Global Sterilization: Making the Standards Standard

The new harmonized documents may hold the key to sterilization standards, but critical changes are in store for manufacturers.

Robert Reich, Philip M. Schneider, and Carolyn Kinsley

Sterilization is a critical step in the overall manufacture of medical devices. The sterilization process is unique in that its effectiveness cannot be verified by inspection or testing. Therefore, the process must be validated and highly controlled. National and international standards provide the framework for this control.

This article addresses some of the impending changes in these standards and discusses how they may affect U.S. medical device manufacturers.

Three primary standards organizations currently develop sterilization standards that are used on an international level. The International Organization for Standardization (ISO) is a worldwide federation of national standards bodies. It develops its sterilization standards through ISO/TC 198, Sterilization of Healthcare Products. The ISO standards are voluntary consensus standards that are adopted by countries worldwide. The European Committee for Standardization (CEN) is an organization that develops sterilization standards through CEN/TC 204, Sterilization of Medical Devices. These and other recognized standards have a formal regulatory role for European Union countries as mandated by the European Medical Devices Directive.

The Association for the Advancement of Medical Instrumentation (AAMI) is a standards organization that authors consensus standards, recommended practices, and technical information reports (TIRs) for the U.S. medical industry. The American National Standards

Institute (ANSI) approves AAMI standards. As ISO is a worldwide federation of national standards bodies, AAMI is the official U.S. mechanism for participation in ISO. One of the principal emphases of AAMI activities is developing international standards that assist its membership in complying with both domestic and global regulations. Therefore, AAMI’s goal is to harmonize with international standards whenever possible.

One reason that AAMI standards activities have been highly successful is because the organization has had support from FDA. Numerous AAMI sterilization documents have been included on FDA’s list of recognized consensus standards. Consequently, medical device manufacturers can quote conformance to these standards as proof of meeting FDA requirements in support of various submissions.

The sterilization standards produced by the ISO, CEN, and AAMI organizations are very similar in nature. However, subtle but critical differences have created confusion and discord between medical device manufacturers and auditors. To address this confusion, these organizations have recently taken steps toward developing more-harmonized standards.

In September 1999, at the 12th meeting of ISO/TC 198 in London, ISO/TC 198 and CEN/TC 204 agreed to a joint revision of sterilization standards under provision of the Vienna Agreement with ISO leading this effort. Included in this harmonized revision were the standards for:

• Sterilization using moist heat: ISO 11134, ISO 13683, and CEN 554.
• Sterilization using ethylene oxide (EtO): ISO 11135 and EN 550.
• Sterilization using radiation: ISO 11137 and EN 552.
• Biological indicators (BIs): ISO 11138 series and EN 866 series.
• Chemical indicators (CIs): ISO 11140 series and EN 867 series.

All of these revised documents are now either in the final draft international standard (FDIS) or draft international standard (DIS) stage, which means that subsequent modifications will be primarily editorial. All of these standards are undergoing parallel balloting by the respective AAMI sterilization standards working groups and will likely be adopted by AAMI as future U.S. standards as well.

FDA Harmonization Concerns

One significant change will influence the structure and content of the harmonized sterilization process standards for EtO and moist heat. The European position is that these standards must apply equally to industry and healthcare facilities as outlined in the European Medical Devices Directive. Historically, AAMI has authored separate standards for industry and healthcare applications in recognition of their operational and functional differences.

In the United States, healthcare facilities rely on the sterilizer manufacturer and the medical device manufacturer to provide sterilization cycle documentation and rationale, rather than conducting validation studies for specific products or product families. Industrial sterilization, however, requires comprehensive validation to support the processing of each product or product family per statutory FDA requirements. Validation of the sterilization process in healthcare facilities is not required in the United States, as FDA does not regulate them.

The sterilization process is unique in that its effectiveness cannot be verified by inspection or testing. Therefore, the process must be validated and controlled.

To obtain consensus in the harmonized ISO/CEN revision for EtO and moist-heat sterilization, some of the mandatory requirements that were historically contained in the existing ISO and CEN documents are being relocated to the guidance (nonmandatory) sections of the harmonized versions. While the European Community prefers this approach, it has created some potential issues for FDA in that former requirements may now become elective. There is some fear among U.S. standards participants that FDA will not recognize the new harmonized standards once they are approved and issued. Both ISO and AAMI working groups 1 and 5 are making plans to draft either technical specifications (TSs) or TIRs to augment and clarify FDA’s expectation for domestic compliance with the harmonized standards. AAMI has stressed that it will do so with strong input from FDA.

Before the September 1999 agreement for harmonized revision of the ISO and CEN sterilization standards, the joint chairman advisory panel (JCAP) presented several requirements to the working groups charged with the task of harmonization. These requirements were

• That the format identified in ISO 14937 be used for the EtO, moist-heat, and radiation process documents.¹
• That the quality system requirements defined by JCAP be used so that they would be common for all three sterilization methods (EtO, moist heat, and radiation). This mandate may be a concern because the current quality requirements do not meet FDA requirements.
• That text be incorporated into the scope of the process standards indicating that these documents are applicable for use in healthcare facilities.

Moist-Heat Sterilization

ISO 11134:1994, ISO 13683:1997, and CEN 554:1994 are being jointly revised to meet the JCAP requirements and to keep current with technology and moist-heat sterilization practices.2-4 The new document is designated ISO/DIS 17665 and titled, “Sterilization of healthcare products—Moist heat—Requirements for the development, validation, and routine control of a sterilization process for medical devices.”⁵ There are three major modifications in ISO/DIS 17665 with respect to the current ISO 11134 industrial process standard.

First, some of the specific requirements have been relocated to the guidance section of the standard to make the document more consistent with European practices.

Next, new text ensures that specific concerns of healthcare facilities are addressed. This text includes emphasis on the necessity of cleaning devices before reprocessing. It also provides recognition that healthcare facilities generally do not validate every product or product configuration. The concept of product families and validation by adoption into a previously validated product family has been added to the section dealing with moist-heat sterilization in healthcare facilities.

And third, the new standard recognizes that industry uses methods of moist-heat sterilization besides that of saturated steam. Alternative steam sterilization cycles that are referenced include fluids in a bottle, water-spray cycles, air and steam mixtures, and water immersion.

Because FDA has some concerns, it is generally believed that a compromise on ISO 17665 is necessary. One possibility is that the current version of the document will be approved as an FDIS in the second quarter of 2005. However, because there are a number of significant comments on the current draft, the document may be reissued as a DIS that will then allow for more substantive changes. In either case, AAMI working group 3 will begin work on a TIR to specifically outline the requirements for the U.S. users of this standard.

Ethylene Oxide

The EtO sterilization standards being jointly revised are ISO 11135:1994, and EN 550:1994.^6,7 The new harmonized standard, which will retain the ISO designation, i.e., ISO 11135, has dealt with two significant issues relative to the requirements identified by JCAP.

Mandated changes in formatting of the new document have separated product and process definitions. Users of the new document will, therefore, have to spend considerable time working through the process flow when transitioning from the current standards to the new one.

Another challenge has been the inclusion of text in the new ISO 11135 regarding the standard’s applications in healthcare facilities. The sterilization practices of these institutions differ from industry practices because of the variety and function of devices being processed. Under the guidelines, facilities must define and develop a suitable process challenge device (PCD), establish product families, and create a bioburden test program. Additionally, cleaning and disinfecting reusable devices is outside of the scope of the new EtO document, although this subject is included in the new moist-heat standard. As improperly cleaned devices cannot be effectively sterilized, this could lead to inconsistencies in the definition of EtO-sterilized items.

A few of the significant changes being proposed in the requirements of ISO/DIS 1-11135, “Sterilization of healthcare products—Ethylene oxide—Requirements for development, validation, and routine control of a sterilization process for medical devices” include the following:⁸

• Cycle development methods are now presented in normative Annexes A and B. These methods include the Bioburden/BI—Approach 2 and Overkill—Approach 3. (The current standard references the overkill and fractional cycle development methods using BIs only). These methods may be used to validate routinely used processes with either a BI-based product release or a parametric release approach when appropriate controls are used. Guidance for these approaches will be critical to ensure proper use.
• Use of developmental chambers, i.e., research vessels, as well as production chambers for process development has been expanded.
• Thermal sensor requirements as stated in EN 552 and ISO 11135 have been merged to provide a common ground, and sensor numbers for small-volume production chambers have been defined.
• Text has been added on chamber and process equivalency. (The original AAMI standard contained such information but it is now found only in AAMI TIR 28:2001).
• The application of microbiological and physical performance qualification (PQ) studies was clarified. These studies can be performed independently or simultaneously. The combined data are evaluated to understand the sterilization chamber’s response to the sterilization process.
• Some parametric release requirements moved into the routine process control section because the information benefits all mechanisms.

If a manufacturer does not have a well-defined EtO sterilization validation process, these changes will add work during cycle development and process validation. However, the changes will reduce the amount of process development work required to achieve parametric release for those manufacturers with existing overkill programs.

ISO/TC 198 working group 1 members believe that additional guidance is needed to apply the requirements of the ISO 11135 revision to the end-user. They have therefore agreed that a Part 2 or a technical specification (TS) will be written to address this need. A TS is an informative ISO document written to provide guidance to users of ISO standards. A draft TS document will be reviewed at the next ISO/TC 198 WG 1 meeting in April 2005.

Radiation Sterilization

The joint revision of the radiation sterilization standards ISO 11137:1995 and EN 552:1994 followed the revision requirements of JCAP.^9,10 Adoption of the format requirements caused some difficulties in the revision process; however, the inclusion of healthcare facilities was not an issue, because this method of sterilization is generally not used in healthcare facilities.

Even though radiation sterilization knowledge and understanding have not changed significantly since ISO 11137 was published, continued technology improvements have enhanced the radiation processes. Advances have been made in gamma sterilization processing and the use of E-beam and x-ray processing has expanded since 1995. Much of the newer information on these processes has been incorporated into informative AAMI TIR or ISO TS documents, including the following:

• New dose-setting methods.
• New enhanced dosimetry systems.
• Clarification of enhanced process control measures.

Because this type of information was included in existing documents, the revised radiation sterilization standard ISO/DIS 11137 was divided into three parts.¹¹ The first section is ISO/DIS 11137-01, “Sterilization of healthcare products—Radiation—Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.” Some of the enhancements to this document consist of:

• Inclusion of operational and performance qualification requirements for gamma, E-beam, and x-ray units.
• Identification of the requirements for performing dose audits and the audit frequencies.
• Guidance for transferring from one radiation sterilization process to another, i.e., gamma to E-beam.
• Guidance on the requirements needed for radiation process control.

The second section, designated ISO/DIS 11137-02, “Sterilization of healthcare products—Radiation—Part 2: Establishing the sterilization dose,” addresses two dose-setting methods that are readily accepted. These methods are commonly used in industry to establish the sterilization dose needed to deliver the appropriate sterility assurance level (SAL).

Methods 1 and 2 for dose setting are discussed in detail and the table used to select the verification dose and the routine sterilization dose for method 1 has been expanded. The expansion accommodates so-called cleaner products that have a bioburden of less than one colony-forming unit (CFU) per item. This is in recognition of generally improved control in manufacturing environments and processes that result in reduced bioburden levels.

Part 2 also adds two new VDMAX values, 15 and 25 kGy, and “any other dose-setting method that can substantiate a 10-6 SAL.” These dose-setting methods are very attractive to many manufacturers because they require a smaller number of test samples and subsequently reduce testing costs. This document also addresses bioburden validation recovery factors that ensure that the user understands the true bioburden levels and the effect of the sterilization process when such a factor is used. Examples for each of the dose-setting methods and maintenance requirements will be presented in the new draft document.
This standard may be viewed as a guidance document initially, but if a manufacturer adopts one of the methods for dose setting, the standard then becomes normative for the user.

ISO/DIS 11137-03, titled “Sterilization of healthcare products—Radiation—Part 3: Guidance on dosimetric aspects,” was designed to provide guidance on dosimetry systems. This document addresses calibration and the use of dosimeters throughout the radiation validation process. It also provides a significant amount of process-related information.
These documents should all move to an FDIS stage in the near future.

Biological Indicators

The harmonization process for BIs includes the combined revision of the ISO 11138 BI standards series and the EN 866 BI standards series.^12,13

Currently, there are three parts in the ISO 11138 series. Part 1 covers general requirements; Part 2 is specific for BIs for EtO sterilization processes; and Part 3 deals with BIs for moist-heat sterilization processes.

The EN series consists of eight parts: Parts 1, 2, and 3 are for general requirements, EtO, and moist heat, respectively; Part 4 details BIs for irradiation sterilization processes; Part 5 is specific for BIs for low-temperature steam and formaldehyde sterilization processes (LTSF); Part 6 covers BIs for dry-heat sterilization processes; Part 7 details self-contained BI systems for moist-heat sterilization processes; and Part 8 focuses on self-contained BI systems for EtO sterilization processes.

Additionally, there are three ANSI/AAMI BI standards adapted from ISO 11138, Parts 1–3 with minor deviations for the United States. The ANSI/AAMI BI standards are ST59, ST21, and ST19.^14-16

The primary function of these standards is to specify general production, labeling, and performance requirements for manufacture of BIs and spore suspensions used in sterilization processes. They are also important to medical device and pharmaceutical manufacturers.

The respective standards for moist-heat and EtO sterilization process validation and routine control (i.e., ISO 11134 and 11135) specify that if BIs are used in the sterilization process, they must comply with the applicable parts of the ISO 11138 BI standards series. Compliance with the EN BI standards and the future harmonized ISO BI standards will be required for medical device manufacturers and healthcare facilities within the European Union as mandated by the European Medical Devices Directive.

There will be five parts in the combined revision of the ISO 11138 and EN 866 standards series:

• ISO 11138-1, “Sterilization of healthcare products—Biological indicator systems—Part 1: General requirements.”
• ISO 11138-2, “Sterilization of healthcare products—Biological indicator systems—Part 2: Use in assessing ethylene oxide sterilization processes.”
• ISO 11138-3, “Sterilization of healthcare products—Biological indicator systems—Part 3: Use in assessing moist-heat sterilization processes.”
• ISO 11138-4, “Sterilization of healthcare products—Biological indicator systems—Part 4: Use in assessing dry heat sterilization processes.”
• ISO 11138-5, “Sterilization of healthcare products—Biological indicator systems—Part 5: Use in assessing low temperature steam and formaldehyde sterilization processes.”

Important changes that will be reflected in these combined revisions include the following:

• Elimination of EN 866, Part 4 on BIs for radiation sterilization processes. (ISO 11137 specifies dose-setting methods for the validation and routine control of radiation sterilization processes and does not recommend the use of BIs.) Although BIs for radiation sterilization process can comply with the revised ISO 11138 general requirements standard, this change may have an effect on medical device manufacturers that use BIs in validation protocols.
• Elimination of EN 866, Parts 7 and 8 on self-contained BIs for the moist-heat and EtO sterilization processes. The requirements for self-contained BIs have been included in ISO 11138, Part 1.
• Elimination of the “10” requirement in ISO 11138-3 and EN 866-3. That is, the requirement that the product of the log10 of the population and the D = D121.1C value must be Ž 10 for BIs used for moist-heat processes. (The new value will be Ž 7.5, which is the product of the log10 of the minimum requirement for population [1.0 ¥ 105 CFU] and the minimum requirement for D121.1C value [1.5 minutes]).
• Calculation of D value by the Holcomb-Spearman-Karber; the limited Spearman-Karber; or the Stumbo,
Murphy-Cochran procedures. Current ISO 11138-1 specifies fraction-negative D value calculation by only the limited Spearman-Karber method.

Additionally, Parts 2–4 contain test methodology only for determination of resistance. Test equipment (i.e., resistometer) specifications will be contained in a separate standard, ISO 18472.

The medical device marketplace is clearly global in nature. The necessity of manufacturers to monitor several standards is time consuming, expensive, and has inherent regulatory implications because of subtle differences in the documents.

The standard does not have restrictions on the use of dual-species BIs if the compliance requirements can be demonstrated. There is also a stipulation that allows for compliance with the ISO 11138 standards series for BIs that do not meet the minimum population or D value requirements of the standards. The stated requirements for compliance in this situation are as follows:

• That all other requirements of the relevant standard(s) must be met.
• That the product information contains a clear statement of the actual population and D value.
• That the product label contains a clear statement that the population or D value is below the value specified in the relevant part of ISO 11138.

The ISO 11138 BI standards series is currently in the DIS stage and should move to the FDIS stage following the ISO/TC 198 working group 4 meeting in April 2005.

Chemical Indicators

Like the BI standards, the CI standards have multiple parts. The harmonization process for CIs includes the combined revision of the ISO 11140 CI standards series and the EN 867 CI standards series.^17,18 Currently, there are five parts for both of these standards series. The ISO 11140 series consists of (1) general requirements, (2) test equipment, (3) Class 2 indicators for steam penetration sheets, (4) Class 2 indicators for steam penetration test packs, and (5) Class 2 indicators for air-removal test sheets and packs. The EN 867 CI series is consistent with most of ISO 11140 parts 1, 3, and 4, but differs in that part 2 is specific for process indicators, and part 5 specifies indicator systems and PCDs for testing small sterilizers.

ANSI/AAMI ST60 is a modified version of ISO 11140, Part 1, the general requirements, and ANSI/AAMI ST66 is similar to the ISO 11140 section that deals with Class 2 indicators for air-removal test sheets and packs.^19,20

The primary purpose of the three general requirements documents is to define the requirements for various classes of CIs. However, there are differences in classification schemes within the three sets of CI standards. While Classes 1–4 (ISO and AAMI) and Classes A–D (EN) are basically equivalent, only the ISO and AAMI standards include a Class 5 integrating indicator and only ISO 11140-1 includes a Class 6 emulating indicator (or cycle-verification indicator). The new combined revision of ISO 11140, general requirements, will include all six of these CI classes.

Currently ISO 11140, Parts 3–5; EN 867, Parts 3–4; and ANSI/AAMI ST66 all specify various applications of the Bowie Dick or steam-penetration tests. These standards are being developed in the combined revision process but may not be finalized at the same time as the ISO 11140-1 general requirements standard. ISO 11140, Part 2 on test equipment will be eliminated and replaced by the BI and CI test equipment standard, ISO 18472. The status of EN 867, Part 5 on indicator systems and PCDs for testing small sterilizers has not yet been determined.

Unlike BIs, CIs are generally not used by medical device manufacturers. However, Class 1 process indicators (or throughput indicators) are frequently used to facilitate product control. As these indicators would be considered an accessory in the manufacturing process, compliance to the ISO 11140-1 standard will likely be required.

Some changes that will be made in the revised general requirements section of ISO 11140 include the following:

• Testing requirements for Class 5 integrating indicators that will be aligned more closely with BI performance.
• A statement that the class number, i.e., 1–6, is not hierarchal in terms of the information provided. (As an example, Class 2 Bowie Dick indicators are generally more sophisticated than Class 3 or 4 indicators.)
• Inclusion of Class 1 process indicators for the vapor-phase hydrogen peroxide sterilization process with testing requirements.

The revised ISO 11140-1 is now in the FDIS stage. Although it may not be available for review prior to the ISO/TC 198 working group 6 meeting in April 2005, it is expected to move forward following the meeting.

BI and CI Equipment

The ISO, EN, and ANSI/AAMI BI and CI standards all require specialized test equipment (resistometers) to demonstrate compliance with the respective performance requirements. Currently ISO 11138, Parts 2–3, and EN 866, Parts 2–8, specify test equipment requirements for BIs in various subpart annexes. ISO 11140, Part 2, contains test equipment specifications for the CI testing indicated in ISO 11140-1. AAMI ST44:2002 defines resistometer specifications (formerly referred to as BIER and CIER vessels) for the characterization of BI and CI performance.

The new ISO 18472 is titled “Sterilization of healthcare products—Biological and chemical indicators—Test equipment.”²¹ This standard is intended to provide the appropriate resistometer specifications for use with the revised ISO 11138 BI series and ISO 11140–1 CI standards. Consequently, the standard will contain resistometer performance requirements for steam, EtO, dry-heat, and vaporized hydrogen peroxide processes. (The LTSF process does require a resistometer for compliance testing.) Although the standard is an ISO document with global contribution, there has been strong input from the United States to ensure that the equipment specifications are achievable with commonly available test vessels.

This standard will affect sterilization indicator manufacturers, contract testing laboratories, and medical device manufacturers who use resistometers to conduct in-house certification testing of BIs and CIs. It is anticipated that auditors and inspectors will require compliance with this standard for any test equipment used to certify label claims for sterilization indicators.

ISO 18472 is in the committee draft (CD) stage but is being scheduled for completion to coincide with the publication of the ISO 11138 series and ISO 11140-1.

Conclusion

It is critically important to understand the role of ISO and CEN in the development of international sterilization standards and their current status for the medical device industry.

The medical device marketplace is clearly global in nature. The necessity of manufacturers to monitor several standards dealing with the identical subject is not only time-consuming and expensive but has inherent regulatory implications because of subtle differences in the documents.

In validation of the EtO sterilization process, for example, the interpretation of ISO 11135 guidance regarding the number of sensors (BIs, thermocouples, and RH) is different from the interpretation of EN 550 guidance on the same subject. From a technical standpoint, the difference in a few probes is not significant relative to the characterization of chamber/load conditioning. However, the auditing body may take a very literal interpretation of the EN standard, insisting that its method must be followed. Consensus harmonization of the sterilization standards would eliminate such possibilities and many other possible scenarios. Additionally, device manufacturers would be required to monitor and be responsible for complying with only one set of sterilization standards and regulations.

The processes involved in achieving a consensus for harmonized sterilization standards often seems frustratingly slow. However, the goal is achievable, and it is currently in sight. It is a process that all medical device manufacturers should monitor and actively support whenever possible.

References

1. ISO 14937:2000, “Sterilization of healthcare products—General requirements for characterization of a sterilizing agent and the development, validation, and routine control of a sterilization process for medical devices” (Geneva: International Organization for Standardization [ISO], 2000).
2. ISO 11134:1994, “Sterilization of healthcare products—Requirements for validation and routine control—Industrial moist-heat sterilization” (Geneva: ISO, 1994).
3. ISO 13683:1997, “Sterilization of healthcare products—Validation and routine control of moist-heat sterilization in healthcare facilities” (Geneva: ISO, 1997).
4. CEN 554:1994, “Sterilization of medical devices—Validation and routine control of sterilization by moist heat” (Brussels: European Committee for Standardization [CEN], 1994).
5. ISO/DIS 17665, “Sterilization of healthcare products—Moist heat—Requirements for the development, validation, and routine control of a sterilization process for medical devices” (Geneva: ISO, 2004).
6. ISO 11135:1994, “Medical devices—Validation and routine control of ethylene oxide sterilization” (Geneva: ISO, 1994).
7. EN 550:1994, “Sterilization of medical devices—Validation and routine control of ethylene oxide sterilization” (Brussels: CEN, 1994).
8. ISO/DIS 11135, “Sterilization of healthcare products—Ethylene Oxide—Requirements for development, validation, and routine control of a sterilization process for medical devices” (Geneva: ISO, 2004).
9. ISO 11137:1995, “Sterilization of healthcare products—Requirements for validation and routine control—Radiation sterilization” (Geneva: ISO, 1995).
10. EN 552:1994, “Sterilization of medical devices—Validation and routine control of sterilization by irradiation” (Brussels: CEN, 1994).
11. ISO/DIS 11137, “Sterilization of healthcare products—Radiation” (Geneva: ISO, 2004).
12. ISO 11138:1995 “Sterilization of healthcare products—Biological indicators” (Geneva: ISO, 1995).
13. EN 866:1997–2000, “Biological systems for testing sterilizers and sterilization processes” (Brussels: CEN, 1997–2000).
14. ANSI/AAMI ST59:1999, “Sterilization of healthcare products—Biological indicators—Part 1: General” (Arlington, VA: Association for the Advancement of Medical Instrumentation [AAMI], 1999).
15. ANSI/AAMI ST21:1999, “Sterilization of healthcare products—Biological indicators—Part 2: Biological indicators for ethylene oxide sterilization” (Arlington, VA: AAMI, 1999).
16. ANSI/AAMI ST19:1999 “Sterilization of healthcare products—Biological indicators—Part 3: Biological indicators for moist-heat sterilization” (Arlington, VA: AAMI, 1999).
17. ISO 11140:2000, “Sterilization of healthcare products—Chemical Indicators” (Geneva: ISO, 1998–2000).
18. EN 867:1997–2001, “Nonbiological systems for use in sterilizers” (Brussels: CEN, 1997–2001).
19. ANSI/AAMI ST60:1996, “Sterilization of healthcare products—Chemical indicators—Part 1: General requirements” (Arlington, VA: AAMI, 1996).
20. ANSI/AAMI ST66:1999, “Sterilization of healthcare products—Chemical indicators—Part 2: Class 2 indicators for air removal test sheets and packs”(Arlington, VA: AAMI, 1999).
21. ISO 18472, “Sterilization of healthcare products—Biological and chemical indicators—Test equipment” (Geneva: ISO, 1999).

Robert Reich is president of PSI (Mundelein, IL). Phillip M. Schneider is a senior technical specialist, sterilization products, for 3M Health Care (St. Paul, MN). Carolyn Kinsley is a senior consultant at PSI.