ISO-10993-7-2008.pdf

Reference number ISO 10993-7:2008(E) © ISO 2008 INTERNATIONAL STANDARD ISO 10993-7 Second edition 2008-10-15 Biological evaluation of medical devices Part 7: Ethylene oxide sterilization residuals Évaluation biologique des dispositifs médicaux Partie 7: Résidus de stérilisation à l'oxyde d'éthylène ISO 10993-7:2008(E) PDF disclaimer This PDF file may contain embedded typefaces. In accordance with Adobe's licensing policy, this file may be printed or viewed but shall not be edited unless the typefaces which are embedded are licensed to and installed on the computer performing the editing. In downloading this file, parties accept therein the responsibility of not infringing Adobe's licensing policy. The ISO Central Secretariat accepts no liability in this area. Adobe is a trademark of Adobe Systems Incorporated. Details of the software products used to create this PDF file can be found in the General Info relative to the file; the PDF-creation parameters were optimized for printing. Every care has been taken to ensure that the file is suitable for use by ISO member bodies. In the unlikely event that a problem relating to it is found, please inform the Central Secretariat at the address given below. COPYRIGHT PROTECTED DOCUMENT © ISO 2008 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO's member body in the country of the requester. ISO copyright office Case postale 56 CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyrightiso.org Web www.iso.org Published in Switzerland ii © ISO 2008 All rights reserved ISO 10993-7:2008(E) © ISO 2008 All rights reserved iii Contents Page Foreword iv Introduction. vi 1 Scope 1 2 Normative references1 3 Terms and definitions .1 4 Requirements.2 4.1 General2 4.2 Categorization of devices .2 4.3 Allowable limits3 4.4 Determination of EO and ECH residuals.5 5 Product release10 5.1 General10 5.2 Release of products without dissipation curve data .10 5.3 Procedure for product release using residue dissipation curves10 Annex A (normative) Evaluation of gas chromatograms12 Annex B (informative) Gas chromatographic determination for EO and ECH15 Annex C (informative) Flowchart and guidance for the application of this part of ISO 10993 series of standards to the determination of EO and ECH residuals in medical devices.19 Annex D (informative) Factors influencing product residual26 Annex E (informative) Extraction conditions for determination of residual EO.28 Annex F (informative) Rationale for the provisions of this part of ISO 10993 29 Annex G (informative) Establishment of allowable limits for EO.33 Annex H (informative) Establishment of allowable limits for ECH.50 Annex I (informative) Establishment of allowable limits for EG.59 Annex J (informative) Preparation of EO and ECH standards63 Annex K (informative) Ethylene oxide residue measuring methods .67 Bibliography74 ISO 10993-7:2008(E) iv © ISO 2008 All rights reserved 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 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 non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2. 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. 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 10993-7 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-7:1995) 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 within a risk management system 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 Part 10: Tests for irritation and skin sensitization 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 ISO 10993-7:2008(E) © ISO 2008 All rights reserved v 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 Technical Specification Part 20: Principles and methods for immunotoxicology testing of medical devices Technical Specification ISO 10993-7:2008(E) vi © ISO 2008 All rights reserved Introduction Requirements for the development, validation and routine control of an ethylene oxide sterilization process for medical devices are given in International Standards developed by ISO/TC 198. Certain requirements relating to medical devices for biological testing, selection of tests, and the allocation of devices to categories are dealt with in a variety of International Standards developed by ISO/TC 194. The specific requirement for ethylene oxide and other sterilization process residuals was referred to ISO/TC 194. Other International Standards delineate particular requirements for biological testing for specific products. As noted in the introduction to ISO 11135-1:2007, when determining the suitability of ethylene oxide (EO) for sterilization of medical devices, it is important to ensure that the levels of residual EO, ethylene chlorohydrin (ECH) and ethylene glycol (EG) pose a minimal risk to the patient in normal product use. Therefore, it is important that the use of alternative materials and sterilization processes be considered during product design and development. EO is known to exhibit a number of biological effects. In the development of this part of ISO 10993, consideration was given to these effects, which include irritation, organ damage, mutagenicity and carcinogenicity in humans and animals, and reproductive effects in animals. Similar consideration was given to the harmful effects of ECH and EG. In practice, for most devices, exposure to EO and ECH is considerably lower than the maximum values specified in this part of ISO 10993. Moreover, when the choice for EO sterilization has been made, irrespective of the provisions of this part of ISO 10993, exposure to EO residues should be minimized. Requirements herein are in addition to the biological evaluation and testing requirements for each individually designed medical device as indicated in ISO 10993-1. The biological evaluation and testing requirements, combined with the EO-sterilization process residue limits, form the justification that an EO-sterilized device is acceptable for use. Maximum allowable residues for ethylene chlorohydrin (ECH), when ECH has been found to be present in medical devices sterilized with EO, are also specified. Local effects (e.g., irritation) have been considered and are incorporated in the tolerable contact limit (TCL) as given in 4.3.5.2 and Annex G for EO, and in 4.3.5.3 and Annex H for ECH. INTERNATIONAL STANDARD ISO 10993-7:2008(E) © ISO 2008 All rights reserved 1 Biological evaluation of medical devices Part 7: Ethylene oxide sterilization residuals 1 Scope This part of ISO 10993 specifies allowable limits for residual ethylene oxide (EO) and ethylene chlorohydrin (ECH) in individual EO-sterilized medical devices, procedures for the measurement of EO and ECH, and methods for determining compliance so that devices may be released. Additional background, including guidance and a flowchart showing how this document is applied, are also included in the informative annexes. EO-sterilized devices that have no patient contact (e.g., in vitro diagnostic devices) are not covered by this part of ISO 10993. NOTE This part of ISO 10993 does not specify limits for ethylene glycol (EG). 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 10993-1:1), Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management process ISO 10993-3, Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity ISO 10993-10, Biological evaluation of medical devices Part 10: Tests for irritation and delayed-type hypersensitivity ISO 10993-12, Biological evaluation of medical devices Part 12: Sample preparation and reference materials ISO 10993-17:2002, Biological evaluation of medical devices Part 17: Establishment of allowable limits for leachable substances 3 Terms and definitions For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-17 and the following apply. 3.1 simulated-use extraction extraction to demonstrate compliance with the requirements of this part of ISO 10993, by evaluating residue levels available to the patient or user from devices during the routine use of a device with water extraction to simulate product use 1) To be published. (Revision of ISO 10993-1:2003) ISO 10993-7:2008(E) 2 © ISO 2008 All rights reserved 3.2 exhaustive extraction extraction until the amount of EO or ECH in a subsequent extraction is less than 10 % of that detected in the first extraction, or until there is no analytically significant increase in the cumulative residue levels detected NOTE As it is not possible to demonstrate the exhaustive nature of residual recovery, the definition of exhaustive extraction adopted is as above. 4 Requirements 4.1 General NOTE Information on the derivation of the limits in this part of ISO 10993 as well as other important background information and guidance relevant to the use of this document is contained in the informative annexes. This clause specifies maximum allowable residues for ethylene oxide (EO) for each individual medical device sterilized with EO. As noted in the introduction to ISO 11135-1:2007, when determining the suitability of EO for sterilization of medical devices, it is important to ensure that the levels of residual EO, ethylene chlorohydrin (ECH) and ethylene glycol (EG) pose a minimal risk to the patient in normal product use. Moreover, when the choice for EO sterilization has been made, irrespective of the provisions of this standard, exposure to EO residues should be minimized. Maximum allowable residues for ECH, when ECH has been found to be present in medical devices sterilized with EO, are also specified. Local effects (e.g., irritation) have been considered and are incorporated in the tolerable contact limit (TCL) as discussed in 4.3.5.2 and Annex G for EO, and 4.3.5.3 and Annex H for ECH. No device limits are specified for EG because a risk assessment (Annex I) indicates that calculated allowable levels are higher than those likely to occur in a medical device. However, the potential exists for acute haemodynamic and haemolytic effects to occur following rapid intravenous administration of hyperosmolar compounds like EG. Ethylene oxide sterilization of medical devices would not be expected to produce hyperosmolar solutions. Methods for the determination of EO and ECH are given in 4.4. The requirements in this part of ISO 10993 are in addition to the biological testing requirements set out in ISO 10993-1. For devices sterilized using ethylene oxide, attention shall be paid in particular to ISO 10993-3 and ISO 10993-10. All applicable requirements of ISO 10993-1 shall take into account the EO residual level at the time of release for each individually designed medical device. Results of the biological assessment of the device may dictate more stringent limits than those specified in 4.3, which are designed to protect against systemic effects. 4.2 Categorization of devices In establishing the maximum daily doses of EO and ECH that a medical device is allowed to deliver to patients, devices shall be categorized according to the duration of contact. Devices shall be placed into one of three exposure categories in accordance with ISO 10993-1:, 5.3: a) limited exposure (A) devices whose cumulative single, multiple or repeated use or contact is up to 24 h; b) prolonged exposure (B) devices whose cumulative single, multiple, or repeated long-term use or contact is likely to exceed 24 h but not 30 d; c) permanent contact (C) devices whose cumulative single, multiple or repeated long-term use or contact exceeds 30 d. If a material or device can be placed in more than one duration category, the more rigorous testing and/or evaluation considerations should apply. With multiple exposures, the decision into which category a device is placed should take into account the potential cumulative effect, bearing in mind the period of time over which these exposures occur. NOTE As it is applied in this part of ISO 10993, “multiple use” is defined to mean repeated use of the same device type, e.g. dialyser cartridges. ISO 10993-7:2008(E) © ISO 2008 All rights reserved 3 4.3 Allowable limits 4.3.1 General For each medical device, the maximum allowable doses of EO and ECH delivered to patients shall not exceed the values given below for the exposure category that the device has been placed into in accordance with 4.2. The limits for permanent contact and prolonged exposure devices are ex