Sterilization Validation: A 25-Year Retrospective

While techniques of sterilizing medical devices have not changed much over the past quarter century, the levels at which they are monitored and controlled have.

Robert R. Reich

I was extremely flattered when the editors of MD&DI asked me to author a 25-year retrospective on medical device sterilization validation. It then dawned on me that to receive this honor I must be very old! I remember the inaugural issue of the magazine and discussions surrounding the creation of the first MD&M Conference. The year 1979 sounds like ancient history; however, many of my memories do not seem that old to me. I guess time does fly when you are having a good time.

In many respects, my career in the medical device sterilization area has paralleled the history of MD&DI. I was honored to serve on the editorial advisory board of the magazine at its inception, and have continued to serve for 25 years. During this time, I have had the opportunity to directly participate in and review many of the developments, discoveries, and refinements in the sterilization field.

Early Sterilization

In 1979, the principal medical device sterilization modalities in use were ethylene oxide (EtO) and radiation�primarily gamma�as well as some saturated steam. This was mainly due to the proliferation of disposable medical devices. For the most part, they were constructed of heat-labile plastics and required a low-temperature (below 121.1�C) sterilization process. This trend continues today with the development of new and improved medical-grade materials for construction and packaging films. These materials have provided unique properties for packaging novel medical devices. While contract sterilizers now sterilize an increased percentage of medical devices, the principal modes of sterilization remain the same: EtO and radiation.

The basic principles of these sterilization processes have not changed significantly. Steam and EtO processes still involve exposing a device in a pressurized chamber to a predetermined set of conditions for a specific time. Radiation still involves exposing a device to a specific dose of radiation in a carrier tote (gamma) or conveyor system (E-beam). Early literature references (for example, Kaye and Phillips, Bruch, Tallentire, Pflug, Perkins, Davis, Stumbo, Masefield, Christensen, Whitby, and Block) remain valid and pertinent today.

In With the New: Validation

What has changed significantly since 1979, however, is how those sterilization processes are monitored and controlled. The introduction of programmable logic and microprocessor controllers, self-contained monitoring systems, real-time parameter readouts, sophisticated software, and control algorithms have revolutionized how sterilization processes are monitored, controlled, and evaluated. But these changes have also resulted in a concomitant increase in the complexity of validation requirements and effort necessary to reproducibly ensure, demonstrate, and document the delivered lethality of the process.

Another significant change in medical device sterilization is the presence of consensus standards and guidelines for conducting validation studies. Not only are these practices now expected, they are regulatory requirements. The evolution of these standards has been, and continues to be, a dynamic process with the ultimate objective of achieving total global harmonization.

The expansion and aggressive acquisition of many multinational medical device companies have made consensus standards a paramount goal. This is coupled with the expansion of the European Union and the desire of many countries to export either to the United States or Europe. In addition, the explosive growth in Asia has made consensus standards a primary objective of many medical device companies. The industry is getting closer to harmonization, but it has not as yet achieved this objective. More work is needed in this area.

Creating Standards

Loaded cobalt-60 rods will provide gamma-radiation sterilization.

AdvaMed. How have sterilization standards evolved and reached their current state of development? In 1979, there were two principal medical device trade associations involved in generating voluntary sterilization guidelines.

The first was the Health Industry Manufacturers Association (HIMA), now AdvaMed. In 1978 and 1979, HIMA published a series of medical device sterilization monographs on a variety of sterilization-related topics, including:

� 78�4.1: Validation of Sterilization Systems.
� 78�4.2: Sterilization Cycle Development.
� 78�4.4 Biological and Chemical Indicators.
� 78�4.5: Operator Training for Ethylene Oxide Sterilization Equipment.
� 78�4.10: Contract Sterilization.

Industry members of HIMA�s Manufacturing, Engineering, and Quality Assurance Section wrote the monographs. Their stated purpose was to provide the �collective expertise of the industry�s most knowledgeable sterilization personnel and indicate the substantial effort of association members and staff to encourage achievable, high standards for medical device sterilization.�

In 1982, I chaired a committee to review HIMA Monographs 78�4.1 and 78�4.2, vis-�-vis current practices. Many considerations for improvement were suggested to make the documents contemporary. At that time, HIMA was involved with both the generation of technical monographs and with lobbying activities for the medical device industry. HIMA decided to concentrate its efforts on its lobbying functions and to become an even more effective voice for the medical device industry, a status it maintains to this day.

AAMI, ANSI, and ISO. In 1979, the second principal medical device trade association active in the generation of sterilization guidelines was AAMI. AAMI has become the primary organization developing sterilization standards in the United States because of its active involvement with the American National Standards Institute (ANSI) and the international standards organizations. The association writes consensus standards, recommended practices, and technical information reports (TIRs). Its 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 board, and in the case of American national standards, ANSI. A TIR is not subject to the same formal approval process as a standard. However, a technical committee and the AAMI standards board approve a TIR for distribution.

AAMI also often works with ANSI as the administrator of technical advisory groups to the International Organization for Standardization (ISO). ISO Technical Committee TC 198, Sterilization of Health Care Products, authors sterilization standards for medical devices. ISO is a worldwide federation of national standards bodies; therefore, AAMI must work through ANSI for official participation in the generation of any international sterilization standards.

The preparation of international standards is carried out through ISO technical committees. Each member body interested in a subject has the right to be represented on the committee. Publication as an international standard requires approval of at least 75% of the member bodies casting a vote.

Another reason for AAMI�s acceptance as a domestic standards-generating organization is the active participation of FDA representatives on AAMI committees. This allows FDA input into and acceptance of the documents prior to their issuance. This is highlighted by FDA�s inclusion of many AAMI sterilization-related documents on its list of recognized consensus standards. Organizations can use this list of accepted documents to meet FDA requirements.

EtO Validation

AAMI has been an active participant in generating the industrial validation standards for all major sterilization processes used to process medical devices since the 1970s. For example, in 1981, the Industrial Ethylene Oxide Sterilization Working Group authored AAMI Recommended Practice OPEO:

1981. This document, titled �Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices,� was subsequently revised several times. In 1988, it was issued as ANSI/AAMI ST27:1988. As part of the review of the document in 1992, the working group examined ISO document 11135. It should be noted that the ISO document was based on a draft standard prepared by the European Standardization Committee (CEN), and thus reflected a global perspective on the subject. It is part of AAMI�s practice to harmonize its work with international standards wherever possible.

At that time, AAMI decided to adopt ISO 11135 verbatim as the ANSI/ AAMI revision to ST27. The document was subsequently published in 1994 as ANSI/AAMI/ISO 11135:1994. This international document mainly addressed requirements, though ANSI/ AAMI documents historically provided additional guidance to industrial users also. Consequently, the working group decided to develop TIRs to supplement the information contained in 11135. To date, there have been a series of TIRs published for EtO:

� AAMI TIR 14:1997, �Contract Sterilization for Ethylene Oxide.�
� AAMI TIR 15:1997, �Ethylene Oxide Sterilization Equipment, Process Considerations, and Pertinent Calculations.�
� AAMI TIR 16:2000, �Process Development and Performance Qualification for Ethylene Oxide Sterilization.�
� AAMI TIR 20:2001, �Parametric Release for Ethylene Oxide Sterilization.�
� AAMI TIR 28:2001, �Product Adoption and Process Equivalency for Ethylene Oxide Sterilization.�

One of the important advancements over the last decade has been the acceptance of parametric release of EtO-processed product lots. This practice is now offered by most contract sterilizers. Parametric release of EtO product lots allows a product turnaround time of days, rather than the weeks traditionally required with EtO sterilization.

Radiation Validation

On an analogous path and parallel timeframe, AAMI was also developing radiation-sterilization standards. The Radiation Sterilization Working Group developed two American National Standards in the 1980s. One was the �Guideline for Electron Beam Radiation Sterilization of Medical Devices,� ANSI/AAMI ST31:1990, and the other was the �Guideline for Gamma Radiation Sterilization,� ANSI/AAMI ST32:1991.
As part of the required review of these documents, the AAMI working group reviewed the corresponding ISO 11137 document, �Sterilization of Health Care Products�Requirements for Validation and Routine Control�Radiation Sterilization.�

The group tried to ascertain whether the documents could be harmonized. The working group decided to adopt ISO 11137 verbatim as the ANSI/AAMI revisions to ST31 and ST32. The document was subsequently published as ANSI/AAMI/ISO 11137:
1994. As with the EtO document, AAMI also generated TIRs to provide additional guidance for U.S. users of 11137:

� AAMI/ISO TIR 13409:1996, �Sterilization of Health Care Products� Radiation Sterilization�Substantiation of 25 kGy as a Sterilization Dose for Small or Infrequently Produced Batches.�
� AAMI TIR 17:1997, �Radiation Sterilization�Material Characterization.�
� AAMI/ISO TIR 15844:1998, �Sterilization of Health Care Products�Radiation Sterilization�Selection of a Sterilization Dose for a
Single Product Batch.�
� AAMI/ISO TIR 13409/A1:2000, �Sterilization of Health Care Products�Radiation Sterilization�Substantiation of 25 kGy as a
Sterilization Dose for Small or Infrequently Produced Batches, Amendment.�
� ANSI/AAMI/ISO TIR 15843:
2000, �Sterilization of Health Care Products�Radiation Sterilization�Product Families and Sampling Plans for Verification Dose Experiments and Sterilization Dose Audits, and Frequency of Sterilization Dose Audits.�
� AAMI TIR 27:2001, �Sterilization of Medical Products�Radiation Sterilization�Substantiation of 25 kGy as a Sterilization Dose�
Method VDmax.�

Steam Validation

Concurrently with the activities in the EtO and radiation arenas, the Industrial Moist Heat Sterilization Working Group was also developing standards. ANSI/AAMI ST25, �Guideline for Industrial Sterilization of Medical Products,� was published in the 1980s. The last revision of this document was published in 1987.

As a part of the required review of this document, the group decided to adopt ISO 11134, �Sterilization of Health Care Products�Requirements for Validation and Routine Control�Industrial Moist Heat Sterilization,� verbatim as the ANSI/AAMI revision. The document was subsequently published as ANSI/AAMI/ISO 11134:

1993. AAMI TIR 13:1997, �Principles of Industrial Moist Heat Sterilization,� was written to provide additional guidance on 11134.

Conclusion

The subject of sterilization validation is dynamic. Discussions continue on a worldwide basis with the ultimate goal of achieving global harmonization. ANSI/AAMI/ISO 14937, �Sterilization of Health Care Products: General Requirements for Characterization of a Sterilizing Agent and the Development, Validation, and Routine Control of a Sterilization Process for Medical Devices,� was published in 2000. It provides a standardized procedure for validating new sterilization technologies.

The current revisions of ISO and CEN documents are proceeding. The desired results are single harmonized standards for all sterilization processes. We are therefore getting closer to the objective. Unfortunately, the progress of the standards-generation process at times appears glacial in speed. However, it is a process that is worth the effort and ultimate reward. Watch the pages of MD&DI for developments in the process.