コメント送付先：中村晃忠 E-mail: nakamura@nihs.go.jp
FAX: 03-3707-6950

AAMI TIR No.XX-199X

Technical Information Report for
ANSI/AAMI/ISO 10993-7,
Biological evaluation of medical devices - Part 7:
Ethylene oxide sterilization residuals

Approved XXXXXX 199X

Abstract: This AAMI Technical Information Report (TIR) provides additional guidance to augment ANSI/AAMI/ISO 10993-7, Biological evaluation of medical devices - Part 7.Ethylene oxide sterilization residuals. This TIR enables the user to follow the steps necessary to apply the standard and provide guidance for the interpretation of the alternatives given in the standard

Published by Association for the Advancement of Medical Instrumentation 3330 Washington Boulevard, Suite 400 Arlington, VA 22201-4598
Copyright 199X by the Association for the Advancement of Medical Instrumentation
All rights reserved
No part of this publication may be reproduced in any form, in an electronic retrieval system or otherwise, without prior written permission of the publisher.
Printed in the United States of America
ISBN XXXXXXX

AAMI TECHNICAL INFORMATION REPORT

A technical information report (TIR) is a publication of the AAMI Standards Board that has evolved during the development of a standard for a particular aspect of medical technology.

Although the material presented in a TIR may need further evaluation by experts, there is value in releasing the information because of the immediate need for it by the industry and the professions.

A TIR differs markedly from a standard or recommended practice, and readers should understand the differences between these documents.

Standards and recommended practices are subject to a formal process of committee approval, public review, and resolution of all comments. This process of consensus is supervised by the AAMI Standards Board and, in the case of American National Standards, the American National Standards Institute.

A TIR is not subject to the same formal approval process as a standard. However, a TIR is approved for distribution by a technical committee and the AAMI Standards Board.

Another difference is that, although both standards and TIRs are periodically reviewed, a standard must be acted upon - either reaffirmed, revised, or withdrawn - and the action formally approved usually every 5 years but at least every 10 years. For a TIR, AAMI consults with a technical committee about 5 years after the publication date (and periodically thereafter) for guidance on whether the document is still useful that is, to check that the information is relevant or of historical value. In the event that the information is not useful, the TIR is removed from circulation.

A TIR may be developed because it is more responsive to underlying safety or performance issues than a standard or recommended practice, or because achieving consensus is extremely difficult or unlikely. Unlike a standard, a TIR permits the inclusion of differing viewpoints on technical issues.

CAUTION NOTICE: This AAMI Technical Information Report may be revised or withdrawn at any time. Because it addresses a rapidly evolving field or technology, readers are cautioned to ensure that they have also considered information that may be more recent than this document.

CONTENTS

Committee representation
Foreword
1 Introduction
2 Guidance
Annex A Simulated use extraction procedure
Flow chart

Committee representation

This technical information report was developed by the AAMI Sterilization Residuals Working Group under the auspices of the AAMI Sterilization Standards Committee.

The AAMI Sterilization Standards Committee, which authorized the distribution of this report, has the following members:

Cochairs:


Members:

.
The AAMI Sterilization Residuals Working Group has the following members:
Cochairs:


Members:


Alternates:


NOTE - Participation by federal agency representatives in the development of this technical report does not constitute endorsement by the federal government or any of its agencies.

Foreword

This Technical Information Report (TIR) was developed by the Task Group on Ethylene Oxide Sterilization Residuals of the AAMI Sterilization Residuals Working Group, under the auspices of the AAMI Sterilization Standards Committee. The Task Group has the following members:

In Memoriam

The Sterilization Standards Committee and the Sterilization Residuals Working Group would like to gratefully acknowledge the contributions of the late Barbara Whittaker, PhD, Becton Dickinson, whose input and assistance contributed to the writing of this document.

Comments on this Technical Information Report are invited and should be sent to AAMI, 3330 Washington Boulevard, Suite 400, Arlington, VA 22201-4598.

Introduction

This TIR is to provide guidance in the application of standards of the ISO 10993 series to the biological evaluation of medical devices that have been sterilized with ethylene oxide. The International Standard ISO 10993-7, Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals, specifies the requirements for establishing allowable limits for EO residues and analytical methods to show that an EO-sterilized device is in compliance with the allowable limits. Maximum allowable residues for ethylene chlorohydrin (ECH) when ECH has been found to be present in medical devices sterilized with EO are also specified. No exposure limits are set for ethylene glycol (KG) because when EO residues are controlled, it is unlikely that biologically significant residues of EG would be present. Dose to patient and contact site effects are the basis for establishing the allowable limits and dose to patient is the reference method for showing compliance with this standard.

The introduction to the standard notes that, during product development and design, alternative materials and sterilization methods should have been considered to minimize exposure to residues. In addition, an EO-sterilized product must meet the biological testing requirements of ISO 10993, in particular ISO 10993-10, Biological evaluation of medical devices - Part 10: Tests for irritation and sensitization, as well as the EO residue requirements.

There are certain circumstances, for example major surgery, where the life saving nature of the therapy significantly influences the risk-benefit analysis of the use of an EO-sterilized medical device. The exposure limits given in ISO 10993-7 are based on risks and benefits associated with less critical circumstances. In consequence, there is scope for relaxation of the proposed limits in life-threatening situations where it is not possible to meet the specified limits.

The TIR consists of a flow chart that enables a user to follow through the steps necessary to apply the standard, showing the decision points and providing guidance for the interpretation of the alternatives given in the standard. Some of the interpretations represent a practical means to apply the standard to different products based on factors such as: nature of exposure, duration of exposure, frequency of use, special situations of use, e.g., as cited in clause 4.3.4, and product size. There is also an interpretive text which provides more detail than can be included in the flow chart.

Clause 4.4 of the standard gives the requirements for determining EO and ECH residues and analytical procedures are described in normative Annex B. Extraction conditions for the determination of residual EO are given in informative Annex D. Guidance on developing an appropriate simulated use extraction procedure are given in informative Annex A to this TIR and this enables users to develop and document the rationale for an appropriate simulated-use extraction procedure for their EO-sterilized products.

TIR for ANSI/AAMI/ISO 10993-7: Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals.

This text should be used in conjunction with the flow chart appended as Figure 1. The flow chart is annotated and the text here describes the basis for the decision taken from the standard.

NOTE In this TIR, where the statement Reduce EO is made this shall be accomplished by additional aeration of the medical device.

1. Use of alternate materials and sterilization methods should have been considered during product development and design with the aim of minimizing exposure to residues. The rationale and basis for the decision made should be documented.

2. If the device has no patient contact[1], the standard is met.[2]

3. If this is a multi-device system, the limits apply to each individual patient-contact device.

4. If the device is in a special category;

4.a. If the device is an intraocular lens, the limits are 0.5 ug/lens/day, not to exceed 1.25 ug total.[3] Limits for other intraocular devices can be pro-rated on the basis of the mass of the device, with the mass of an intraocular lens taken as 20 ma. When EO residues are controlled as specified here for intraocular devices, it is unlikely that significant amounts of ECH will be present.

4.b. If the device is a blood oxygenator or blood separator, determine EO residues.[3,4] The average daily dose shall not exceed 60 mg per device. If it does, determine EO residues by simulating product use by extracting the device at 37 _C for up to 24 h, but not less than 1 h (see Annex A). If the daily dose from simulation of product use exceeds 60 ma, reduce EO. Otherwise, if the daily EO dose is less than 60 ma, go to 9.

4.c. If the device is a blood purification set-up, the limited (daily) and prolonged (monthly) duration category dose requirements shall be met, but the lifetime dose may be exceeded.

[1] Examples include in vitro diagnostic devices, back table covers, Mayo stand covers, light handles, etc.
[2] Employee exposure limitations may be required by local occupational health regulations.
[3] An exhaustive extraction procedure as specified in Table D. 1, annex D and defined in clause 3.2 of ISO 10993-7 is required to determine EO residues. The analyst shall verify and document the procedure used..
[4] An exhaustive extraction procedure may be impractical for these products in which case proceed directly to the simulated use procedure.

5. Determine total EO residues: [5]

6. For limited exposure devices, those contacting the patient for up to 24 hours:

6.a. Multiple or neonatal use: If consideration of the cumulative effects of multiple use[6] or of neonatal use of the device results in a decision to move the device to the next exposure category, document the rationale for the decision and use the allowable daily dose limit for the prolonged exposure category (24 hours up to 30 days) of 2 mg/day for this limited exposure category device and go to 6.c. If it is concluded that it is not necessary to move the device to the next category, document the rationale for the decision and continue at 6.b.

6.b. No change in category: If the measured EO residue is less than 20 ma, go to 9, otherwise use appropriate temperatures (either 37 _C [body temperature] or 25 _C [room temperature]) and times (based on anticipated use time, but with a minimum of 1 hour), with water as the extracting medium to simulate product use.[7,8] If the measured EO dose from simulated use is less than 20 ma, go to 9, otherwise, reduce EO.

6.c. Change in category: If the measured EO for these devices is less than 2 ma, go to 9, otherwise use appropriate temperatures (either 37 _C [body temperature] or 25 _C [room temperature]) and times (based on anticipated use time, but with a minimum of 1 hour), with water as the extracting medium to simulate product use.[7] If the measured EO dose from simulated use is less than 2 ma, go to 9, otherwise, reduce EO.

7. For prolonged exposure devices, those contacting the patient for more than 24 hours up to 30 days:

[5] An exhaustive extraction procedure as specified in Table D. l, annex D and defined in clause 3.2 of ISO 10993-7 is required to determine EO residues. The analyst shall verify and document the procedure used. For very large products, an exhaustive extraction procedure may be impractical. In such cases, continue at 6 and follow the requirement to employ a simulated use procedure for the appropriate device category.
[6] Frequently used devices are those used more than one hundred (100) times on the average person in a lifetime. (Appendix D in: Ethylene oxide residues on sterilized medical devices. HIMA report 88-6, prepared by ENVIRON Corporation, published by the Health Industry Manufacturers Association, Washington, D.C., 1988.
[7] See Annex A.
[8] In certain exceptional situations where simulated use extraction may be neither feasible nor practical (e.g., for large, surface contacting devices such as gowns or drapes), the dose of EO transferred to the patient may be estimated on a weight- or surface area-proportional basis using, for example, the transfer reduction factor approach described the section Exposure per use in: Data requirements for assessment of device risks: J. V. Rodricks and S.L. Brown; J Am. Coll. Toxicol. i, 509-518, 1988.

7.a. If the measured EO for these devices is <20 mg: go to 9. Otherwise use appropriate temperatures (either 37 _C [body temperature] or 25 _C [room temperature]) and extract the device for 24 h with water to simulate product use.[9] If the measured EO dose from simulated use for the first 24 h is less than 20 mg go to 7.b, otherwise reduce EO.

7.b. If the measured EO is > 20 mg but < 60 mg: Simulate use of the device by using appropriate temperatures (either 37 _C [body temperature] or 25 _C [room temperature]) and times (based on anticipated use time), extracting with water.[9] If the measured EO dose from simulated use is less than 2 mg/day, go to 9, otherwise reduce EO.

8. For permanent exposure devices, those contacting the patient from 30 days to lifetime:

8.a. If the measured EO is < 20 mg, go to 9, otherwise go to 8.b. or 8.d.

8.b. If the measured EO is < 2 mg/day for 30 days (i.e. 60 mg), extract the device using water at 37 _C for 24 hours and go to 8.c, otherwise reduce EO.

8.c. If the measured EO dose for the first 24 hours from simulated use is < 20 mg: go to 9, otherwise reduce EO.

8.d. If the measured EO is > 60 mg, extract the device at 37 _C for 24 h. If the measured EO dose for the first 24 hours from simulated use exceeds 20 mg reduce EO, otherwise extract at 37 _C for 30 days and go to 8.e.

8.e. If the measured EO dose for the first 30 days from simulated use is >2 mg/day (i.e. 60 mg), reduce EO. Otherwise extract the same device on day 31 at 37 _C for 24 hours. [10] If the measured EO dose is less than 0.1 mg reduce EO, otherwise go to 9.

9. The device shall not be irritating with the amount of EO to be allowed on the device at release when tested following the appropriate procedures described in ANSI/AAMI/ ISO 10993-10:1995, Biological evaluation of medical devices - Part 10: Tests for irritation and sensitization, paying particular attention to A.2.7 in this part. The AAMI EO residues Working Group has evaluated available data and determined that medical devices will not meet the requirements of ANSI/AAMI/ISO 10993-10:1995 if the EO concentration exceeds 250 ppm. If the device is irritating, or the EO residue exceeds 250 ppm, reduce EO, otherwise the device meets the requirements of ANSI/AAMI/ ISO 10993-7:1995.

[9] See Annex A.
[10] NOTE: The dose to patient shall not exceed 0.1 mg/day from day 31 for devices in the permanent exposure category and this specific test is to confirm that this requirement is met.

Annex A (informative)

Simulated use extraction procedure

A.1 Extraction fluid: Water should be used for simulated-use extraction of EO residues (Ref: Kroes, R., Bock, B. and Martis, L. Ethylene oxide extraction and stability in water and blood Personal communication to the AAMI committee, Jan. 1985).

A.2 Extraction temperature: Devices wholly or in part in contact with the body during use shall be extracted at 37 _C (body temperature). Devices having no immediate body contact during use (e.g., hypodermic syringes) shall be extracted at 25 _C (room temperature). When devices are extracted at 37 _C the conversion of EO to EG shall be evaluated.

A.3 Extraction time: The expected reasonable worst-case range of times over which the device use is recommended or anticipated shall be considered in establishing extraction times. In addition, it may be useful to collect data to establish the extraction rate for EO from the device at the use temperature established by reference to clause A.1 (10993-7:1995 clause 4.4.6.1.1). These data or other pertinent information shall be evaluated to determine an extraction time appropriate for the device that takes into account the available data. The minimum extraction time shall be one (1) hour.

A.4 Extraction of device: Where pre-treatment of the device is required prior to use this shall be performed before the device is extracted. Where the device is filled for extraction this shall be done in a manner that eliminates entrained air pockets. The device shall be extracted with water at the temperature and for the time established. Where use of the device involves circulation of fluids (e.g., blood, dialyzer fluid), extraction shall be carried out with water to simulate the fluids circulating in a manner consistent with product use. Note that where blood is returned from the device to the patient it must be assumed that any EO will stay in the body. The rationale for the conditions established shall be documented.

A.5 Grouping of devices: Devices of similar design but different sizes may be grouped and the worst-case selected for testing as representative of the group. The rationale for this decision shall be documented.

A.6 Device kits and trays: Residues shall initially be determined for each EO-absorbing patient-contact device in kits and trays and the worst-case device established. Additional data can then be collected using the worst- case device. The rationale for the selection shall be documented.

Flow chart


Flow chart upper part (big)


Flow chat lower part (big)