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

ETO STERILIZATION

By following a structured method, process engineers can design and validate safe and efficacious EtO steilization cycles.

Among the sterilization technologies currently available to the medical device industry, 100% ethylene oxide (EtO) gas remains one of the most popular. Validated EtO processes can be run in sterilizers ranging from BIER vessels of a few cubic feet to industrial-sized vessels exceeding 4500 cu ft. Typically, the EtO process can be broken down into four basic phases, each of which needs careful planning to ensure a safe and efficacious process. The four phases are: (1) air removal, (2) steam injection and conditioning dwell, (3) EtO injection and gas dwell, and (4) gas purge and air inbleed.

Mid-infrared gas spectrometer measures EtO and water vapor during sterilization. Photo courtesy Spectros Instruments, Inc. (Whitinsville, MA).

This article is intended to guide the reader through the components of each phase of two hypothetical 100% EtO with nitrogen processes. The following assumptions were made for the purpose of explaining the rationale behind the design of the cycles and the options available:

An effective EtO process can be properly designed for almost every type of medical device and permeable packaging configuration, provided that all variables are assessed through thorough process design and development. It is here, in fact, that one notices how EtO processes possess a greater number of variables in comparison with other sterilization technologies. However, by following a structured method that systematically examines and considers each of these variables, the process engineer can design, validate, and routinely sterilize with a safe and efficacious process.

The critical parameters of an EtO sterilization cycle are typically given as temperature, pressure, humidity, EtO concentration, and gas dwell time. However, the process engineer must also identify and evaluate relationships that may exist between any given process parameter(s), the product being sterilized, and the equipment used.

The sterilization process must consistently deliver all critical process parameters to each and every component contained within the load, to a degree that will ensure a 10^-6 sterility assurance level (SAL) without causing any deleterious effect to the product or its sterile barrier packaging. In addition, this process must occur under controlled conditions that will protect the sterilization personnel monitoring the operation, the equipment employed, and ultimately the end-user.

Each product component contained in the load must be examined for the following characteristics: natural bioburden, physical configuration, raw-material composition, sensitivity to both negative and positive pressure changes, maximum heat tolerance, and chemical reaction to water vapor and ethylene oxide. For example, surgical sutures may present an extreme sensitivity to what are often considered even moderate temperature levels. Other materials, especially those containing salts, may react strongly with EtO to form ethylene chlorohydrin (ECH), a residual chemical produced during the EtO process. Some materials may bind, through a positive reaction, large quantities of EtO molecules, presenting the problem of excessively high postprocess levels of EtO and ethylene glycol (EG), another process residual.¹ Those components presenting the greatest challenge to the process—due either to physical configuration (obstruction of gas permeation) or high bioburden (natural fibers, for example)—should be selected for the microbiological challenge. Other product sensitivities should also be noted, as they will determine maximum ramp rates and set points employed in the cycle. For the validation of the process, a reference load must be selected that will represent the most difficult combination to heat, humidify, sterilize, and aerate.

Each level of packaging, from master cartons to the unit package (the primary sterile barrier), must be examined and evaluated for its ability to allow heat, moisture, and sterilant to permeate. Gas delivery to and permeation within the product, in addition to aeration of the gas from the product, are all important considerations. Data obtained from fractional studies can provide the basis for the calculation of the dwell times for the conditioning and gas exposure. The process engineer must be cautious of excessively long gas-exposure dwells or high gas concentrations, as they can result in the need for long multiple evacuations and/or aeration times that will delay product release. The objective is to decide whether to adopt a cycle using a long gas-exposure time with low EtO concentration or one with brief gas exposure and a high EtO concentration. Naturally, if gas is easily aerated from the product, production times are improved by a short exposure to a high concentration of sterilant.

Before a preliminary cycle plan can be drafted, the process engineer must have a thorough knowledge of the process equipment, including the minimum and maximum operating ranges of the preconditioning facility, the sterilizer and ancillary equipment, and the aeration facility. The sterilizer control system must be able to perform all evacuations and gas injections (nitrogen, steam, EtO, and air) at steady, preprogrammed rates. Accurately calibrated proportional valves facilitate the delivery of these rates. The objective is to perform each process ramp at gradual (linear) rates.

Both in the first part of the sterilization cycle (air removal) and in the final stage (sterilant removal), the safety of the facility and personnel are paramount issues. During the air-removal phase, the sterilizer is evacuated and then backfilled with nitrogen. After each vacuum/nitrogen sequence, a calculated amount of air is displaced. Depending on the depth of each vacuum and the final pressure achieved by the nitrogen addition, the process engineer must determine the minimum number of sequences necessary to bring the air content of the sterilizer atmosphere to a composition at which there is insufficient oxygen left to pilot a combustible reaction. EtO is flammable and can ignite in the presence of static electricity.² It is, therefore, essential to know, prior to EtO injection, the volume percentage of air (%vol_air) left in the chamber before deciding upon the maximum amount of sterilant to be used. Later, when the volume percentages of air, of the inert gases (%vol_steam and %vol_nitrogen), and of EtO (%vol_EtO) are known, they can be plotted on a flammability chart to confirm the nonflammability of the cycle.³

Following gas contact, the EtO must be displaced from the load and removed from the chamber. In planning this segment of the cycle, the same routine—postvacuums followed by nitrogen flushes—is followed. A volumetric calculation of the percentage of EtO left in the sterilizer after each vacuum/nitrogen sequence will determine when the level of EtO has been brought down to an acceptable level. Usually, after the final evacuation is performed, the sterilizer is backfilled with ambient air instead of nitrogen. In the final stage of the cycle, the sterilizer rear exhaust is activated while fresh air is allowed into the sterilizer either through a dedicated vent or by partially opening the door. Sufficient time must be allotted to flushing the sterilizer headspace so that the EtO concentration is brought to a safe level before the sterilizer is unloaded. Some workers wear industrial respirators with catalytic filter canisters rated for atmospheres containing not more than 50 ppm of EtO.

Flammability is not the only factor that determines the number of evacuations. In most cases, increasing the number of evacuations will also lower the EtO residuals left on the product, thus decreasing the amount of time the load must be quarantined for aeration. Although in this case "more is better," limitations are imposed by product and packaging tolerances as well as by equipment demands. A greater number of evacuations will subject the load to increased physical stress, which, when combined with EtO, heat, and humidity, could have a negative effect on product and packaging constructions such as, for example, glues or seals. Time spent for additional postvacuums also reduces the overall productivity of the sterilizer, which can affect facility profitability.

AIR REMOVAL

Before 100% EtO can be introduced into the sterilizer, the original air content (%vol_air = 100% of the initial sterilizer atmosphere) must be displaced and substituted with an inert gas such as nitrogen (N₂). The physical parameters for the air-removal phase are determined by the tolerances of the most sensitive products or packaging (e.g., nonpermeable foil pouches or sealed cavities). If data are not available from the respective component or product manufacturers, they can be generated by conducting preliminary studies during which samples are exposed to different ramp rates (i.e., change in pressure per unit time) and vacuum set points. Each set of samples is then tested (both product and packaging) for conformity to original manufacturing specifications until the fastest permissible ramp rate and deepest acceptable evacuation set point are determined and recorded in the sterilization process design history record.

The initial pressure inside the sterilizer at the moment the door is closed is equivalent to atmospheric pressure (14.7 psia at sea level). The first evacuation will remove a quantifiable amount of air. For example, an initial evacuation from P_initial = 14.7 psia to a depth of P_final = 7.35 psia will eliminate 50% of the original air content in the sterilizer. While the volume percentage of air is still 100%, the partial pressure of air is reduced in direct proportion to the pressure change:

The sterilizer is programmed to backfill with nitrogen to a set point of 14.7 psia. The resulting sterilizer atmosphere is now 50% air and 50% nitrogen. After this first vacuum/nitrogen sequence, the volume percentages of air and nitrogen are represented as:

After the second vacuum/nitrogen sequence, the amount of air in the sterilizer reduces again by half (%vol_air = 25%), while the nitrogen increases by half (%vol_nitrogen = 75%). This sequence is repeated as many times as necessary, until the %vol_air is reduced to a safe level.

Ethylene oxide requires oxygen to ignite. The term safe level is intended to mean that the air originally contained in the sterilizer at the beginning of the process has been reduced to the point that there remains insufficient oxygen to allow a reaction to occur should a source of ignition be available.⁴ Here it should be easy for the reader to see the relationship between the final set point of each vacuum/nitrogen sequence and the total number of sequences that will be required to render the cycle safe.

In selecting the ramp rates and set points for the vacuum/nitrogen sequences of an EtO process, there are various options. In general, a deep vacuum set point is preferred because it allows the air-removal process to be completed more efficiently. As stated earlier, determination of a maximum vacuum set point is a function of product/packaging tolerance as well as equipment limitations. Once the maximum ramp rate tolerances are determined for the vacuum and nitrogen sequences, the process engineer must decide what rate is best for the given product configuration. While the air-removal phase ensures that the sterilizer atmosphere is almost void of air, a consequence of these purges is loss of product moisture. The goal of process design is to displace air as efficiently as possible while minimizing load desiccation.

Deeper vacuums can complete air removal with fewer sequences. When dealing with a vacuum-resistant product, one vacuum from atmospheric (14.7 psia) to 2.0 psia, followed by a nitrogen backfill to 14.7 psia, will quickly reduce the %vol_air to 13.6% (Table I). Products that can withstand this rate and depth of vacuum will usually tolerate an equally rapid nitrogen injection. Fast ramp rates for nitrogen backfilling also minimize product-level moisture loss.

Table I. Process calculations for cycle 1—deep-vacuum type.

In the case of a vacuum-sensitive product, such as a kit containing multiple devices, the air-removal phase could require multiple slow vacuums—down to 7.0 psia, for example. The first vacuum/nitrogen sequence will only bring the %vol_air from 100% down to 47.62% (Table II). In this case, the process engineer must consider that the desiccating effect inherent in this process is further amplified. Multiple vacuum/nitrogen injections coupled with slow ramp rates mean that there is more time for moisture to be driven out of the load by the induced pressure gradient. Water becomes more volatile as temperature is increased and pressure is decreased. In these circumstances, one must begin the steam-injection phase as soon as possible in order to replace some of the moisture lost during the multiple slow-vacuum phases.

Table II. Process calculations for cycle 2—shallow-vacuum type.