A Guide to AAMI's TIR for EtO-Sterilized Medical Devices

Medical Device & Diagnostic Industry Magazine
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An MD&DI  February 1998 Column

STERILIZATION

A step-by-step approach to applying ANSI/AAMI/ISO 10993-7:1995 and AAMI TIR-19 to EtO-sterilized medical devices.

While sterilization is a necessary element in the medical device manufacturing process because it destroys viable organisms, one should not be surprised that all sterilization procedures are potentially hazardous to humans. Limits for residues remaining on devices sterilized with ethylene oxide (EtO) have been set by a number of national pharmacopoeias and by FDA in a proposed rule published in 1978.

A STANDARD IN THE MAKING

In 1990, the International Organization for Standardization (ISO) through its Technical Committee (TC) 194, Biological Evaluation of Medical Devices, established Working Group (WG) 11 to develop a standard for EtO residuals, resulting in the publication of ISO 10993-7 in 1995. In 1992, the Association for the Advancement of Medical Instrumentation (AAMI) EtO Sterilization Residuals Working Group, a technical working group of the AAMI Sterilization Standards Committee, formed a task group to write a technical information report (TIR) that would guide manufacturers and regulators responsible for EtO-sterilized medical devices as they applied ISO 10993-7. At the same time, FDA convened an internal committee to consider the application of the ISO standard to the review of submissions of EtO-sterilized devices and how (and whether) to use the ISO standard to replace the 1978 proposed rule.

The ISO standard for EtO residues was accepted through parallel ballot by ISO and the European Committee for Standardization (CEN) and was quickly accepted as an American National Standard.^1,2 However, in a letter to Medical Device & Diagnostic Industry, Donald E. Marlowe, director of the Office of Science and Technology at FDA's Center for Devices and Radiological Health (CDRH), indicated that FDA still had a number of questions concerning the application of the ISO standard and was thus postponing the implementation of ISO 10993-7:1995 as a replacement for the FDA 1978 proposed rule.^3,4 FDA and others had expressed concerns about the manner in which certain issues, including multiple device use and use of devices on neonates, were addressed in the 1995 ISO standard.

ISO continues to refine ISO/DIS 14538, which is a general procedure for deriving permissible limits for sterilization and process residues using health-based risk assessment, and this activity probably will take another two to three years to complete. The ISO committee responsible for the preparation of the EtO residue standard plans to revise the current standard by applying ISO 14538 to the generation of the allowable limits for EtO.

CREATING GUIDANCE DOCUMENTS

In its quest to guide manufacturers and regulators through this new standard, in August 1996 AAMI's TIR task group concluded that a flowchart with an accompanying text was the most practical approach. The group also developed test protocols for manufacturers to use to simulate product use and show conformity with the requirements of the standard. AAMI's EtO Sterilization Residuals Working Group reviewed the TIR flowchart and simulated-use extraction protocol in January 1997, and the ISO/TC 194/WG 11 examined the materials in April.

Some staff members of CDRH's Office of Device Evaluation who are responsible for the review of premarket approval applications and premarket notification (510(k)) submissions raised some concerns about the specific language of the accompanying text at a joint meeting between FDA and the TIR task group in August. The revised text from this meeting, with the flowchart and simulated-use extraction protocol, has since been circulated to the full EtO Sterilization Residuals Working Group, which agreed to some minor editorial changes to the document at its meeting in September 1997 and recommended to the AAMI Sterilization Standards Committee that the TIR be circulated for ballot to establish final consensus before publication of AAMI's TIR.

At the September 1997 meeting, Donald Marlowe indicated that FDA would use ANSI/AAMI/ISO 10993-7 accompanied by the guidance documents provided in the TIR as the basis for evaluating the EtO residue requirements for EtO-sterilized medical devices. He noted that the agency had not yet determined precisely how it would proceed since the 1978 proposal also applies to drugs, which are regulated by another center at FDA and are not addressed by ANSI/AAMI/ISO 10993-7. There are a number of options available to CDRH, including reopening the proposed rule making or publishing a blue book memorandum on this topic. The agency will decide on the appropriate course to take once the TIR is published early this year.

A GUIDE TO AAMI TIR-19

AAMI TIR-19 is intended to assist manufacturers in applying the standards of the ISO 10993 series to the biological evaluation of EtO-sterilized medical devices. 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 EtO residues and the analytical methods to show that an EtO-sterilized device is in compliance with the allowable limits.

The standard specifies maximum allowable residues for ethylene chlorohydrin (ECH); however, no exposure limits for ethylene glycol (EG) are set. When ISO/TC 194/WG 11 experts conducted risk assessment for EG, they found that when EtO residues are controlled, it is unlikely that biologically significant residues of EG will be present. Note that "dose to patient" is the basis for establishing the allowable limits and the reference method for showing compliance with ANSI/AAMI/ISO 10993-7.

The flowchart outlining the steps necessary to apply the standard is shown on pages 74—75 (editor's note: the flowchart could not be reproduced in electronic format). The numbers appearing within parentheses in the flowchart indicate specific clauses within the TIR text. When the TIR states "reduce EtO," manufacturers should extend the aeration time for the medical device and/or raise the aeration temperature.

Meeting the biological testing requirements for each individually designed medical device as indicated in ANSI/AAMI/ISO 10993-1, combined with satisfying the EtO-sterilization process residue limits, forms the justification that an EtO-sterilized device is acceptable for use with regard to its biocompatibility.

EXTRACTION PROCEDURES

Informative annex A of TIR-19 provides an outline to enable users to develop a simulated-use extraction procedure. Water should be used for simulated-use extraction of EtO residues.⁵ Devices that contact the body in any way during use should be extracted at 37°C, and the conversion of EtO to EG should be evaluated. Devices having no immediate body contact during use (e.g., hypodermic syringes) should be extracted at 25°C.

In determining the appropriate extraction time for a device, testers should consider the expected, reasonable worst-case use time the device would encounter. In addition, it may be useful to refer to clause 4.4.6.1.1 in ISO 10993-7:1995, which suggests that analysts establish extraction rates for EtO from various devices at various use temperatures. The minimum extraction time is 1 hour.

Any pretreatments a device must undergo prior to use, e.g., priming, should also be performed before a device is extracted. If the device is filled with water before the extraction, care should be taken to avoid air pockets. If use of the device involves circulation of fluids (e.g., blood, dialysis fluid), the extraction process should 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 EtO will stay in the body. Manufacturers must document the rationale for using the conditions established. Devices of similar design but different sizes may be grouped, with the worst-case conditions for the group selected for testing.

When evaluating EtO residues on device kits and trays, manufacturers should determine residue levels for each EtO-absorbing patient-contact device, and then choose a worst-case device to use in testing.

CONCLUSION

We hope that manufacturers and regulators who are responsible for producing and evaluating EtO-sterilized medical devices will find the guidance contained in AAMI TIR-19 a useful adjunct to ANSI/AAMI/ISO 10993-7:1995. We also hope that annex A to TIR-19 will enable analysts and others responsible for evaluating EtO residues on medical devices to develop adequate test protocols. These documents should enable those responsible for the biological evaluation of EtO-sterilized medical devices submitted for regulatory approval to make appropriate, timely decisions.

In a follow-up article this spring, we will examine the mechanism by which FDA will implement ANSI/AAMI/ISO 10993-7:1995, and we will evaluate the similarities and differences between the ISO standard and the FDA 1978 proposed rule, which has been used by both industry and the agency. In addition, we will discuss the application of ISO 10993-7:1995 to certain devices, including hemodialyzers, custom kits, and surgical gowns and drapes.

REFERENCES

1. ANSI/AAMI/ISO 10993-7:1995, "Biological Evaluation of Medical Devices—Part 7: Ethylene Oxide Sterilization Residuals," Arlington, VA, Association for the Advancement of Medical Instrumentation, 1995.

2. Page B, "ISO Standard Redefines Limits for EtO Residuals," Med Dev Diag Indust, 18(6):68—73, 1996.

3. Marlowe DE, "ISO Standard on EtO Sterilization," Med Dev Diag Indust, 18(7):32—33, 1996.

4. "Ethylene Oxide, Ethylene Chlorohydrin and Ethylene Glycol-Proposed Maximum Residue Limits and Maximum Levels of Exposure," Federal Register, 43FR:27474-27483, 1978.

5. Kroes R, Bock B, and Martis L, "Ethylene Oxide Extraction and Stability in Water and Blood," personal communication to the AAMI committee, January 1985.

Barry F.J. Page is an industry consultant, a member of the AAMI Sterilization Standards Committee, cochair of the AAMI Ethylene Oxide Sterilization Residuals Working Group, and was convener of ISO/TC 194/WG 11 when ISO 10993-7 was published. W. Howard Cyr, PhD, is a research biophysicist in CDRH's Division of Life Sciences, Office of Science and Technology.

Illustration by Brad Hamann

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