NEW WORK ITEM PROPOSAL
Date of presentation

Reference number(to be given by secretariat)

2001-06-08
Proposer

ISO/TC 194 /SC

AAMI (for ANSI)

N 377

Secretariat

DIN
A proposal for a new work item (including proposals for amendment or revision of an existing standard) within the scope of an
existing technical committee or subcommittee shall be submitted to the secretariat of that technical committee orsubcommittee with a copy to the Central Secretariat and, in the case of a sub-committee, a copy to the secretariat of the parent
technical committee. The proposal will be circulated to the P-members of the technical committee or subcommittee for voting,and to the O-members for information. The proposer may be a member body of ISO, the secretariat itself, another technicalcommittee or subcommittee, an organization in liaison, the Technical Management Board or one of the advisory groups, or the
Secretary-General. Guidelines for proposing and justifying a new work item are given in the ISO/IEC Directives (part 1,
annex Q) (see extract overleaf).
The proposal (to be completed by the proposer)
Title of proposal (in the case of an amendment or revision, or a new part, of an existing standard, show the standard
number)Revision of ISO 10993-1:1997, Biological evaluation of medical devices - Part 1:
Evaluation and testing
Scope (as defined in 6.2.1 of part 3 of the ISO/IEC Directives)

Describes a) the general principles governing the
medical devices; b) the categorization of devices
duration of their contact with the body; and c) thetests.

biological evaluation of
based on the nature andselection of appropriate

Purpose and justification (attach a separate page as annex, if necessary)

This revision was initiated for the purposes of user clarification. The sections
that have been clarified/revised are subclauses 5.2.5, 5.2.6, 5.2.7, 5.2.8,
5.3.1, Table 1 and Annex A (see attached redline/strikeout revision).

Target date (indicate the date by which the availability of theInternational Standard is considered to be necessary)

2003

Relevant documents to be considered

10993 series of standards
Relationship of project to activities of other international bodies

Liaison organizations

Need for coordination within ISO and IEC

CEN/TC 206
Preparatory work
A draft is attachedAn outline is attached and it will be possible to supply a draft by (date)
Proposed project leader (name and address): James M. Anderson, MD, PhD, Institute of
Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.

Concerns known patented items(see part 2 of the ISO/IEC Directives)

Signature of the proposer

James M. Anderson

yesno
If YES, provide full information as annex
Date of circulation

Closing date for voting

2001-06-08

2001-09-08

Signature of the TC or SC secretary

FORM 4 ISO)
Version/V97.1

See overleaf

Comments and recommendations of the TC or SC secretariat
Comments with respect to the proposal in general, and recommendation thereon(Indicate any issues to be brought to the notice of committee members. For instance, refer to any associated vote on
form 5 regarding adoption of any attached draft for direct progression to CD or DIS.)

Elements to be clarified when proposing a new work item (new standard)
Title
Indicate the subject matter of the proposed new standard.
Scope
Give a clear indication of the coverage of the proposed new work item and, if necessary for clarity, exclusions.
Purpose and justification
Give details based on a critical study of the following elements wherever practicable.
a) The specific aims and reason for the standardization activity, with particular emphasis on the aspects of standardization
to be covered, the problems it is expected to solve or the difficulties it is intended to overcome.
b) The main interests that might benefit from or be affected by the activity, such as industry, consumers, trade,governments, distributors.
c) Feasibility of the activity: Are there factors that could hinder the successful establishment or general application of thestandard?
d) Timeliness of the standard to be produced: Is the technology reasonably stabilized? If not, how much time is likely to beavailable before advances in technology may render the proposed standard outdated? Is the proposed standard required asa basis for the future development of the technology in question?
e) Urgency of the activity, considering the needs of other fields or organizations. Indicate target date and, when a series ofstandards is proposed, suggest priorities.
f) The benefits to be gained by the implementation of the proposed standard; alternatively, the loss or disadvantage(s) if nostandard is established within a reasonable time. Data such as product volume or value of trade should be included andquantified.
g) If the standardization activity is, or is likely to be, the subject of regulations or to require the harmonization of existing
regulations, this should be indicated.
If a series of new work items is proposed, the purpose and the justification of which is common, a common proposal may be
drafted including all elements to be clarified and enumerating the titles and scopes of each individual item.
Relevant documents
List any known relevant documents (such as standards and regulations), regardless of their source. When the proposer
considers that an existing well-established document may be acceptable as a standard (with or without amendments) indicate
this with appropriate justification and attach a copy to the proposal.
Cooperation and liaison
List relevant organizations or bodies with which cooperation and liaison should exist.
Preparatory work
Indicate whether the proposer or the proposer's organization is prepared to undertake the preparatory work required for the
new work item.

FORM 4 (ISO) page 2
Version/V97.1

Proposed Revision of ISO 10993-1:1997

Biological evaluation of medical devices–Part 1:
Evaluation and testing

Abstract:

This standard describes the general principles governing the biological evaluation of medical
devices; the categorization of devices based on the nature and duration of contact with thebody; and the selection of appropriate tests.

Keywords: medical devices, categories, biological tests, cytotoxicity, sensitization, irritation, intracutaneous
reactivity, systemic toxicity, subchronic toxicity, genotoxicity, implantation, hemocompatibility,
chronic toxicity, carcinogenicity, reproductive toxicity, developmental toxicity, andbiodegradation.

Contents

Page
Foreword…………………………………………………………………………………………………………………iv
Introduction……………………………………………………………………………………………………………..v
1

Scope ....................................................................................................................................................... 1

2

Definitions ................................................................................................................................................ 1

3

General principles applying to biological evaluation of materials and devices......................................... 1

4

Categorization of medical devices ........................................................................................................... 2

5

Testing ..................................................................................................................................................... 4

6

Selection of biological evaluation tests .................................................................................................... 6

7

Assurance of test methods....................................................................................................................... 6

AnnexesA

Rationale .................................................................................................................................................. 9

B

Flow chart to aid in systematic approach to biological evaluation of medical devices ........................... 10C

Bibliography ........................................................................................................................................... 11

Foreword
ISO (the lnternational Organization for Standardization) is a worldwide federation of national standards bodies (ISOmember bodies). The work of preparing International Standards is normally carried out through ISO technicalcommittees. 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 nongovernmental, in
liaison with ISO, also take part in the work. ISO collaborates closely with the International ElectrotechnicalCommission (IEC) on all matters of electrotechnical standardization.
Draft International Standards adopted by the technical committees are circulated to the member bodies for voting.
Publication as an International Standard requires approval by at least 75% of the member bodies casting a vote.
International Standard ISO 10993-1 was prepared by Technical Committee ISO/TC 194, Biological evaluation of
medical devices.
This second edition cancels and replaces the first edition (ISO 10993-1:1992) which has been technically revised.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:—Part 1:

Evaluation and testing—Part 2:

Animal welfare requirements—Part 3:

Tests for genotoxicity, carcinogenicity and reproductive toxicity—Part 4:

Selection of tests for interactions with blood—Part 5:

Tests for cytotoxicity: in vitro methods—Part 6:

Tests for local effects after implantation—Part 7:Ethylene oxide sterilization residuals—Part 9:Framework for the identification and quantification of potential degradation products—Part 10: Tests for irritation and sensitization—Part 11: Tests for systemic toxicity—Part 12: Sample preparation and reference materials—Part 13: Identification and quantification of degradation products from polymers—Part 14: Identification and quantification of degradation products from ceramics—Part 15: Identification and quantification of degradation products from metals and alloys—Part 16: Toxicokinetic study design for degradation products and leachables
Future parts will deal with other relevant aspects of biological testing.
Annexes A, B and C of this part of ISO 10993 are for information only.

iv

Introduction
This part of ISO 10993 is a combination/harmonization of numerous International and National Standards andguidelines concerning the biological evaluation of medical devices. It is intended to be the overall guidance
document for the selection of tests enabling evaluation of biological responses relevant to the safety of medical
devices and materials.
The role of this part of ISO 10993 is to serve as a framework in which to plan such a biological evaluation which
minimizes the number and exposure of test animals.
The protection of humans is the primary goal of ISO 10993.
The appropriate selection and interpretation of biological evaluation tests requires an understanding of therationale behind such testing. An informative rationale for the use of this part of ISO 10993 is provided in annex A.
Annex B contains a flow chart to aid in the systematic approach to the biological evaluation of medical devices.
Annex C contains an informative bibliography.

v

Proposed Revision of ISO 10993-1:1997

1 ScopeThis part of ISO 10993 describesa)the general principles governing the biological evaluation of medical devices;b)the categorization of devices based on the nature and duration of their contact with the body;c)the selection of appropriate tests.

This part of ISO 10993 does not cover testing of materials and devices that do not come into direct or indirectcontact with the patient's body, nor does it cover biological hazards arising from any mechanical failure. Other
parts of ISO 10993 cover specific tests as indicated in the foreword. (See also the rationale in A.2.)

2

Definitions

For the purposes of this part of ISO 10993, the following definitions apply.
2.1 medical device: Any instrument, apparatus, appliance, material or other article, including software, whether
used alone or in combination, intended by the manufacturer to be used for human beings solely or principally forthe purpose of:—diagnosis, prevention, monitoring, treatment or alleviation of disease;—diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or handicap;—investigation, replacement or modification of the anatomy or of a physiological process; and—control of conception
and which does not achieve its principal intended action in or on the human body by pharmacological,
immunological or metabolic means, but which may be assisted in its function by such means.
NOTES
1 Devices are different from drugs, and their biological evaluation requires a different approach.
2 Use of the term “medical device” includes dental devices.

2.2 material: Any synthetic or natural polymer, metal, alloy, ceramic, or other nonviable substance, including
tissue rendered nonviable, used as a medical device or any part thereof.
2.3 final product: Medical device in its "as-used' state.

3 General principles applying to biological evaluation of medical devices
3.1 The selection and evaluation of any material or device intended for use in humans requires a structured
programme of assessment.
In the design process, an informed decision shall be made and documented that weighs theadvantages/disadvantages of the various choices of material and test procedure. To give assurance that the final
product will perform as intended and be safe for human use, the program shall include a biological evaluation.
The biological evaluation shall be planned, carried out, and documented by knowledgeable and experienced
individuals capable of making informed decisions based on the advantages and disadvantages of the various
materials and test procedures available.
3.2 In the selection of materials to be used in device manufacture, the first consideration should be fitness forpurpose with regard to characteristics and properties of the material, which include chemical, toxicological,
physical, electrical, morphological and mechanical properties.

13.3 The following should be considered for their relevance to the overall biological evaluation of the device:a)the material(s) of manufacture;b)

intended additives, process contaminants and residues;c)leachable substances;d)degradation products;e)other components and their interactions in the final product;f)the properties and characteristics of the final product.

NOTE—If appropriate, identification and quantification of extractable chemical entities of the final product should precede
biological evaluation (see ISO 10993-9).

3.4 Tests and their interpretation to be used in biological evaluation should take into account the chemicalcomposition of the materials, including the conditions of exposure as well as the nature, degree, frequency andduration of exposure of the device or its constituents to the body. By following these principles, devices can be
categorized to facilitate the selection of appropriate tests (see clause 4). This part of ISO 10993 is concerned withthe tests to be carried out on materials and/or the final product.
The range of potential biological hazards is wide and may include:a)short-term effects (e.g. acute toxicity, irritation to the skin, eye and mucosal surfaces, sensitization, hemolysis
and thrombogenicity);b)

long-term or specific toxic effects [e.g. subchronic and chronic toxic effects, sensitization, genotoxIcity,
carcinogenicity (tumorigenicity) and effects on reproduction including teratogenicity].

3.5 All potential biological hazards should be considered for every material and final product, but this does not
imply that testing for all potential hazards will be necessary or practical (see clause 6).
3.6 Any in vitro or in vivo tests shall be based on end-use applications and appropriate good laboratory practicefollowed by evaluation by competent informed persons. Whenever possible, in vitro screening should be carriedout before in vivo tests are commenced. Test data, complete to the extent that an independent analysis could be
made, shall be retained (see A.2, subclause 3.6).
3.7 The materials or final product shall be considered for biological re-evaluation if any of the following occurs:a)any change in the source or in the specification of the materials used in the manufacture of the product;b)

any change in the formulation, processing, primary packaging or sterilization of the product;c)

any change in the final product during storage;d)

any change in the intended use of the product;e)

any evidence that the product may produce adverse effects when used in humans.

3.8 The biological evaluation performed in accordance with this part of ISO 10993 should be considered inconjunction with the nature and mobility of the ingredients in the materials used to manufacture the device andother information, other non-clinical tests, clinical studies, and post-market experience for an overall assessment(see A.2, subclause 3.8).

4 Categorization of medical devices
Following the general principles laid down in clause 3, medical devices can be categorized to facilitate theselection of appropriate tests.
The testing of any device that does not fall into one of the categories described should follow the general principles
contained in this part of ISO 10993. Certain devices may fall into more than one category, in which case testing
appropriate to each category should be considered.

2

4.1 Categorization by nature of body contact
Medical devices shall be categorized according to the nature of body contact as follows:
4.1.1

Non-contact devices

Medical devices that do not contact the patient's body directly or indirectly are not included in the scope of ISO
10993.
4.1.2 Surface-contacting devices
These include medical devices in contact with the following:a)skin: devices that contact intact skin surfaces only; examples include electrodes, external prostheses, fixation
tapes, compression bandages and monitors of various types;b)mucosal membranes: devices that contact intact mucosal membranes; examples include contact lenses,
urinary catheters, intravaginal and intraintestinal devices (stomach tubes, sigmoidoscopes, colonoscopes,
gastroscopes), endotracheal tubes, bronchoscopes, dental prostheses, orthodontic devices and intrauterine
devices;c)breached or compromised surfaces: devices that contact breached or otherwise compromised bodysurfaces; examples include dressings or healing devices and occlusive patches, for ulcers, burns, andgranulation tissue.

4.1.3 External communicating devices
These include medical devices in contact with the following application sites:a)blood path, indirect: devices that contact the blood path at one point and serve as a conduit for entry into thevascular system; examples include solution administration sets, extension sets, transfer sets and bloodadministration sets;b)

tissue/bone/dentin: devices that contact tissue, bone or pulp/dentin systems; examples include
laparoscopes, arthroscopes, draining systems, dental cements, dental filling materials and skin staples;c)circulating blood: devices that contact circulating blood; examples include intravascular catheters, temporary
pacemaker electrodes, oxygenators, extracorporal oxygenator tubing and accessories, dialyzers, dialysis
tubing and accessories, hemoadsorbents and immunoadsorbents.

4.1.4 Implant devices
These include medical devices in contact with the following application sites:a)b)tissue/bone:1)

devices principally contacting bone; examples include orthopedic pins, plates, replacement joints, bone
prostheses, cements and intraosseous devices;2)

devices principally contacting tissue and tissue fluid; examples include pacemakers, drug supply devices,
neuromuscular sensors and simulators, replacement tendons, breast implants. artificial larynxes,
subperiosteal implants and ligation clips;

blood: devices principally contacting blood; examples include pacemaker electrodes, artificial arteriovenus
fistulae, heart valves, vascular grafts, internal drug-delivery catheters and ventricular assist devices.

4.2 Categorization by duration of contact
Medical devices shall be categorized according to the duration of contact as follows:a)limited exposure (A): devices whose single or multiple use or contact is likely to be up to 24 h;b)prolonged exposure (B): devices whose single, multiple or long-term use or contact is likely to exceed 24 h
but not 30 days;c)permanent contact (C): devices whose single, multiple or long-term use or contact exceeds 30 days.

3

If a material or device may be placed in more than one duration category, the more rigorous testing requirements
should apply. With multiple exposures to the device, the decision into which category a device is placed shouldtake into account the potential cumulative effect, bearing in mind the period of time over which these exposuresoccur.

5 Testing
5.1 General
In addition to the general principles laid down in clause 3, the following shall apply to biological testing of medical
devices.
a)Testing shall be performed on the final product, or representative samples from the final product or materials.

b)

The choice of test procedures shall take into account:1)

the nature, degree, duration, frequency and conditions of exposure to or contact of humans to the device
in the normal intended use;2)

the chemical and physical nature of the final product;

3)

the toxicological activity of the chemical elements or compounds in the formulation of the final product;

4)that certain tests (e.g. those designed to assess systemic effects) may not be applicable where thepresence of leachable materials has been excluded, or where leachables have a known and acceptabletoxicity profile;5)

the relationship of device surface area to recipient body size;

6)

the existing information based on the literature, experience and non-clinical tests;

7)

the protection of humans is the primary goal of this document; a secondary goal is to ensure animal
welfare and to minimize the number and exposure of test animals.

c)

If extracts of the devices are prepared, the solvents and conditions of extraction used should be appropriate to
the nature and use of the final product.

d)Positive and negative controls should be used where appropriate.

e)

Test results cannot ensure freedom from potential biological hazard, thus biological investigations should be
followed by careful observations for unexpected adverse reactions or events in humans during clinical use of
the device.

Annex C provides a bibliography of International Standards and guidelines on biological response test methods.
5.2 Initial evaluation tests
The tests that shall be considered for initial biological response are given in 5.2.1 to 5.2.9.
5.2.1 Cytotoxicity
With the use of cell culture techniques, these tests determine the lysis of cells (cell death), the inhibition of cell
growth, and other effects on cells caused by medical devices, materials and/or their extracts. Cytotoxicity tests aredescribed in ISO 10993-5.
5.2.2 Sensitization
These tests estimate the potential for contact sensitization of medical devices, materials and/or their extracts,
using an appropriate model. These tests are appropriate because exposure or contact to even minute amounts ofpotential leachables can result in allergic or sensitization reactions. Sensitization tests are described in ISO
10993-10.
5.2.3 Irritation
These tests estimate the irritation potential of medical devices, materials and/or their extracts, using appropriate
site for implant tissue such as skin, eye and mucous membrane in a suitable model. The test(s) performed should4be appropriate for the route (skin, eye, mucosa) and duration of exposure or contact to determine irritant effects ofdevices, materials and potential leachables.
5.2.4 lntracutaneous reactivity
These tests assess the localized reaction of tissue to medical device extracts. These tests are applicable where
determination of irritation by dermal or mucosal tests are inappropriate (e.g. medical devices having access to theblood path). These tests may also be useful where extractables are hydrophobic. Intracutaneous reactivity tests
are described in ISO 10993-10.
5.2.5 Systemic toxicity (acute toxicity)
These tests estimate the potential harmful effects of either single or multiple exposures, during a period of lessthan 24 h, to medical devices, materials and/or their extracts in an animal model. These tests are appropriate
where contact allows potential absorption of toxic leachables and degradation products.
Pyrogenicity tests are included to detect material-mediated pyrogenic reactions of extracts of medical devices ormaterials. No single test can differentiate pyrogenic reactions that are material-mediated from those due toendotoxin contamination. Systemic toxicity tests are described in ISO 10993-11.
Immunotoxicity tests should be considered only for devices where data from sources is suggestive of
immunotoxicological effects.
Systemic toxicity tests may be included in subacute and subchronic toxicity test protocols and implantation test
protocols.
5.2.6 Subacute and Subchronic toxicity (subacute toxicity)
These tests determine the effects of either single or multiple exposures or contact to medical devices, materials
and/or their extracts for a period not less than 24 h to a period not greater than 10% of the total life-span of the test
animal (e.g. up to 90 days in rats). These tests may be waived for materials with chronic toxicity data. The reason
for waiving of the tests should be included in the final report. These tests should be appropriate for the route andduration of contact. Subchronic toxicity tests are described in ISO 10993-11.
5.2.7 Genotoxicity
These tests apply mammalian or non-mammalian cell culture or other techniques to determine gene mutations,changes in chromosome structure and number, and other DNA or gene toxicities caused by medical devices,materials and/or their extracts. Genotoxicity tests are described in ISO 10993-3.
Subacute and subcronic toxicity tests may be included in implantation test protocols.
5.2.8 Implantation
These tests assess the local pathological effects on living tissue, at both the gross level and microscopic level, of asample of a material or final product that is surgically implanted or placed into an implant site or tissue appropriate
to the intended application (e.g. special dental usage tests). These tests should be appropriate for the route andduration of contact. For a material, these tests are equivalent to subchronic toxicity tests if systemic effects arealso investigated. Implantation tests are described in ISO 10993-6.
Implantation test protocols may be expanded to include systemic toxicity tests, subacute and subchronic toxicity
tests, and chronic toxicity tests.
5.2.9 Hemocompatibility
These tests evaluate effects on blood or blood components by blood-contacting medical devices or materials orusing an appropriate model or system. Specific hemocompatibility tests may also be designed to stimulate thegeometry, contact conditions and flow dynamics of the device or material during clinical applications.
Hemolysis tests determine the degree of red blood cell lysis and the release of hemoglobin caused by medical
devices, materials and/or their extracts in vitro. Hemocompatibility tests are described in ISO 10993-4.
5.3 Supplementary evaluation tests
The supplementary biological evaluation tests that shall be considered are given in 5.3.1 to 5.3.4.

5

5.3.1 Chronic toxicity
These tests determine the effects of either single or multiple exposures to medical devices, materials and/or their
extracts during a period of at least 10% of the life-span of the test animal (e.g. over 90 days in rats). These tests
should be appropriate for the route and duration of exposure or contact. Chronic toxicity tests are described in ISO
10993-11.
Chronic toxicity tests may be included in subacute and subchronic toxicity test protocols and implantation test
protocols.
5.3.2 Carcinogenicity
These tests determine the tumorigenic potential of medical devices, materials and/or their extracts from either
single or multiple exposures or contacts over a period of the major portion of life-span of the test animal. These
tests may be designed in order to examine both chronic toxicity and tumorigenicity in a single experimental study.
Carcinogenicity tests should be conducted only if there are suggestive data from other sources. These tests should
be appropriate for the route and duration of exposure or contact. Carcinogenicity tests are described in ISO 109933.
5.3.3 Reproductive and developmental toxicity
These tests evaluate the potential effects of medical devices, materials and/or their extracts on reproductivefunction, embryonic development (teratogenicity), and prenatal and early postnatal development. Reproductive/developmental toxicity tests or bioassays should only be conducted when the device has potential impact on
the reproductive potential of the subject. The application site of the device should be considered. Reproductive anddevelopmental toxicity tests are described in ISO 10993-3.
5.3.4 Biodegradation
Where the potential for resorption and/or degradation exists, corresponding tests may determine the processes ofabsorption, distribution, biotransformation and elimination of leachables and degradation products of medical
devices, materials and/or their extracts. Biodegradation tests are described in ISO 10993-9.

6 Selection of biological evaluation tests
Evaluation may include both a study of relevant experience and actual testing. Such an evaluation may result in
the conclusion that no testing is needed if the material has a demonstrable history of use in a specified role that isequivalent to that of the device under design.
Table 1 identifies the initial evaluation tests that shall be considered for each device and duration category. Table 2
identifies the supplementary evaluation tests that shall be considered for each device and duration category.
Due to the diversity of medical devices, it is recognized that not all tests identified in a category will be necessaryor practical for any given device. It is indispensable for testing that each device be considered on its own merits:
additional tests not indicated in the table may be necessary.
The tests considered and the rationale for selection and/or waiving of tests shall be recorded.

7 Assurance of test methods
7.1 Test method assurance
The test methods used in the biological evaluation shall be sensitive, precise and accurate. The test results should
be reproducible (intralaboratory) as well as repeatable (interlaboratory).
7.2 Continued assurance
The assurance that a material is initially acceptable for its intended use in a medical device, and its continued
acceptability in the long term, is an aspect of a quality management system. (See A.2, subclause 7.2).
NOTE—ISO 9001 specifies the requirements for such quality management systems. ISO 9004-1 provides more detailed
guidance for designing and manufacturing products.

6

Table 1—Initial evaluation tests for consideration

Medical device categorization by

Biological effectContact

x

x

Skin

B

x

x

x

C

x

x

x

A

x

x

x

Surface device

Mucosal membrane

B

x

x

x

C

x

x

x

Breached orcompromised
surface

A

x

x

x

B

x

x

x

C

x

x

x

A

x

x

x

x

x

Blood path, indirect

B

x

x

x

x

x

C

x

x

External
communicating
deviceAx

xx

Tissue/bone/dentin

B

x

x

C

x

A
Circulating blood

Tissue/bone

C—permanent(> 30 days)

x

x

x

x

Hemocompatibility

Category

Implantationx

B—prolonged(>24 h to 30 days)

Genotoxicity

Irritation or introcutaneous
reactivity(see 4.1)

A—Limited(≤ 24 h)Subchronic toxicity(subacute toxicity)

Sensitization

Nature of body contact

Systemic toxicity (acute)

Cytotoxicity

A

Contact duration(see 4.2)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

B

x

x

x

x

x

x

x

x

C

x

x

x

x

x

x

x

x

A

x

x

x

B

x

x

x

x

x

x

x

C

x

x

x

x

x

x

x

A

x

x

x

x

x

B

x

x

x

x

x

C

x

x

x

x

x

x

Implant device
Blood

x

x

x

x

x

x

x

x

NOTE—This table is a framework for the development of an assessment program and is not a checklist (see clause 6).

7

Table 2—Supplementary evaluation tests for consideration

Medical device categorization by

Biological effectCategory

Contactxx

C—permanent(> 30 days)

Biodegradation

B—prolonged(>24 h to 30 days)

Carcinogenicity(see 4.1)

A—Limited(≤ 24 h)Chronic toxicity

Nature of body contact

Reproductive/developmental

Contact duration(see 4.2)

A
Skin

B
C
A

Surface device

Mucosal membrane

B
CA

Breached orcompromised surface

B
CA

Blood path, indirect

B
C

External
communicating
deviceA
Tissue/bone/dentin

B
C

x

A
Circulating blood

B
C

x

x

x

x

x

x

A
Tissue/boneBC

Implant device
A
Blood

B
C

NOTE—This table is a framework for the development of an assessment program and is not a checklist (see clause 6).

8Annex A(informative)
Rationale

A.1 General
This part of ISO 10993 is concerned with the safety-in-use of medical devices and materials. It is intended toassess the biological response of devices and materials as part of the overall evaluation and development ofdevices and materials. Like other current work on this subject, it addresses the determination of the effects ofdevices and materials on tissue in a general way, rather than for specific individual applications. This part of ISO
10993 thus classifies medical devices into broad categories and indicates, in matrices, the biological tests that arethought to be relevant for consideration for each device category.
Expanded test protocols may combine initial evaluation tests. Examples could be sensitization, irritation andintracutaneous reactivity tests in a single, expanded protocol; or systemic toxicity, subacute and subchronic
toxicity, chronic toxicity and, implantation tests in a single, expanded protocol.
The range of biological hazards is wide. The tissue interaction of a material cannot be considered in isolation fromthe overall device design. The best material with respect to tissue interaction may result in a less functional device,tissue interaction being only one characteristic of a material. Where the material is intended to interact with tissue
in order for the device to perform its function, evaluation takes on dimensions not generally addressed in standards
and guidelines to date.
Biological reactions that are adverse for a material in one application may not be adverse for the use of thematerial in a different application. Biological testing relies upon animal models and a material cannot, therefore, be
conclusively shown to have the same tissue reactions in humans. In addition, differences between humans
suggest that some patients may have adverse reactions even to well-established materials.
Currently, biological testing relies on animal models. However, as scientific knowledge advances ourunderstanding of basic mechanisms, preference should be given to in vitro models in situations where scientificevidence yields equally relevant information.
For medical devices and materials, the application of a rigid set of test methods and pass/fail criteria might result ineither an unnecessary restriction, or a false sense of security in their use. Where a particular application warrants,
experts in the product or application area involved may choose to establish specific tests and criteria specified in a
product-specific vertical standard.
This part of ISO 10993 is not, therefore, intended to be a set of definitive statements to be followed by individuals
not qualified by training and experience; it should be applied with interpretation and judgement by the appropriate
professionals qualified by training and experience, taking into consideration the factors relevant to thedevice/material, its intended use, and the current knowledge of the device/material provided by scientific literatureand previous clinical experience.

A.2 Rationale for specific clauses
The following are rationale for specific clauses in this part of ISO 10993, with clause numbers parallel to those in
the body of the document.
Clause 1 It is worth acknowledging that there are important material characteristics other than biological ones thatshould be taken into account in the overall design of the device.
Subclause 3.6 Evaluation may include both a study of relevant experience and actual testing. Such an evaluation
may result in the conclusion that no testing is needed if the material has a demonstrable history of use in a specificrole that is the same as that of the device under design.
Evaluation should consider intended and unintended interactions between the material and tissues.
Subclause 3.8 This clause is intended to avoid the need for redundant experiments when information about thematerial and/or device is available from other sources.

9Subclause 7.2 The selection and evaluation of materials that will come into contact with tissue require a structured
process so that the materials incorporated in the final design contribute to the overall biological evaluation
assurance of the design.

10Annex B(informative)
Flow chart to aid in systematic approaches to biological evaluation of medical
devices

1) Refers to clause in main document: AAMI/ISO 10993-1

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Annex C(informative)
Bibliography

C.1 International Organization for Standardization (ISO)[1] ISO 7405:1997, Dentistry—Preclinical evaluation of biocompatibility of medical devices used in dentistry—
Test methods for dental materials.
[2] ISO 9000-1:1994, Quality management and quality assurance standards—Part 1: Guidelines for selection anduse.
[3] ISO 9001:1994, Quality systems—Model for quality assurance in design, development, production, installationand servicing.
[4] ISO 9004-1:1994, Quality management and quality system elements—Guidelines.
[5] ISO 10993-3:1992, Biological evaluation of medical devices—Part 3: Tests for genotoxicity, carcinogenicity
and reproductive toxicity.
[6] ISO 10993-4:1992, Biological evaluation of medical devices—Part 4: Selection of tests for interaction withblood.
[7] ISO 10993-5:1999, Biological evaluation of medical devices—Part 5: Tests for in vitro cytotoxicity.
[8] ISO 10993-6:1994, Biological evaluation of medical devices—Part 4: Tests for local effects after implantation.
[9] ISO 10993-9:1999, Biological evaluation of medical devices—Part 9: Framework for identification andquantification of potential degradation products.
[10] ISO 10993-10:1995, Biological evaluation of medical devices—Part 10: Tests for irritation and sensitization.
[11] ISO 10993-11:1993, Biological evaluation of medical devices—Part 4: Tests for systemic toxicity.
[12] ISO 13485:1996, Quality systems—Medical devices—Particular requirements for the application of ISO 9001.
[13] ISO 13488:1996, Quality systems—Medical devices—Particular requirements for the application of ISO 9002.
[14] ISO/IEC Guide 25:1990, General requirements for the competence of calibration and testing laboratories.

C.2 Organization for Economic Cooperation and Development (OECD)[15] Guidelines for testing of chemicals—Section 4: Health effects.

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