

1 Stage 1 - Identification of the standards and references applied for the medical
device related to biological evaluation. 5

2 Stage 2 - Formulation, description, manufacturing and use of the medical device 5

3 Stage 3 - Categorization of the medical device: nature and duration of contact 6

4 Stage 4 - Identification of potential biological risks of the medical device / biological hazards 7

5 Stage 5 - Physical and chemical information for biological risk analysis /

medical device characterization 7

6 Stage 6 - Gap analysis and selection of biological endpoints for evaluation 9

7 Stage 7 - Overall analysis of the results 10

D RE-EVALUATION OF THE BIOLOGICAL EVALUATION FILE 11

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO THE ISO 10993-1 STANDARD

A 
INTRODUCTION
OCTOBER 2021 EDITION

This guidance document is applicable to all classes and types of medical devices.

In order to carry out a biological evaluation according to the current standard, some of the general principles are remind-
ed below:

• The biological evaluation of any material or medical device intended for use in human shall be part of a structured
biological evaluation plan within a risk management process;
• This risk management process involves the identification of biological hazards, the estimation of the associated biolog-
ical risks, and the determination of their acceptability;
• This approach combines the review and evaluation of all existing data from all sources with, where necessary, the selec-
tion and application of additional tests;
• It enables a full evaluation to be made of the biological responses to each medical device, relevant to its safety in use;
• The biological evaluation shall be planned, carried out, and documented by knowledgeable and experienced professionals;
• The risk management plan shall identify aspects of the biological evaluation requiring specific technical competencies
and shall identify the person(s) responsible for the biological safety evaluation;
• Information on material chemical constituents, and possible other substances that can be present in the medical devices
or released from the medical device, and consideration of chemical characterization shall precede any biological testing;
• The biological evaluation is to be considered on the finished product, ready to be used;
• The biological safety of a medical device shall be evaluated over its whole life-cycle, taking into account the risks caused
by potential modifications of the medical device over time, and if applicable, for the maximum number of processing
cycles defined by the manufacturer.

The following recommendations also need to be considered:

Generally, biological responses that are regarded as adverse, caused by a material in one application, might not be regard-
ed as such in a different situation (indication, condition of use, location in the human body) and vice versa.

Moreover, clinical investigations are not sufficiently sensitive to identify potential biocompatibility concerns. Indeed,
clinical symptoms that result from the presence of a non-biocompatible material may not be identifiable, or not distinc-
tive from those generated by another disease.

Each case is to be assessed individually. For example, if a metal stent has a polymer coating that may degrade over time,
the results of the biocompatibility evaluation of the finished device may not be fully representative its long-term clinical
performance, and the biocompatibility evaluation of the stent with and without the coating may be necessary.

Another example; for a system incorporating devices with different durations of contact, it is recommended to perform
a biological hazards assessment individually for each device, and then to add those hazards to represent the ones for
the entire system.

Note: The attention of the manufacturer is drawn to the fact that despite the realization of a biological evaluation
compliant with the current applicable standard, that could include biological testing, this evaluation does not con-
stitute any insurance against the emergence of adverse events.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO THE ISO 10993-1 STANDARD OCTOBER 2021 EDITION

B DÉFINITIONS

In order to harmonize the interpretation made under this guidance document, the following definitions are
provided:

Degradation Decomposition of a material or of the device over time.

Corrosion Attack on metallic materials by chemical or electrochemical reactions.

Degradation
product Any particle or chemical compound that is derived from the chemical breakdown of the original
material.

Leachable 
Substance that is released from a medical device or material during its clinical use.

Extractable Substance that is released from a medical device or material of construction when the medical
device or material is extracted using laboratory extraction conditions and vehicles.

The attention of the manufacturer is drawn to the definitions provided in the dedicated sections in the applicable
ISO 10993 series of standards, leading to additional meanings and clarifications to facilitate the understanding of
the standards and their interpretation.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO THE ISO 10993-1 STANDARD OCTOBER 2021 EDITION

C SUGGESTED METHODOLOGY Description of the medical device: The characteris-

tics of the finished device have to be described, taking
into account the physical effects when it impacts the
For the purposes of assessment by GMED, the man- biocompatibility (see ISO/TR 10993-19 standard for
ufacturer shall document all the stages as mentioned further information). Depending on the considered
below, knowing that all the supporting data used for device and the demonstration to achieve, information
the demonstration have to be provided, should the on the following aspects shall be provided:
data be from the literature, from the experience or gen-
erated through testing, and whatever the testing type • Porosity:
is (physical, chemical or biological). - Classical;
- Connectivity;
Note that each step described below corresponds to - Scaffolds.
each section of the GMED assessment report for bio-
logical evaluation. • Morphology:
- Crystalline;
- Amorphous;
1 Stage 1 - Identification of the standards - Multiple phases;
and references applied for the medical - Hard/soft surfaces.
device related to biological evaluation
• Surface energy/charge:
• Standards and references applied for the medical - Hydrophobic;
device subject to biological evaluation; - Hydrophilic;
• When specific standards exist for the type of medical - Protein adsorption;
devices (example: ISO 7405 standard – Dentistry – - Protein repulsion.
Evaluation of biocompatibility of medical devices
in dentistry), it is recommended to use the most • Abrasion resistance:
specific standard, or the one with the highest level - Stability of treated surface;
of requirement. - Surface friction.

• Topography:
2 Stage 2 - Formulation, description, - Surface chemical mapping;
manufacturing and use of the medical - Roughness (smooth, pitted, grooved, irregular ter-
device rain, textured).

Formulation of the medical device: • Particles:

- Size;
• Identification of the construction materials of the - Size distribution;
medical device(all materials in direct and indirect - 3D shape.
contact with the human body);
• Information regarding the formulation of each com- • Shape and Form
ponent (qualitative and quantitative):
- Chemical name, CAS number if relevant; • Swelling:
- Proportion / amount / weight percent of each chem- - Water absorption;
ical component present in the medical device; - Solvent absorption;
- Function of each chemical component in the medi- - Shape change;
cal device. - Surface crazing;
- Weight gain.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO THE ISO 10993-1 STANDARD OCTOBER 2021 EDITION

Where applicable, and in relation to the physical prop- 3 Stage 3 - Categorization of the medical
erties intrinsic to the medical device, the manufacturer device: nature and duration of contact
has to define the expected and claimed biological effect,
such as an expected tissue response or an expected Nature of contact with the human body:
response from an appropriate host in a specific applica-
tion, i.e. cell attachment or cell repulsion or cell prolifer- • Non-contacting devices: neither direct nor indirect
ation or bacterial and / or protein interaction, ... contact with the body;
• Surface-contacting devices: skin/ mucosal mem-
For example, an orthopedic implant may promote branes/ breached or compromised surfaces;
tissue growth, or a heart implant may promote adhe- • External communicating devices: blood path, indi-
sion of certain bacteria or proteins. rect/ tissue, bone, dentin/ circulating blood;
• Implant devices: tissue, bone/ blood.
Manufacturing of the medical device:
Duration of contact with the human body:
• List of the manufacturing steps of the medical device
and location(s) of corresponding manufacturing; • Limited exposure (A): devices whose cumulative sum
• Processing adjuvants/additives used, expected pro- of single, multiple or repeated durations of contact is
cess contaminants and residues; up to 24 hours;
• Packaging materials that directly or indirectly contact • Limited exposure (A) with transitory-contact: devic-
the medical device; es with very brief/transitory contact with the human
• Known or suspected impurities, if relevant; body;
• Sterilization method used, including the number of • Prolonged exposure (B): devices whose cumulative
cycles claimed, if relevant. sum of single, multiple or repeated contact duration is
likely to exceed 24 hours but doesnt exceed 30 days;
Use: • Permanent contact (C): devices whose cumulative
sum of single, multiple or repeated long-term contact
• Intended use of the medical device, clinical perfor- duration exceeds 30 days.
mance claimed;
• Lifetime claimed;
• Shelf-life; Single contact: one device used alone or several of
• Storage conditions. this device used during a unique contact duration and
uninterrupted.
Multiple contacts: one device which needs to be changed
repeatedly at the end of its lifetime, which contact durations
of its use are added.
Repeated contact: a device with uninterrupted use and
during different contact durations, which are added.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO ISO 10993-1 STANDARD OCTOBER 2021 EDITION

4 Stage 4 - Identification of potential Gathering and generating of information on material

biological risks of the medical device / characterization shall address as a minimum:
biological hazards
• The chemical constituents of the medical device and
Based on the composition of the medical device, its possible residual processing additive and processing
use and its categorization, the manufacturer is invited aids used in its manufacture in relation with the data
to define the parameters to be evaluated when assess- described in Stage 2;
ing the biological risk (see informative Annex A of ISO • The presence and the nature of leachable substanc-
10993-1 standard or other risks specific to certain types es of the medical device during clinical conditions of
of medical devices, such as degradation potential or use;
toxicokinetics for example). • The estimation of the potential of the medical device
or its materials of construction to release chem-
ical substances during clinical conditions of use
5 Stage 5 - Physical and chemical (extractables);
information for biological risk analysis / • The possible combinations/interactions between the
medical device characterization chemical constituents;
• The measurement/ proportion/ amount/ weight per-
Gathering physical and chemical information on the cent of each chemical component identified;
medical device or component is a crucial first step in the • Sufficient chemical data (quantitative and quali-
biological evaluation process. Sufficient qualitative and tative) to serve as the basis for a toxicological risk
quantitative toxicological data should be available to assessment (see questions raised in Figure 1 of ISO
assess the biological risk. 10993-1 standard).

Consideration of the chemical characterization process

shall precede any biological testing. The characterization shall identify the potential pres-
ence and the nature of degradation products. The
The chemical characterization process must be car- characterization is performed according to ISO 10993-
ried out according to ISO 10993-18 standard, version in 9 standard, and then 10993-13, 10993-14 and 10993-15
force, on the basis of data from several sources (liter- standards, current versions. If relevant, this characteriza-
ature, supplier documentation, chemical databases…) tion is applied at different stages of the device lifetime.
whether or not supplemented by tests on the compo-
sition of the medical device or its constituent materials. For the devices undergoing a change (e.g. polymer-
ization) and/or degraded in situ, the tested product
This aims to conduct the toxicological risk assessment has to be representative of the device in its final ver-
using appropriate toxicological thresholds and thus sion. Moreover, it is also recommended to evaluate the
determine whether or not it is necessary to conduct biocompatibility at different states of the modification
additional biological tests (see Annex B of ISO 10993- and/or degradation, to ensure that the initial products,
1 standard, ISO 10993 -17 and ISO 10993-18 standards). intermediate products and products of final degrada-
tion have been assessed.

It should be noted that chemical characterization is

usually insufficient to identify all the risks of the device
in its final form, because it does not take into account
the properties of the final medical device, especially
the surface ones.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO ISO 10993-1 STANDARD OCTOBER 2021 EDITION

Chemical characterization process and data collection: Recommendations for literature research:

It is recommended to establish a chemical character- • It is recommended to establish a protocol for the
ization protocol giving rise to a protocol for identify- identification, selection, collection and review of all
ing, selecting, collecting and reviewing all the existing available existing studies/data;
data/studies used to thoroughly characterize the med- • The objectives of the literature review have to be
ical device, and if necessary, for carrying out chemi- clearly defined;
cal characterization tests according to ISO 10993-18 • The criteria for including or excluding data have to be
standard. defined with an appropriate rationale;
• The literature review shall clearly assess the quality
• Literature search to perform according to the results of the documents and the extent to which the liter-
obtained at the previous stage, taking into account ature relates to the specific characteristics and fea-
the categorization of the medical device (nature and tures of the material or device under consideration,
duration of the contact); taking into account the intended use of the device,
• Use of historical data held by the manufacturer, if especially:
relevant; - Relevance of the experimental animals used in the
• For leachables which have known toxicological data, selected studies for the biological evaluation of the
verification of the adequate safety margin; device considered;
• If several leachables, potential synergy to evaluate; - Conditions of use of the material or device in the
• Assessment of the time of release/quantity of selected documents and the intended use of the
leachable; device considered.
• If relevant, use of the ISO 10993-17 standard for the • Justified conclusion, based on the state of art and the
assessment of toxicological risks in relation to toxico- analyzed data;
logical thresholds and the calculation of acceptable • Dated and signed report by the competent assessors,
safety margins; along with the articles used.
• Same considerations for the degradation products:
existing toxicological data, time of degradation, etc.
• Where applicable, the implementation of chemi-
cal characterization tests according to ISO 10993-18
standard must be the subject of a protocol describ-
ing the methodology of appropriate tests leading to
the associated tests report;
• The competence of the test laboratory, the justifica-
tion of the selection of the test articles, the tests con-
ditions, the analytical evaluation thresholds are to be
documented in addition to the results obtained;
• Justified conclusion, based on the state of art and the
analyzed data;
• Dated and signed report by the competent assessors,
along with the articles used.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO ISO 10993-1 STANDARD OCTOBER 2021 EDITION

6 Stage 6 - Gap analysis and selection of Biological testing program

biological endpoints for evaluation
• Definition of an additional biological testing program
• In connection with stages 4 and 5, assessment of the to be performed, in order to address the potential
information available and comparison with the data risks, that cannot be controlled by the literature data
necessary for the biological safety assessment of the or by the physical, chemical, and toxicological infor-
medical device (see Clause 4, informative Annexes A mation obtained;
and C of ISO 10993-1 standard) in order to identify • For each test selected in the testing program, the
options that can fill the gaps. following information has to be documented in a
report: the test methodology description, the claimed
It is reminded that the impact of the surface properties standard, the competence of the test laboratory, the
can only be assessed by placing the device in contact justification of the selection of the test article (as
with the cells/tissues. being representative of the device), the operating
conditions, the results obtained. The relevance of the
tests has to be demonstrated.
Justification on the need to carry out additional tests
or not: For the in vivo testing of medical devices made in situ
(e.g. polymerization) or of absorbable materials, the
• Are the data issued from the previous stages, and if evaluation and/or the tests performed must take into
relevant the historical data held by the manufacturer, account the kinetics of polymerization and of degra-
sufficient to address all the potential hazards identi- dation during the lifetime of the device. It is expect-
fied in stage 4? ed to demonstrate how the device materials degrade
over time and to analyze the biological risk and con-
- Yes: proceed to Stage 7; tinue until the absorbable materials and/or its degra-
dation products are no longer present in human body
- No: continue with the Biological testing program. (e.g. a bio-resorbable bone substitute) or if necessary
removed from the human body (e.g. an ophthalmic gel
• To conclude that no additional biological testing is injected into the ocular cavity and then removed after
necessary, the manufacturer has to justify that, for surgery). Alternatively, it may be acceptable to provide
each material: the type and duration of contact with a rationale for ending the study earlier, if the rationale
the tissue considered, the physical form, the formu- includes an estimate of the percentage of absorbable
lation, the manufacturing, the components interac- material remaining in the tissue, and confirmation that
tions, the lifetime claimed, the shelf-life and stor- a steady state biological tissue response is achieved.
age conditions are identical to the data issued from
the literature and from the manufacturer’s historical
data, if relevant, and that all biological hazards are
addressed and the risks are considered acceptable. If
there are differences or remaining gaps, it would be
necessary to analyze each of them and justify them.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO THE ISO 10993-1 STANDARD OCTOBER 2021 EDITION

7 Stage 7 - Overall analysis of the results Post market data

Summary and analysis of all the data described and/ It is reminded to the manufacturer that despite carrying
or results obtained in the previous stages the biological evaluation in accordance with the appli-
cable standard, which may include carrying out biolog-
• A conclusion on the acceptability of each identified ical testing, this evaluation is not an assurance against
biological risk in order to confirm the biological safety the emergence of adverse events. As such, the monitor-
of the medical device is expected; ing of adverse reactions or events in humans is neces-
• The conclusion can involve the following data: sary in order to:
- Historical data held by the manufacturer, if relevant; • Verify the control of the actions;
- Literature data; • Identify new risks, if any;
- Results of the biological testing. • Update the scientific surveillance related to the tox-
icity and biological risks associated to the medical
Risk management device.

• Finalization of the risk management file: In relation with the risk management file, the provisions
Overall evaluation allowing to demonstrate the con- in place for the collection, analysis and evaluation of pro-
trol of all potential risks at an acceptable level and the duction and post production information, specific to the
benefit to health from the use of the device as intend- biological evaluation will be verified.
ed by the manufacturer, against probable risks of inju-
ry or illness from such use;
• It is expected from the manufacturer a reference to the
risk management file, allowing the tracking of the anal-
ysis and the control of the biological hazards.

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GUIDE
BIOLOGICAL ASSESSMENT
OF MEDICAL DEVICES ACCORDING TO THE ISO 10993-1 STANDARD OCTOBER 2021 EDITION

D RE-EVALUATION OF THE BIOLOGICAL EVALUATION FILE

The biological evaluation has to be re-evaluated in case of following modification:

• Any change in the source or in the specification of the materials used (components and/or additives) in the
manufacturing of the product (source or specification);
• Any change in the physical configuration of the final medical device (for example size, geometry, surface
properties);
• Any change in the formulation, processing, primary packaging or sterilization of the product;
• Any change in the manufacturer’s instructions or expectations concerning storage, e.g. changes in shelf life and/
or transportation;
• Any change in the intended use of the product;
• Any evidence that the product may produce adverse effects when used in humans: Post market surveillance data.

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