1、 ISO 2017 Biological evaluation of medical devices Part 11: Tests for systemic toxicity valuation biologique des dispositifs mdicaux Partie 11: Essais de toxicit systmique INTERNATIONAL STANDARD ISO 10993-11 Third edition 2017-09 Reference number ISO 10993-11:2017(E) ISO 10993-11:2017(E)ii ISO 2017
2、All rights reserved COPYRIGHT PROTECTED DOCUMENT ISO 2017, Published in Switzerland All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the in
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4、47 copyrightiso.org www.iso.org ISO 10993-11:2017(E)Foreword v Introduction vi 1 Scope . 1 2 Normative references 1 3 T erms and definitions . 1 4 General considerations 3 4.1 General . 3 4.2 Selection of animal species . 3 4.3 Animal status 3 4.4 Animal care and husbandry . 3 4.5 Size and number of
5、 groups . 4 4.5.1 Size of groups 4 4.5.2 Number of groups . 4 4.5.3 Treatment controls 4 4.6 Route of exposure . 5 4.7 Sample preparation 5 4.8 Dosing . 5 4.8.1 Test sample administration 5 4.8.2 Dosage volumes 5 4.8.3 Dosage frequency 6 4.9 Body weight and food/water consumption . 6 4.10 Clinical o
6、bservations 6 4.11 Clinical pathology . 6 4.12 Anatomic pathology 7 4.13 Study designs 7 4.14 Quality of investigation 7 5 Acute systemic toxicity . 7 5.1 General . 7 5.2 Study design 8 5.2.1 Preparations 8 5.2.2 Experimental animals 8 5.2.3 Test conditions. 8 5.2.4 Body weights . 9 5.2.5 Clinical o
7、bservations 9 5.2.6 Pathology 9 5.3 Evaluation criteria .10 5.3.1 General.10 5.3.2 Evaluation of results 10 5.4 Final report .10 6 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic toxicity) 12 6.1 General 12 6.2 Study design .12 6.2.1 Preparations .12 6.2.2 Experimental
8、 animals.12 6.2.3 Test conditions13 6.2.4 Body weights 13 6.2.5 Clinical observations .13 6.2.6 Pathology .13 6.3 Evaluation criteria .14 6.3.1 General.14 6.3.2 Evaluation of results 14 ISO 2017 All rights reserved iii Contents Page ISO 10993-11:2017(E)6.4 Final report .15 Annex A (informative) Rout
9、es of administration .16 Annex B (informative) Dosage volumes .18 Annex C (informative) Common clinical signs and observations 19 Annex D (informative) Suggested haematology, clinical chemistry and urinalysis measurements 20 Annex E (informative) Suggested organ list for histopathological evaluation
10、 .22 Annex F (informative) Organ list for limited histopathology for medical devices subjected to systemic toxicity testing 24 Annex G (informative) Information on material-mediated pyrogens .25 Annex H (informative) Subchronic rat Dual routes of parenteral administration .26 Bibliography .28 iv ISO
11、 2017 All rights reserved ISO 10993-11:2017(E) Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each me
12、mber body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International E
13、lectrotechnical 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 typ
14、es 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
15、 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). Any trade name used in this document is inform
16、ation given for the convenience of users and does not constitute an endorsement. For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISOs adherence to the World Trade Organization (W
17、TO) principles in the Technical Barriers to Trade (TBT) see the following URL: www.iso.org/iso/foreword.html. This document was prepared by Technical Committee ISO/TC 194 Biological and clinical evaluation of medical devices. This third edition cancels and replaces the second edition (ISO 10993-11:2
18、006), which has been technically revised with the following changes: a) reduction in group size for chronic toxicity testing in Table 1; b) a new Annex F was added; c) the original Annex F was moved to Annex G; d) a new Annex H was added; e) the Bibliography was updated. A list of all parts in the I
19、SO 10993 series can be found on the ISO website. ISO 2017 All rights reserved v ISO 10993-11:2017(E) Introduction Systemic toxicity is a potential adverse effect of the use of medical devices. Generalized effects, as well as organ and organ system effects can result from absorption, distribution and
20、 metabolism of leachates from the device or its materials to parts of the body with which they are not in direct contact. This document addresses the evaluation of generalized systemic toxicity, not specific target organ or organ system toxicity, even though these effects may result from the systemi
21、c absorption and distribution of toxicants. Because of the broad range of medical devices, and their materials and intended uses, this document is not overly prescriptive. While it addresses specific methodological aspects to be considered in the design of systemic toxicity tests, proper study desig
22、n has to be uniquely tailored to the nature of the devices materials and its intended clinical application. Other elements of this document are prescriptive in nature, including those aspects that address compliance with good laboratory practices and elements for inclusion in reporting. While some s
23、ystemic toxicity tests (e.g. long term implantation or dermal toxicity studies) can be designed to study systemic effects as well as local, carcinogenic or reproductive effects, this document focuses only on those aspects of such studies, which are intended to address systemic effects. Studies which
24、 are intended to address other toxicological end points are addressed in ISO 10993-3, ISO 10993-6, ISO 10993-10 and ISO/TS 10993-20. Prior to conducting a systemic toxicity study, all reasonably available data and scientifically sound methods in the planning and refinement of the systemic toxicity s
25、tudy design should be reviewed. This includes the suitability of use of input data such as existing toxicological data, data from chemical characterization studies and/or other biological tests (including in vitro tests and less invasive in vivo tests) for the refinement of study design, dose select
26、ion, and/or selection of pathological end points to cover in the evaluation of a study. For the repeated exposure systemic toxicity study in particular, the use of scientifically sound study design, the use of pilot studies and statistical study design and the use of unbiased, quantitative end point
27、s/methods in the pathological (including histopathological) and clinical chemistry methods are important so as to obtain data which have sufficient scientific validity. Finally, toxicology is an imperfect science. The outcome of any single test should not be the sole basis for making a determination
28、 of whether a device is safe for its intended use.vi ISO 2017 All rights reserved Biological evaluation of medical devices Part 11: Tests for systemic toxicity 1 Scope This document specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical
29、device materials to cause adverse systemic reactions. 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, th
30、e latest edition of the referenced document (including any amendments) applies. ISO 10993-1, Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management process ISO 10993-2, Biological evaluation of medical devices Part 2: Animal welfare requirements 3 T erms a n
31、d definiti ons For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply. ISO and IEC maintain terminological databases for use in standardization at the following addresses: IEC Electropedia: available at http:/ /www.electropedia.org/ ISO Online brows
32、ing platform: available at http:/ /www.iso.org/obp 3.1 dose dosage amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area 3.2 dose-effect relationship between the dosage and the magnitude of a defined biological effect either in an individual or in a
33、 population sample 3.3 dose-response relationship of dosage to the spectrum of effects related to the exposure Note 1 to entry: There are two types of dose-response relationships. The first type is the response of an individual to a range of doses. The second type is the distribution of responses of
34、 a population of individuals to a range of doses. INTERNATIONAL ST ANDARD ISO 10993-11:2017(E) ISO 2017 All rights reserved 1 ISO 10993-11:2017(E) 3.4 leachable substance chemical removed from a device or material by the action of water or other liquids related to the use of the device Note 1 to ent
35、ry: Examples of leachable substances are additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, colouring agents, fillers and monomers. 3.5 limit test use of a single group treated at a suitable dosage of test
36、 sample in order to delineate the presence or absence of a toxic hazard 3.6 systemic toxicity toxicity that is not limited to adverse effects at the site of contact between the body and the device Note 1 to entry: Systemic toxicity requires absorption and distribution of a toxicant from its entry po
37、int to a distant site at which deleterious effects are produced. 3.7 acute systemic toxicity adverse effects occurring at any time within 72 h after single, multiple or continuous exposures of a test sample for 24 h 3.8 subacute systemic toxicity adverse effects occurring after multiple or continuou
38、s exposure between 24 h and 28 d Note 1 to entry: Since this term is semantically incorrect, the adverse effects occurring within the specified time period may also be described as a short-term repeated exposure systemic toxicity study. The selection of time intervals between 14 d and 28 d is consis
39、tent with most international regulatory guidelines and considered a reasonable approach. Subacute intravenous studies are generally defined as treatment durations of 24 h but 14 d. 3.9 subchronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sa
40、mple for a part of the lifespan Note 1 to entry: Subchronic toxicity studies are usually 90 d in rodents but not exceeding 10 % of the lifespan of other species. Subchronic intravenous studies are generally defined as treatment durations of 14 d to 28 d for rodents and non-rodents, respectively. 3.1
41、0 chronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a major part of the life span Note 1 to entry: Chronic toxicity studies usually have a duration of 6 months to 12 months. 3.11 test sample material, device, device portion, comp
42、onent, extract or portion thereof that is subjected to biological or chemical testing or evaluation2 ISO 2017 All rights reserved ISO 10993-11:2017(E) 4 General considerations 4.1 General Before a decision to perform a systemic toxicity test is made, ISO 10993-1 shall be taken into account. The deci
43、sion to perform a test shall be justified on the basis of an assessment of the risk of systemic toxicity. Selection of the appropriate test(s) for a device shall be in accordance with ISO 10993-1, giving due consideration to mode and duration of contact. Testing shall be performed on the final produ
44、ct and/or representative component samples of the final product and/or materials. Test samples shall reflect the conditions under which the device is normally manufactured and processed. If deviations are necessary, they shall be recorded in the test report, together with their justification. For ha
45、zard identification purposes, it may be necessary to exaggerate exposure to the test samples. Physical and chemical properties of the test sample including, for example, pH, stability, viscosity, osmolality, buffering capacity, solubility and sterility, are some factors to consider when designing th
46、e study. When animal tests are considered, all reasonably and practically available replacement, reduction and refinement alternatives should be identified and implemented to satisfy the provisions of ISO 10993-2. For in vivo acute toxicity testing, in vitro cytotoxicity data are useful in estimatin
47、g starting doses. 4.2 Selection of animal species There is no absolute criterion for selecting a particular animal species for systemic toxicity testing of medical devices. However, the species used shall be scientifically justified and in line with the provisions of ISO 10993-2. For acute oral, int
48、ravenous, dermal and inhalation studies of medical devices the rodent (mouse or rat) is preferred with the option of the rabbit (lagomorph) in the case of dermal and implantation studies. Other non-rodent species may also need to be considered for testing, recognizing that a number of factors might
49、dictate the number or choice of species for study. It is preferred that a single animal species and strain are used when a series of systemic toxicity studies of different durations are performed, e.g. acute, subacute, subchronic and/or chronic systemic toxicity. This controls the variability between species and strains and facilitates an evaluation related solely to study duration. Should multiple species or strains be used, justification for their selection shall be documented. 4.3 Animal status Generally, healthy purpose-bred young adu
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