ISO/TS 10993-20:2006
(Main)Biological evaluation of medical devices — Part 20: Principles and methods for immunotoxicology testing of medical devices
Biological evaluation of medical devices — Part 20: Principles and methods for immunotoxicology testing of medical devices
ISO/TS 10993-20:2006 presents an overview of immunotoxicology with particular reference to the potential immunotoxicity of medical devices. It gives guidance on methods for testing for immunotoxicity of various types of medical devices. ISO/TS 10993-20:2006 is based on several publications written by various groups of immunotoxicologists over the last few decades in which the development of immunotoxicology as a separate entity within toxicology took place.
Évaluation biologique des dispositifs médicaux — Partie 20: Principes et méthodes relatifs aux essais d'immunotoxicologie des dispositifs médicaux
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TECHNICAL ISO/TS
SPECIFICATION 10993-20
First edition
2006-08-01
Biological evaluation of medical
devices —
Part 20:
Principles and methods for
immunotoxicology testing of medical
devices
Évaluation biologique des dispositifs médicaux —
Partie 20: Principes et méthodes relatifs aux essais
d'immunotoxicologie des dispositifs médicaux
Reference number
©
ISO 2006
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ii © ISO 2006 – All rights reserved
Contents Page
Foreword. iv
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions. 1
4 Risk assessment and risk management.2
5 Identification of hazards . 2
6 Methods of assessment of immunotoxicity. 4
6.1 General. 4
6.2 Inflammation. 5
6.3 Immunosuppression. 5
6.4 Immunostimulation. 7
6.5 Hypersensitivity . 7
6.6 Auto-immunity. 7
7 Extrapolation of data provided by pre-clinical assays . 7
Annex A (informative) Current state of knowledge. 8
Annex B (informative) Clinical experience with medical devices . 12
Annex C (informative) Flow chart for immunotoxicity testing. 14
Bibliography . 15
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
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The main task of technical committees is to prepare International Standards. 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.
In other circumstances, particularly when there is an urgent market requirement for such documents, a
technical committee may decide to publish other types of normative document:
— an ISO Publicly Available Specification (ISO/PAS) represents an agreement between technical experts in
an ISO working group and is accepted for publication if it is approved by more than 50 % of the members of
the parent committee casting a vote;
— an ISO Technical Specification (ISO/TS) represents an agreement between the members of a technical
committee and is accepted for publication if it is approved by 2/3 of the members of the committee casting a
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International Standard or be withdrawn.
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.
ISO/TS 10993-20 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical
devices.
ISO/TS 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 in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 9: Framework for identification and quantification of potential degradation products
iv © ISO 2006 – All rights reserved
⎯ Part 10: Tests for irritation and delayed-type hypersensitivity
⎯ Part 11: Tests for systemic toxicity
⎯ Part 12: Sample preparation and reference materials
⎯ Part 13: Identification and quantification of degradation products from polymeric medical devices
⎯ 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
⎯ Part 17: Establishment of allowable limits for leachable substances
⎯ Part 18: Chemical characterization of materials
⎯ Part 19: Physico-chemical, morphological and topographical characterization of materials
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices
Introduction
International and European Standards are the main focus for demonstration of the safety and compliance of
medical devices. There has been increasing attention over the past few years on the potential for medical
devices to cause changes in the immune system. It was felt necessary to provide guidance on how to address
adverse effects of medical devices on the immune system. As there are no standardized tests available, this
document provides a framework on how to approach the evaluation of immunotoxicity.
The intention of this document is:
⎯ to summarize the current state of knowledge in the area of immunotoxicology, including information on
methods of assessment of immunotoxicity and their predictive value;
⎯ to identify what the problems are and how they have been dealt with in the past.
For clinical indications of immune alterations due to medical devices, an extensive literature review has been
performed, primarily through Medline. The key areas which have been researched are:
⎯ immunosuppression;
⎯ immunostimulation;
⎯ hypersensitivity;
⎯ chronic inflammation;
⎯ autoimmunity.
These key words are linked with the following materials:
⎯ plastics and other polymers;
⎯ metals;
⎯ ceramics, glasses and composites;
⎯ biological materials.
NOTE See also Table 1 for possibilities of interaction of materials with the immune system.
vi © ISO 2006 – All rights reserved
TECHNICAL SPECIFICATION ISO/TS 10993-20:2006(E)
Biological evaluation of medical devices —
Part 20:
Principles and methods for immunotoxicology testing of
medical devices
1 Scope
This part of ISO 10993 presents an overview of immunotoxicology with particular reference to the potential
immunotoxicity of medical devices. It gives guidance on methods for testing for immunotoxicity of various
types of medical devices.
This part of ISO 10993 is based on several publications written by various groups of immunotoxicologists over
the last few decades in which the development of immunotoxicology as a separate entity within toxicology
took place.
The current state of knowledge with regard to immunotoxicity is described in Annex A. A summary of clinical
experience to date with immunotoxicology associated with medical devices is given in Annex B.
NOTE See also Bibliographic Reference [11].
2 Normative references
The following referenced documents are indispensable for the application 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 14971, Medical devices — Application of risk management to medical devices
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and delayed-type
hypersensitivity
ISO 10993-11:2006, Biological evaluation of medical devices — Part 11: Test for systemic toxicity
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1
immunotoxicology
study of the adverse health effects that result, directly or indirectly, from the interaction of xenobiotics with the
immune system
3.2
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 on human beings solely or principally for the 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;
⎯ 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 can be assisted in its function by such means.
NOTE 1 Devices are different from drugs and their biological evaluation requires a different approach.
NOTE 2 Use of the term "medical device" includes dental devices.
3.3
xenobiotic
substance foreign to the human body or living organisms
3.4
immunogenic
able to stimulate cells of the immune system resulting in an antigen specific immune response
4 Risk assessment and risk management
Risk assessment includes hazard identification, dose response assessment and exposure assessment, which
together allow characterization of the risk. Based on this risk characterization, risk management shall be
applied.
Because of the difficulties in predicting immunotoxicity of new chemicals and materials, effort and interest
need to be focused on the assessment and management of risks arising from known immunotoxic chemicals
contained in medical devices. Application of risk management to medical devices shall be performed in
accordance with ISO 14971. Possible immunotoxic hazards of the chemicals contained in the medical device
shall be identified first by an extensive literature search. Examples of such hazards are the production of
anaphylactic shock by chlorohexidine in medicines and by proteins in latex rubber. Subsequently the overall
risk management/reduction procedures shall be considered, together with the various possible actions that
could be taken to further reduce remaining risks such as indicating contra-indications on the label, product
recall, design-change and restrictions of use or application.
5 Identification of hazards
Immunological hazards should be
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