MDDI Article Index
Originally Published February 2000
A comparison of ANSI/AAMI/ISO 10993-7:1995 with FDA's 1978 proposed rule for the maximum allowable levels of EtO, ECH, and EG in medical devices.
When the International Organization for Standardization (ISO) developed ISO 10993-7, "Biological Evaluation of Medical Devices—Part 7: Ethylene Oxide (EtO) Sterilization Residuals," its purpose was twofold: to specify the requirements for establishing allowable limits of EtO residues on medical devices, and to provide analytical methods to show that an EtO-sterilized device is in compliance with those allowable limits.1 Prior to the ISO standard, FDA had set limits for EtO residues on devices in a proposed rule published in 1978.2 Although the 1978 proposed rule was never published as a final rule, it has been used by both industry and government as defacto regulation for more than 20 years.
The ISO standard was developed by Working Group (WG) 11 of ISO's Technical Committee (TC) 194, Biological Evaluation of Medical Devices. In 1992, the Association for the Advancement of Medical Instrumentation (AAMI) formed a task group to write a technical information report (TIR) that would serve as guidance for manufacturers and regulators as they applied ISO 10993-7.3,4 (For a step-by-step approach on how to apply ISO 10993-7 and AAMI TIR-19, see "A Guide to AAMI's TIR for EtO-Sterilized Medical Devices," MD&DI, February 1998.5 An updated chart of A Guide to AAMI's TIR for EtO-Sterilized Medical Devices is also available in .pdf format)
At the same time, FDA convened an internal committee to consider the application of the ISO standard as a replacement for the 1978 proposed rule. While FDA has not yet replaced the 1978 proposed rule with ISO 10993-7 and AAMI TIR-19, it does recognize the standard as an acceptable means of meeting the agency's requirements concerning EtO residuals.
Recognition of ISO 10993-7 and AAMI TIR-19 is part of FDA's program to use consensus standards in its review of devices. In recognizing a standard, the agency is saying that it finds the standard acceptable. Compliance with the standard is voluntary, however, and other means of meeting agency requirements are acceptable if supported by a sound scientific rationale.
Therefore, manufacturers who already have their devices cleared for market may wish to keep the limits that were established in their 510(k) submission and make no changes, unless they are marketing in countries that require the new ISO 10993-7 standard. Those manufacturers who would like to use ISO 10993-7 and AAMI TIR-19 can make the switch without a new 510(k), but must be prepared to supply the required data and rationale. Thus, manufacturers are free to use whichever limits they choose, but must show safety and effectiveness data for their device. Referral to a recognized national or international standard should simplify and expedite the review process and inspection audits.
ISO 10993-7 and AAMI TIR-19 apply to medical devices only. Any changes to the use of the 1978 proposed rule for residue levels on pharmaceuticals and biological products will be determined later, and separately. For now, levels of EtO, ethylene chlorohydrin (ECH), and ethylene gycol (EG) on drugs, drug products, and biological products will remain as is, which for most situations is determined by the FDA 1978 proposed rule.
A special situation has already developed pertaining to apheresis kits used to collect plasma from donors. These devices are evaluated by FDA's Center for Biologics Evaluation and Research (CBER). Blood cell separators used in donor and patient blood collection have been placed in a special category by a revision of AAMI TIR-19 to establish a new residue limit of 15mg for these devices.
As a means of interpretation, AAMI TIR-19 provides guidance for users of ISO 10993-7, and limited guidance on other standards in the ISO 10993 series. AAMI TIR-19 provides more specific information in the following areas:
- To address the cumulative effects of multiple use (more than 100 times in a lifetime) or of neonatal use of devices in the limited-exposure category, AAMI TIR-19 proposes that the residue limits for the prolonged category (2mg for EtO) be applied in such cases.
- To ensure that the cumulative dose of EtO to patients from devices in the permanent category does not exceed the allowable limits in ISO 10993-7, AAMI TIR-19 proposes that no more than 0.1mg EtO (and 2mg ECH) be delivered to the patient on day 31 from such devices. The 0.1-mg limit for day 31 (and 2-mg limit for day two) will likely change in the revision of ISO 10993-7, because the revision will be based on the newer concepts described in ISO 10993-17.
- To address the potential irritant effect of EtO residues on EtO-sterilized medical devices, AAMI TIR-19 proposes a concentration limit of 250ppm for EtO as an alternative to conducting the irritation tests specified in ISO 10993-10:1995, "Tests for Irritation and Sensitization."
Members of the AAMI task group that developed TIR-19 evaluated the use patterns of medical devices using data from the Health Industry Manufacturers Association (HIMA) report 88-6, which was prepared by Environ Corp. (Arlington, VA).6 The task group determined from these data that frequently used devices were those devices used more than 100 times in a lifetime (very roughly, once a year averaged over a lifetime). Limiting the daily dose of such frequently used devices to 2mg—coupled with the setting of a concentration limit of 250ppm in lieu of performing an acute irritation test—limits the probability that the daily, monthly, and lifetime limits for EtO given to any patient will be exceeded. Specifically setting the allowable limit of EtO to not more than 0.1mg on day 31 assures that lifetime-dose-to-patient limits are not exceeded.
The 250-ppm concentration limit was established as a practical alternative to the irritation test specified in ISO 10993-10:1995. During the development of ISO 10993-7, ISO TC 194 WG 11 originally proposed a dual-binding constraint on residual EtO, with a delivery rate limit for surface-contacting devices as the second constraint. When this was proposed in 1991, there were limited available data for evaluating the irritation effects of EtO. In addition, ISO TC 194 expressed concern that WG 11 was proposing the establishment of allowable limits for a part of the program of another working group. At that time, WG 11 conceded that the available data were not sufficient to use to establish such a delivery rate limit.
Clause 4.1 of ISO 10993-7 states that the requirements in this section of ISO 10993 are in addition to the biological testing requirements set out in ISO 10993-1. It notes that all applicable requirements shall take into account the EtO residual level at time of release for each individually designed medical device. Furthermore, the clause specifically notes that irritation effects shall be considered for all devices, particularly small devices, and that attention should be paid to the potential for these effects and the concentration of EtO per unit of surface area. WG 11 agreed that when suitable data become available, consideration should be given to the revision of ISO 10993-7 to include a delivery rate limit for protection against irritation effects. This approach may also be included in the development of ISO 10993-17, "Method for the Establishment of Allowable Limits for Residues and Leachable Substances in Medical Devices Using Health Based Risk Assessment," a draft international standard (DIS) that is currently being circulated for ballot.
Throughout this article, references are made to EtO residue levels only. Many of the same comments may apply to ethylene chlorohydrin (ECH) residues. No exposure limits are set in ISO 10993-7 for ethylene gycol (EG) residues because a risk assessment summarized in ISO 10993-7, Section E.2.3, was interpreted by ISO TC 194 WG 11 to indicate that when EtO residues are controlled, it is unlikely that biologically significant residues of EG could be present. Manufacturers must be prepared to support this conclusion.
Manufacturers' most frequently asked questions pertain to how ISO 10993-7 (with AAMI TIR-19) differs from the FDA 1978 proposed rule. After 25 years of using the 1978 proposed rule, most people are quite familiar with it; numerous devices have been approved by FDA or undergone premarket notification requirements using the limits of that rule. Table I provides an instructive comparison of ISO 10993-7 (and AAMI TIR-19) with the 1978 proposed rule.
The required documentation for compliance with ISO 10993-7 is specifically described in AAMI TIR-19. Table II provides a summary of the written documentation manufacturers must maintain. The numbers in parentheses in Table II refer to the numbers in the AAMI TIR-19 flowchart and in annex A of AAMI TIR-19.
AAMI TIR-19 offers an alternative to the requirements for residue limits given in ISO 10993-7 by specifying an EtO concentration limit of 250ppm (in lieu of testing for irritation and sensitization) in addition to the limits on total residues given in ISO 10993-7. These limits cover most devices, with only a few exceptions. Table III compares the residue limits in the FDA 1978 proposed rule with the newer ISO limits. Because device weight is such an important factor, the 1978 categories are expanded to show a more complete comparison. This comparison—the 1978 limit compared to the ISO limits for the limited-exposure category—is shown in Table IV. It is important to note that since the ISO standard has limits on the total amount of EtO residues, the concentration (inppm) of EtO will decrease as device weights increase.
ISO DIS 10993-17
As part of the ongoing deliberations of Working Group 11, a number of important points have been discussed concerning the possible results of applying the ISO DIS 10993-17 method for establishing allowable limits to the revision of 10993-7 and AAMI TIR-19. Among them are a more defined risk assessment procedure, the incorporation of newer data from the last 10 years, a more definitive accounting for the effects of EtO on children and neonates, the use of shorter-term limits as excursion values of a lifetime limit, the incorporation of a concentration (or surface area) irritation limit as part of dual constraints, the incorporation of the usage patterns of medical devices (as utilization factors), and the incorporation of feasibility and benefit factors.
Approval of ISO DIS 10993-17—formerly ISO DIS 14538—is a high priority. ISO DIS 10993-17 has its own technique for establishing allowable limits, which it describes as "methods for the establishment of allowable limits for leachable substances using health based risk assessment." Once the ISO DIS 10993-17 method is approved, a revision of ISO 10993-7 can be made. Data generated or collected from the use of the current version of ISO 10993-7 may be useful in this revision process.
One result of the Modernization Act of 1997 has been that FDA has begun publishing in the Federal Register lists of recognized standards that can be used in support of submissions for premarket approval. Those standards that deal with sterilization were published together as a package and include ANSI/AAMI/ISO 10993-7. They were published in the October 16, 1998, edition of the Federal Register, vol. 63, no. 200, pages 55617–55630. The ISO 10993-7 item #23 on page 55630 has been changed and is now covered by item #37. A supplemental information sheet on item #37 can be found on the Web. As noted in the Federal Register notice and in the supplemental information, ISO 10993-7 will not be recognized by FDA without the accompanying AAMI TIR-19.
While AAMI TIR-19 provides useful guidance for ISO 10993-7, manufacturers attempting to develop testing protocols that are in compliance with the new standard often encounter difficulties. The most common questions can be addressed individually.
What is the allowable residue level for a device used for two days? Neither ISO 10993-7 nor AAMI TIR-19 directly address the question of allowable residue levels on a two-day device. The following suggestion may prove useful in most instances: EtO/device (maximum in milligrams) = (20mg) + (days device used – 1) (2mg) < 60mg. For example, on day two, one would get 22mg = 20mg + (2–1) (2mg). (Note: the 250-ppm value may override the above equation for most small devices.)
How are reduction factors (footnote 8 of AAMI TIR-19) used to determine residue levels? The HIMA-Environ report and Rodricks and Brown describe reduction factors for determining the EtO levels stated in ISO 10993-7 and AAMI TIR-19.6,7 These reduction factors are the product of two components: one for time of use, as a fraction of the total time used to establish an exposure category, and one for the type of tissue contact (e.g., skin contact would result in less residue transfer than blood contact). Reduction factors should rarely be used. The simulated extraction protocols, wherein the reasonable worst-case estimates of time and other conditions of patient contact (percent of device contacting patient, temperature of contact) should be sufficient to determine the levels of residue exposure for almost all devices.
Caution should be exercised when using the time reduction factors from the HIMA-Environ report. In that report, the authors assumed that all residues came off a device in 36 hours in a linear manner, and that shorter times were linearly proportional to the 36 hours. This assumption may not be correct, as dissipation of residues from most medical devices occurs in an exponential manner.
What are simulated-use conditions? Simulated-use conditions are well described in annex A of AAMI TIR-19. Manufacturers should pay particular attention to reasonable worst-case estimates for extraction times and document their rationale for the conditions established.
What is meant by reasonable worst-case estimates for extraction times? Reasonable worst-case estimates for the duration of use of a device (and consequently, extraction time) are not specified in ISO 10993-7 or AAMI TIR-19. Because it must be documented, however, the estimate should be based on data from actual procedures where the device was used. Average time of use does not constitute a worst case.
Is it possible to do a simulated extraction for a permanent-category device, or is exhaustive extraction necessary? Although the technique is not practical, the ISO standard does give the option of doing a simulated extraction for a "lifetime" in cases of permanent-category devices. Simulated extraction also may be impractical for a 30-day prolonged-exposure device, but it may be necessary in evaluating compliance for a relatively large, permanent-exposure device that has been determined through exhaustive extraction to have more than 60mg EtO. In such cases, the manufacturer must show that the device meets the prolonged- and limited-exposure requirements, which involve simulated-use extraction for 30 days.
What is the maximum amount of EtO residue possible on a permanent implant? In most cases, no more than 20mg can be released on a permanent implant on day one, and no more than 60mg in the first month. Having no more than 0.1mg of residue on a device on day 31 assures compliance with all allowable limits for a single device. If the residual EtO on day 31 is 0.1mg or less, the amount on subsequent days will be even less, although ISO 10993-7 and AAMI TIR-19 allow 0.1mg per day for the device's life span.
Should there be special considerations for sensitivity reactions to hemodialyzers? Questions about sensitivity reactions to hemodialyzers were considered during the development of ISO 10993-7. Specifically, there were concerns that frequent exposures of blood to EtO residues reportedly resulted in increased incidences of allergic responses. In the late 1980s, FDA issued a health alert to hemodialysis practitioners advising that flushing hemodialyzers with at least 1 L of saline before use would adequately prep them. The incidence of allergic responses decreased significantly after this recommendation was implemented. Based on that finding, the ISO committee concluded that additional changes in the requirements were not necessary.
The AAMI EtO Residuals Working Group, in a joint meeting with the Co-Chair and members of the AAMI Renal Disease and Detoxification Committee, proposed that the RD&D Committee include new language in the revision of AAMI Hemodialyzer Standards RD16 and RD17. The Standards would now indicate that the residue limits for hemodialyzers would be derived from the prolonged exposure limit by taking into account the average number of procedures for a dialysis patient in a month.
At the April 2000 meeting of the RD&D Committee, it unanimously agreed to the following language for this section of RD16 and RD17: The limit for EO residuals for each hemodialysis device shall be set according to ANSI/AAMI/ISO 10993-7:1995, clause 4.3.2. It states that allowable limits for prolonged exposure devices (presently not to exceed 2 mg/day or 60 mg/month) adjusted for the average number of hemodialysis procedures per month for a dialysis patient, not to exceed 5 mg per device. Additionally, FDA will amend the supplemental information sheet for the EtO residuals standard in the list of recognized consensus standards to remove the specific reference to hemodialyzers.
In instances where two separately manufactured devices are connected and used as one device, how should manufacturers calculate residue? While the ISO standard and the TIR do not specifically delineate residue limits for two interconnected devices, both the standard and the TIR address the possible dangers of cumulative effects. The purpose of the ISO standard and the AAMI TIR is to protect patients from the harmful effects of residues, and to document that risk assessment procedures and extraction protocols have provided an adequate level of safety. If two interconnected devices are also available individually, then the limits apply to each individual device. Manufacturers attempting to double the allowable level of residue on a device to exceed the daily dose-to-patient limits are violating the express purpose of the standard and TIR. If a device exceeds the limit, additional aeration time or aeration at an elevated temperature may reduce residue; the artificial splitting of devices, however, disregards the fundamental safety of the end-user.
Additional information on the definition of a device can be obtained from the medical device regulations, or by calling the appropriate reviewer in the Office of Device Evaluation, Center for Devices and Radiological Health.
1. "Biological Evaluation of Medical Devices—Part 7: Ethylene Oxide Sterilization Residuals," ANSI/AAMI/ISO 10993-7 (Baltimore: Association for the Advancement of Medical Instrumentation, 1995).
2. U.S. Food and Drug Administration, "ETO, ECH, and EG Proposed Maximum Residue Limits and Maximum Levels of Exposure," Federal Register, 43FR:122, 1978.
3. "Guidance for ANSI/AAMI/ISO 10993-7:1995 Biological Evaluation of Medical Devices—Part 7:1995," AAMI TIR-19 (Baltimore: Association for the Advancement of Medical Instrumentation, 1998).
4. Amendment 1 to, "Guidance for ANSI/AAMI/ISO 10993-7:1995 Biological Evaluation of Medical Devices—Part 7," AAMI TIR-19 (Baltimore: Association for the Advancement of Medical Instrumentation, 1999).
5. BFJ Page and WH Cyr, "A Guide to AAMI's TIR for EtO-Sterilized Medical Devices," Medical Device & Diagnostic Industry 18, no. 2 (1998): 73–78.
6. Environ Corp., "Appendix D" in Ethylene Oxide Residues on Sterilized Medical Devices, HIMA report 88-6 (Washington, DC: Health Industry Manufacturers Association, 1988).
7. JV Rodricks and SL Brown, "Data Requirements for Assessment of Device Risks," Journal of the American College of Toxicology 7 (1988) 509–518.
W. Howard Cyr, PhD, is a research biophysicist in the Office of Science and Technology at the Center for Devices and Radiological Health. Barry F.J. Page is a member of the AAMI Sterilization Standards committee and serves as co-chair for the Sterilization Residuals Working Group. He was convener of ISO TC 194 WG 11 when it completed ISO 10993-7, and is now convener of ISO TC 194 WG 15.
Illustration by Michael Hirano
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