Medical device manufacturers that use ethylene oxide (EtO) to sterilize their products, either in-house or at a contract sterilizer, often validate the cycle in one particular vessel and later find it no longer satisfies their requirements. A validated vessel becomes outgrown when the number of devices manufactured per week exceeds its volumetric sterilization capacity. Increased market demand for a particular product, the merger of one manufacturer with another, the expansion of a particular product line, or expansion into foreign markets may cause a manufacturer to go from comfortably processing 5 sterilizer loads a week to needing to process 10 loads, thus creating an ever- increasing backlog.
Consider, for example, a shallow-vacuum cycle engineered for pressure-sensitive products. Among the time-consuming attributes of such a cycle are multiple shallow vacuums and slow ramp rates. When these process steps are added to a 6-hour sterilant dwell, the total resident time per lot inside the vessel may reach 1820 hours. Using a single vessel, a contract sterilizer could treat only 7 or 8 pressure-sensitive loads per week (assuming the contractor had no other customer using the same validated chamberwhich is unlikely).
Cycle optimization is often considered as a means of reducing chamber dwell time to allow more process cycles per week. However, optimization of an already validated cycle is rarely a viable alternative since any modification of critical parameters will usually compromise the original validation. More often, solving the problem of insufficient capacity requires the use of additional sterilizers. If another vessel of identical size and configuration is available, then the protocol used in the validation of the first vessel may be followed to validate the second one. Another possibility is for the manufacturer to increase the size of each production lot and use a larger sterilizer. In this alternative, the volume of product treated per cycle increases while cycle time remains the same. The amount of related paperwork and QA review will also remain constant for the larger vessel.
In either caseusing a second identical vessel or a larger nonidentical vesselthe same issue arises: If the sterilization cycle has already been fully validated and proven effective in the first vessel, and the second vessel performs equivalently, is it necessary to perform a complete validation in the second vessel? Or is there enough scientific support and regulatory tolerance to accept a situation in which a primary vessel is selected and fully validated (physically and microbiologically) while secondary vessels are determined equivalent after a reduced validation (full physical qualification but reduced microbiological qualification)? Both the manufacturer and contract sterilizer would like to avoid performing a full validation of the second vessel, which can take months to prepare. Obviously, the sooner the cycle can be run in the second vessel, the sooner more product can be processed and shipped to satisfy market demand. In addition, a number of sometimes-costly product samples are destroyed during validation-related testing, and the laboratory testing itself is expensive.
Unfortunately, no guidance documents have been available to enable manufacturers and contract sterilizers to determine when, after a full validation is completed for one vessel, additional vessels can be considered equivalent to the first in their ability to deliver the same set of process parameters and obtain the same level of sterility assurance. Probably because of this lack of a standard policy for determining vessel equivalency assurance (VEA), the sterilization industry has remained very conservative, limiting itself to demonstrating process equivalency only between vessels of identical size located within the same facility. In a nutshell, industry practice has been to commission every vessel, conduct empty-vessel test studies in every vessel, perform a full microbiological qualification in one vessel, and then perform a reduced microbiological qualification of identical vessels for the same product family and process. The contents of this reduced equivalency validation have been known to vary from a series of sublethal challenges to simply running one half cycle and one full cycle.
Any standard method of determining process equivalency among sterilizers must begin with a thorough assessment of their physical performance. Only after a physical comparison of the vessels has been successfully completed can a facility think of proceeding with a comparison of their microbicidal performance. Therefore, performing a VEA protocol requires a thorough understanding of how to physically evaluate a vessel. The next section of this article is intended to be a guide to the basic physical testing of industrial-size EtO sterilizers, thus enabling companies to take the first step toward VEA. The section after that discusses the reduced microbiological qualification requirements for validating additional vessels that are now being developed by a task group of the Association for the Advancement of Medical Instrumentation (AAMI).
PHYSICAL PERFORMANCE TESTING
The basic elements for physically qualifying individual sterilizer vessels are detailed in Medical DevicesValidation and Routine Control of Ethylene Oxide Sterilization (ANSI/AAMI/ISO 11135). Upon installation of a vessel, a full commissioning or installation qualification (IQ) is performed. Regardless of whether VEA is intended, no part of this commissioning may be excluded. The IQ process is followed by a performance qualification (PQ), which ANSI/AAMI/ISO 11135 divides into physical qualification and microbiological qualification. Both are fully carried out if no VEA is planned. However, if process equivalency is intended, all parties involved have a mutual interest in avoiding as many repetitious microbiological validation sequences as possible. Physical qualification includes a number of studies performed on empty vessels, including leak tests, wall profiles, and operational qualifications. Each of these test methods is described below, along with several enhancements that are useful to the validation engineers performing the comparative studies needed to determine VEA.
Leak Tests. Multiple leak tests, both under vacuum and under pressure, are conducted during physical qualification to attest to the correct fitting and sealing of all vessel doors, gaskets, valves, welds, and penetration points. The unintentional introduction of air into a sterilizer during operation can alter the efficiency of both the humidification and the sterilant phases of the process cycle. To determine the leak rate, the vessel is pressurized (to 20.0 psia, for example) and left for 12 hours at a steady temperature. During that time, measurements of pressure, jacket temperature, and the vessel's internal air temperature are logged at intervals (commonly every 5 minutes). Next, a vacuum is drawn inside the vessel (down to 1.0 psia, for example) and the same data-logging procedure is followed for another 12 hours.
The main concern of the validation engineer is the total variation in pressure during the respective 12 hours under pressure and under vacuum. Respect for the leak-test tolerances, which are defined in the IQ protocol, and repeatability of the results must be clearly demonstrated. Because the protocol will include such specifications as the minimum and maximum allowable operating pressures for the vessel, all vacuum and pressure leak tests should be engineered to reflect and validate those parameters.
Wall Profiles. The purpose of a wall profile is to map and evaluate the heat-circulation patterns throughout the vessel's system of jackets. To obtain the necessary data, temperature probes are fastened to the six internal surfaces of the sterilizer. The number of probes will vary with the size of the vessel. (Guidance in this area is offered by ANSI/AAMI/ISO 11135, Annex B, paragraph B.2.3.2.) A location diagram of the probe placement must be designed so as to ensure that all internal surface areas are monitored. This diagram becomes a permanent part of the vessel's performance data file.
If VEA is being sought, it is very effective at this point to also determine the temperatures of the vessel's various jacket contents (air, water, steam, or oil). One or more probes can be inserted directly into the fluid pathway within each jacket and the resulting temperature data can be sent to a recorder for later comparison with the temperature spread verified on the internal surfaces of the vessel. Analysis of these comparative data will provide an insight into the vessel's thermal conveyance efficiency. The closer the temperature spread of the internal walls is to the temperature of the fluid content of the jackets, the more efficient is the overall heating system of the vessel. Among other things, this efficiency analysis will indicate whether the vessel (including its feed and return heating lines) is properly insulated, so that heat loss to the surrounding work area is minimal. It will also confirm that the flow within the jacket system is adequate to heat all areas of the vessel to required temperatures.
Once the vessel and jackets are probed, the vessel is closed and a jacket temperature set point is programmed. The vessel is allowed to reach thermal equilibrium by, for instance, leaving the jacket system set at 110°F for 24 hours. Data collection then begins and continues for 12 hours, after which the jacket set point is raised (to 120°F, for example) and data collection continues for another 12 hours. After the test, all data are analyzed for two purposes. First, the range of temperatures from the probes is reviewed to determine the evenness of the temperature spread throughout the vessel and to identify any cold spots. Second, a graph is created and statistical analysis is performed on the data compiled when the jacket temperature was raised to determine the vessel's thermal response time (that is, the time lag between the sterilizer control system's call for additional heat and the actual arrival of that heat to the vessel walls as well as the time to attain a new state of equilibrium). A faster transfer of heat on the jackets' internal walls may contribute to reducing the heat-call response time of the vessel.
Operational Qualifications. Once acceptable results are achieved for the leak tests and wall profile, an operational qualification (OQ) study can be performed on the empty vessel. To prepare for this study the vessel is programmed for a cycle and conditions that closely emulate those expected to be encountered during routine procedures. The ability of the sterilization system to accurately and repeatedly attain all critical parameters is revealed during the OQ.
Following a geometric pattern defined in the OQ validation protocol outlined in ANSI/AAMI/ISO 11135, probes are suspended in the vessel so as to occupy space that would normally hold product. (Guidance in determining the correct number of probes is given in ANSI/AAMI/ISO 11135, Annex B, paragraph B.2.3.2.) According to the document, the object of the study is twofold: (1) to establish the correlation between the test probes and the permanent wall-mounted temperature probes used to monitor and control the vessel's heat supply, and (2) to confirm that heat is distributed evenly throughout the vessel. Thus, for a well-functioning vessel, the OQ will demonstrate that the average of the temperature-control probe data is within a tight range of the preprogrammed air-temperature set point, and that all the test probe readings fall within ±5.4°F of the air-temperature set point. These temperature-limit requirements may be altered provided the change is scientifically supported. If parametric release is planned, for example, requirements may need to be more demanding to demonstrate greater control of the process.
In most cases, an example of an acceptably functioning vessel would be one with a set point of 120.0°F, a verified average temperature-control probe range during the sterilant dwell phase of 118.0°122.0°F, and a suspended probe temperature spread during sterilant dwell of 114.6°F125.4°F. Successful completion of at least three consecutive OQ cycles, with consistent results, ensures the proper functioning of the sterilizer and ancillary equipment. If significant changes to the vessel's heating or recirculation systems are required to meet this goal, the wall profile and operational qualification will need to be redone to evaluate the consequences of the changes.
As was suggested during the discussion of wall profiles, OQ studies can be enhanced to provide more performance data for use in a VEA evaluation. The cycle's sterilant dwell phase should be allowed to proceed until a thermal equilibrium has been reached throughout the vessel. The air-temperature set point should then be increased at least 10°F and the dwell continued until attainment of a new state of equilibrium. The collection of these data will enable the valida- tion engineer to compare the heating char- acteristics of two or more vessels. A careful review of all ramp rates, set points, and temperatures achieved will confirm that the vessels perform each segment of the cycle in an identical fashion.
It is important to stress that the practical value of an OQ study is limited. During the initial vessel-commissioning process, an OQ will immediately reveal the failure of any system component (the recirculation blower, jacket feed pump, temperature-control probes, vacuum pump, gas valves and actuators, and so on). Also, if OQs are repeated semiannually, a comparison of the data collected over time can expose changes in vessel performance. For example, if the probes' temperature range around set point is expanding with each OQ study, it may indicate that some component affecting even heat circulation may require replacement. However, a genuine assessment of a sterilizer's performance can occur only when the vessel is operating with a product load of maximum density. Little heat and recirculation is needed to successfully run an OQ, but with a full vessel load of actual product, all the dynamics concerning heat control and distribution can be realistically studied.
When vessel equivalency is being evaluated, a comparison of leak rates, wall profiles, OQ data, and thermal response times will reveal which vessel should be the primary vessel (which is subject to full microbiological qualification) and which should be the secondary vessel or vessels (cross-validated for the same product family using a reduced microbiological validation). To offer the maximum challenge to the process validation, the vessel with the fastest leak rate, the widest temperature range during the wall profile and OQ studies, and the slowest thermal response times should be the primary vessel. Because the secondary vessels will have more-efficient results during the above-mentioned tests, the use of a less-stringent microbiological qualification will be scientifically justified.
Any standard protocol to determine equivalency among multiple vessels must include extensive physical testing. However, as mentioned above, once this testing is completed and does in fact present data attesting to the similarity of the vessels' performance, a reduced microbiological qualification, which saves both time and resources, can be performed for the secondary vessels following a guidance soon to be published by AAMI.
In June 1995 a task group within the association began working on a technical information report (TIR) to be titled Engineering Aspects of Industrial EO Sterilization. Since then, the guidance document has undergone three revisions. After each draft was circulated to all members of the group, written comments were received and discussed, resulting in modifications to the document. The fourth draft was scheduled to be presented and reviewed by the group this past September during a meeting in Washington, DC. It was expected that the final proposal would then be balloted and published in early 1997.
In its current form, this TIR contains a section dealing with demonstrating process equivalency for multiple preconditioning rooms, sterilization vessels, and aeration rooms. While it advocates a full commissioning and physical performance qualification for every vessel regardless of its size, it also presents a strategy for allowing reduced microbiological qualifications of secondary vessels targeted for process equivalency. The TIR places little importance on a mere structural comparison of the equipment; instead, it suggests that process equivalency be based on the equipment's ability to consistently deliver the same set of physical process parameters. Such equivalency can be demonstrated through a comparison of the commissioning and physical performance testing data. The TIR also defines those cases in which, after a complete microbiological qualification of one vessel or room, subsequent vessels and rooms may be declared equivalent and validated through reduced microbiological qualification.
Once published, the AAMI document will help gain industry and regulatory agency support for process equivalency protocols. The TIR targets every possible scenario: identical vessels and rooms in the same or in different locations, and nonidentical vessels and rooms in the same or in different locations. Suggestions for validation of process equivalency are made for each of the four possible situations. The TIR also offers guidance in using statistical process capability indices to further strengthen the validity of the results. Basic formulas to calculate process capability (Cp) and the process capability index (Cpk) are provided, along with guidance for interpreting the resulting standard deviation data.
Engineering Aspects of Industrial EO Sterilization, AAMI Technical Information Report, 4th working draft, Arlington, VA, Association for the Advancement of Medical Instrumentation (AAMI), June 1996.
Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices, ANSI/AAMI ST27, Arlington, VA, AAMI, 1988.
Hoborn J, "Ethylene Oxide SterilisationA Proven Method," in Ethylene Oxide Sterilisation Conference Proceedings 1989, London, European Confederation of Medical Devices Associations (EUCOMED), pp 3350, 1989.
Medical DevicesValidation and Routine Control of Ethylene Oxide Sterilization, ANSI/AAMI/ ISO 11135-1994, Arlington, VA, AAMI, 1994.
Perkins JJ, Principles and Methods of Sterilization in Health Sciences, Springfield, IL, Charles C. Thomas, 1983.
Winckels H, "Equipment and Process Validation," in Ethylene Oxide Sterilisation Conference Proceedings 1989, London, EUCOMED, pp 1323, 1989.