CHAPTER 6
PANORAMIC IRRADIATORS

SUMMARY

Panoramic irradiators are operated on a contract basis to irradiate single-use medical devices and products, cosmetics, food, and plastics. Their largest business comes from sterilization of medical devices and products. To date, only gamma and electron-beam (e-beam) irradiators have operated on a large-scale commercial basis. The first large x-ray facility is expected to come into operation in the next few years, in Europe. Gamma, x-ray, and e-beam irradiation can all be effective for the different products, although there are some advantages to gamma and x-ray irradiation for thick or dense packages and advantages to e-beam for products that demand high doses.

Gamma and x-ray irradiation are nearly interchangeable from a physics perspective (x-ray irradiation can have higher energy and therefore have slightly better penetration), and so, x-ray irradiators could be a direct replacement for gamma irradiators. There are practical differences between the gamma and x-ray facility designs and operations that could result in differences in costs. Whether x-ray irradiators are economically competitive with gamma irradiators is not clear. A crude and somewhat incomplete cost analysis suggests that the costs could be comparable for a high-throughput facility, but the actual cost differences depend on variable factors such as the cost of electricity, the reliability of the equipment in the x-ray facility, the facility configuration, and the products to be irradiated.

Ethylene oxide (EO) also is used for chemical sterilization of some products. Given the accidents and potential security risks, health risks associated with exposure, and pressures to encourage EO users to switch away from EO because of its toxicity, it is not clear that a shift from irradiation to EO sterilization would be desirable.

USES OF PANORAMIC IRRADIATORS

Panoramic irradiators1 or gamma irradiation facilities are used to sterilize medical devices and products. They are also used to sterilize pharmaceuticals and consumer products (e.g., cosmetics); sterilize male insects to inhibit infestations; kill bacteria and fungi and preserve color in foods; and process polymers to achieve specific characteristics, such as increased hardness or durability. However, in the United States the sterilization of medical supplies and

1

Panoramic irradiators are sometimes described by their American National Standard Institute category, defined below. These should not be confused with the IAEA categories of sources.

Category II — Panoramic, dry source storage irradiator. American National Standard N43.10. A controlled human access irradiator in which the sealed source is contained in a dry container constructed of solid materials, and the sealed source is fully shielded when not in use; the sealed source is exposed within a radiation volume that is maintained inaccessible during use by an entry control system.

Category IV — Panoramic, wet source storage irradiator. American National Standard N43.10. A controlled human access irradiator in which the sealed source is contained in a storage pool (usually containing water), and the sealed source is fully shielded when not in use; the sealed source is exposed within a radiation volume that is maintained inaccessible during use by an entry control system.



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CHAPTER 6 PANORAMIC IRRADIATORS SUMMARY Panoramic irradiators are operated on a contract basis to irradiate single-use medical devices and products, cosmetics, food, and plastics. Their largest business comes from sterilization of medical devices and products. To date, only gamma and electron-beam (e-beam) irradiators have operated on a large-scale commercial basis. The first large x-ray facility is expected to come into operation in the next few years, in Europe. Gamma, x-ray, and e-beam irradiation can all be effective for the different products, although there are some advantages to gamma and x-ray irradiation for thick or dense packages and advantages to e-beam for products that demand high doses. Gamma and x-ray irradiation are nearly interchangeable from a physics perspective (x- ray irradiation can have higher energy and therefore have slightly better penetration), and so, x- ray irradiators could be a direct replacement for gamma irradiators. There are practical differences between the gamma and x-ray facility designs and operations that could result in differences in costs. Whether x-ray irradiators are economically competitive with gamma irradiators is not clear. A crude and somewhat incomplete cost analysis suggests that the costs could be comparable for a high-throughput facility, but the actual cost differences depend on variable factors such as the cost of electricity, the reliability of the equipment in the x-ray facility, the facility configuration, and the products to be irradiated. Ethylene oxide (EO) also is used for chemical sterilization of some products. Given the accidents and potential security risks, health risks associated with exposure, and pressures to encourage EO users to switch away from EO because of its toxicity, it is not clear that a shift from irradiation to EO sterilization would be desirable. USES OF PANORAMIC IRRADIATORS Panoramic irradiators1 or gamma irradiation facilities are used to sterilize medical devices and products. They are also used to sterilize pharmaceuticals and consumer products (e.g., cosmetics); sterilize male insects to inhibit infestations; kill bacteria and fungi and preserve color in foods; and process polymers to achieve specific characteristics, such as increased hardness or durability. However, in the United States the sterilization of medical supplies and 1 Panoramic irradiators are sometimes described by their American National Standard Institute category, defined below. These should not be confused with the IAEA categories of sources. Category II — Panoramic, dry source storage irradiator. American National Standard N43.10. A controlled human access irradiator in which the sealed source is contained in a dry container constructed of solid materials, and the sealed source is fully shielded when not in use; the sealed source is exposed within a radiation volume that is maintained inaccessible during use by an entry control system. Category IV — Panoramic, wet source storage irradiator. American National Standard N43.10. A controlled human access irradiator in which the sealed source is contained in a storage pool (usually containing water), and the sealed source is fully shielded when not in use; the sealed source is exposed within a radiation volume that is maintained inaccessible during use by an entry control system. 101

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102 RADIATION SOURCE USE AND REPLACEMENT devices constitutes by far the largest enterprise among these activities. Sterigenics, Inc., estimates that the current medical device radiation sterilization market is approximately 5.7 million cubic meters per year (m3/yr, or 200 million cubic feet per year, ft3/yr), with about 80 percent using gamma irradiation and about 20 percent using e-beam irradiation (Smith, 2006). This is probably around half of the entire sterilization market, the rest being carried out using other methods. Whether irradiating flies, food, or syringes, these applications generally require high-throughput irradiation to be economically and/or logistically practical. To achieve high throughput, irradiator facilities use large numbers of high-activity radiation sources. As mentioned in Chapter 2, the activity in cobalt-60 sources in panoramic irradiators accounts for over 98 percent of the total activity in all civilian radiation sources in the United States. STERILIZATION OF MEDICAL DEVICES The Food and Drug Administration (FDA) requires that the sterilization of invasive medical devices such as hypodermic needles and scalpels must achieve a sterility assurance level of 10−6.2 The sterility assurance level is the probability or frequency of contaminated products after processing, so a level of 10−6 corresponds to a one in a million chance that one live microbe is in the sterilized load. Three standard sterilization processes are employed worldwide by the majority of single-use medical device manufacturers: gamma irradiation, e- beam irradiation, and ethylene oxide (EO) gas diffusion. Some features of these sterilization methods are summarized in Table 6-1. Also shown in the table are features of autoclave (steam) or dry-heat sterilization, which is usually reserved for multiuse medical devices. X-ray irradiation is not yet used in a major facility, but it is included with gamma irradiation because x-ray generators can meet or exceed the specifications for gamma irradiators listed in the table. The critical differences between these two types of irradiation are discussed in the section of this chapter on x-ray irradiators. Radiation Processing for Sterilization of Medical Devices Because gamma radiation penetrates through a product, killing pathogens along its path, yet does not heat the packaging or the product significantly, it can be used to sterilize devices already sealed in heat-sensitive, air-tight plastic packaging. This is a significant benefit for some single-use medical devices and kits, such as those containing hypodermic needles preloaded with a pharmaceutical. Gamma irradiation has proven performance in killing pathogens and is one of the preferred methods, as evidenced by the quantity of product irradiated each year. To achieve a 10−6 sterility assurance level requires a dose in the range of 15 to 40 kGy (commonly 25 kGy) at the most shielded point in the package, per ISO Standard 11137. 2 A sterility assurance level of 10−3 is used for many noninvasive medical devices. The doses associated with this level are lower and “kinder” to materials, especially in new drug/device combination products. ISO validation methods (ISO 11137-1, -2, and -3, and VD Max) allow for differing doses and product sterility assurance level depending on bioburden and product use.

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PANORAMIC IRRADIATORS 103 TABLE 6-1 Methods of Medical Device Sterilization and Their Features Method Autoclave or Gamma or X-ray Electron Beam Dry Heat Irradiation Irradiation Ethylene Oxide (EO) Processing Batch Continuous or batch Continuous Batch mode Post-treatment None None None Testing required testing required for product release Part of product Mostly surface Complete volume Complete volume, Surface, with the use sterilized but for limited of gas-permeable thickness packaging Material Heat-tolerant Most materials are Most materials are Nearly all materials compatibility product and satisfactory satisfactory are compatible packaging Can be incompatible Similar to gamma with, e.g., PVC, acetal, regarding polypropylene compatibility, homopolymer, and although may have polytetrafluoroethylene lesser oxidative (PTFE) effects Residuals None None None Ethylene chlorohydrin, requires aeration after processing Best process Reusable devices Products that are Products that are Products that cannot match medium to high low density, tolerate irradiation, according to density, and somewhat homogeneous, including both single- sterilizers heterogeneous tolerate high dose use and reusable rates, and in thin devices packages NOTES: In batch mode, a whole batch of product packages undergoes sterilization together. In continuous mode, the product packages are sterilized sequentially. SOURCE: Adapted in part from Sterigenics, Inc. (2007). There are limitations to the use of gamma irradiation based on dose rate and radiation effects in the device material. For example, thick metal parts on a device can act as shields, resulting in low doses in shadowed locations on the device (this is more of a problem for e- beam irradiation). Some plastics discolor or become brittle upon irradiation, although there has been some progress in development of radiation-resistant polymers.3 But for the many products for which gamma irradiation is effective, manufacturers need only consider other business 3 Polyimide, liquid crystal polymer, polyether sulphone, polyetheretherketone, polyethylene terephthalate , and other similar plastics can all be made to be relatively radiation resistant, but many other common polymers such as polyoxymethylene, and polypropylene have poor radiation resistance. Radiation- stabilized grades of these latter polymers have been developed to improve their performance under radiation.

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104 RADIATION SOURCE USE AND REPLACEMENT factors when choosing a sterilization method. Because medical devices and supplies tend to be bulky, low-density products, manufacturers consider the proximity of the sterilization facility and the timeline for processing along with costs. The radiation field in an irradiator is virtually constant during the period of irradiation, but the dose delivered within the product depends on the materials to be irradiated, the density, and the thickness of the product. Each product-package combination requires a dose plan and dose map. Some irradiators do not charge customers for this service directly if the customer is contracting for irradiation of the product on a large scale, but will charge for dose mapping for smaller contracts. For customers that sterilize small batches of products or that need very fast turn time from manufacture to delivery, there may be a market for in-house irradiation (rather than contract irradiation) if economic, relatively simple, and appropriately sized irradiators can be developed. Large-Scale Gamma Irradiation Facilities that carry out large-scale irradiation using radionuclide radiation sources (gamma sources) rather than x-rays or electron beams have large quantities of radioactive material. A typical commercial panoramic irradiator facility may have 110,000 TBq (about 3 million Ci) of cobalt-60, and some have two times that amount. In a panoramic irradiator, the products to be irradiated pass around high-intensity radiation sources inside a shielded room. While in use, the irradiation room has physical and procedural measures in place to prevent worker access. When the source racks in a wet-storage irradiator are not in use, they are lowered into a pool below the irradiation room. The pool provides shielding and cooling.4 Figure 6-1a shows an irradiator in which products are passed around a rectangular source rack using hanging tote boxes. Figure 6-1b shows a less common dual cylindrical source rack used in an irradiator that carries products in their shipping pallets on a conveyer system. Modern irradiation facilities are fully automated, so workers need not enter the irradiation chamber to emplace the product. Simply for safety purposes, these facilities are much more robust than ordinary industrial structures and have security controls in place. Additional security measures have been required for these facilities in recent years (see Chapter 3 for a brief discussion of security issues related to panoramic irradiators). Replacement Technologies As noted above, sterilization can be carried out by irradiation technologies, heat, or EO diffusion. Each of these options is described below. E-Beam Irradiation E-beam irradiators use an accelerator to direct an energetic beam of electrons (usually 5 to 10 MeV) at the product (see Figure 6-2). The beam is scanned across the product in a pattern that ensures that the whole face of the package receives a relatively uniform flux of electrons. The electrons from the beam (the primary electrons) transfer their energy to electrons in the atoms of the product (secondary electrons), which are knocked free and in turn transfer their energy to other electrons in the product. This cascade of electrons delivers its dose throughout the product. Because the beam can be aimed, virtually all of the beam energy can 4 One company, GrayStar, Inc., offers a design in which the source rack remains in a pool at all times and the watertight product totes are lowered into the pool for irradiation.

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PANORAMIC IRRADIATORS 105 SOURCE RACK (RAISED POSITION) (a) (b) FIGURE 6-1 (a) An artist’s rendition of an MDS Nordion JS-10000 panoramic irradiator, which uses a panel-type source rack (not necessarily to scale), and (b) a photograph of different source racks for an MDS Nordion Pallet Irradiator. SOURCE: Images courtesy of MDS Nordion (2002). be directed at the product, although some of the energy exits the product through bremsstrahlung (x-rays from electron collisions) and electrons near the surface that escape. Electrons transfer energy very efficiently to other electrons because they interact with every electron along their path. The x-rays and gamma rays interact more weakly with fewer electrons. Figure 6-3 shows the relative dose versus depth in material for four different radiations: e-beam at 10 MeV, cobalt-60 with its 1.3-MeV gamma rays, and x-rays at 5 and 7 MeV. The depth of penetration (dose as a function of depth) depends on the density of the material and so the dose-depth relationship is characterized by the product of density (g/cm3) and distance (cm), yielding units of grams per square centimeter (g/cm2), rather than actual depth. A given dose-depth value, say 1 Gy at 1 g/cm2, implies that lower densities, for example, 0.5 g/cm3, result in deeper radiation penetration, 1 Gy at (1 g/cm2)/(0.5 g/cm3) = 1 Gy at 2 cm. The chart shows that the electron beam delivers its whole dose in a small depth, whereas gamma rays and x-rays spread their doses over a greater depth. The targeted delivery of the electron beam and the ability to deposit nearly all of the energy in a shallow depth enable e- beam irradiators to achieve much higher dose rates than other technologies, which makes it the preferred technology for some applications.

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106 RADIATION SOURCE USE AND REPLACEMENT Primary Electrons Secondary Electrons FIGURE 6-2 E-beam irradiation. SOURCE: Image courtesy of GAO (2002). 1.2 MeV FIGURE 6-3 Relative dose versus depth in material for four different radiations. The highest relative dose for all depth values greater than 5 g/cm2 is the 7-MeV x-ray. The 5-MeV x-ray is just below that, and the cobalt-60 curve is next. The e-beam curve drops to zero relative dose at about 6 g/cm2. SOURCE: Image courtesy of Cleland, M. (2006). As is described in Chapter 4, accelerators must convert electrical power to beam power. The conversion efficiency ranges from 20 to 45 percent, depending on the design of the system and the power output of the irradiator (high efficiency for high-power systems, in general). X-ray Irradiation A large-scale x-ray irradiator looks nearly identical to an e-beam irradiator, and can even operate using the same accelerator, but has a target that converts the e-beam to x-rays (see Figure 6-4). The target is a thin layer of high-atomic-number, dense material that can withstand

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PANORAMIC IRRADIATORS 107 high heat loads; usually tantalum or tungsten is used. The electron beam strikes the target which stops the beam electrons in a short distance. Slowing and stopping the electrons releases radiation called bremsstrahlung. This “braking radiation” is scattered forward in the direction the electrons were traveling, so the accelerator and target generate a fan beam of x-rays with energies up to the energy of the impinging electrons. The x-rays are not the monoenergetic like the gamma rays released when cobalt-60 decays, but the energy of the x-rays can be adjusted. A major advantage of the x-ray irradiators is the ability to use higher energy x-rays: commonly 5 MeV but higher energies are possible. X-ray irradiation so far has only been used for food irradiation in laboratory and demonstration-scale irradiators and in one moderate-size facility for irradiating packages, described below. Texas A&M University hosts the National Center for Electron Beam Food Research, which does research, training, and contract processing using linacs that deliver e- beam or x-ray irradiation. IBA-Sterigenics constructed a 170-kW facility in Bridgeport, New Jersey, with one 10-MeV e-beam for polymer processing and two x-ray beam lines (one at 5 MV and one at 7 MV) for food irradiation. The 7-MV beam line was constructed at least in part to petition FDA to raise the 5-MeV energy limit for food irradiation, which FDA did. However, the facility won a contract for irradiation of mail for the U.S. Postal Service. The e-beam operation is dedicated entirely to irradiation of flat mail, and the 5-MeV x-ray line is dedicated to irradiation of bulky parcels. The 7-MeV x-ray line is operational but not used. Sterigenics split from IBA, but IBA still has a contract to construct a major x-ray irradiator facility for Sterigenics in Belgium. The companies disagree about whether the new facility will be economically competitive with gamma irradiators. Certainly, higher energy e-beams have better energy conversion efficiency: The conversion efficiency is 8 percent for 5 MeV and about 11.2 percent for 7 MeV. Some supporters of x-ray irradiation have concluded that larger x-ray facilities (several hundred kilowatts) will have economic advantages, and this facility, at around 700 kW, will test that conclusion. The maximum energy used today is 7.5 MeV because of concerns about neutron production and induced radioactivity in the sterilized product. Primary Electrons X-ray Target Photons Secondary Electrons FIGURE 6-4 X-ray irradiation. SOURCE: Image courtesy of Cleland, M. (2006).

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108 RADIATION SOURCE USE AND REPLACEMENT FIGURE 6-5 Conceptual plan view of an x-ray irradiator using the IBA Rhodotron for the electron beam and the Palletron for handling the products. SOURCE: Image courtesy of Cleland, M. (2006). IBA’s concept for an x-ray irradiator facility is illustrated in Figure 6-5, which shows the IBA Rhodotron accelerator as a near-circular device on the left and the products passing through the shielding maze on a conveyor belt, on the right. One pallet or a set of pallets undergoes irradiation at any given time. To even out the dose distribution within a pallet, the design, called a Palletron, rotates the product. Figure 6-6 illustrates the dose as a function of depth in a package irradiated from two sides with cobalt-60. Similar but flatter total dose distributions can be achieved with 5-MV x-ray sources. An alternative facility design has three rotating pallets, one behind another in line with the x-ray beam. This design takes advantage of the fact that a pallet of low-density materials provides only modest shielding of 5-MV x-rays, so much of the x-ray energy can be utilized even in the shadow of another pallet. Three companies, Mevex Corporation, Precision X-ray, Inc., and RadSource Technologies, Inc., told the committee that they are developing or are willing to develop specialized x-ray irradiation systems to meet the demands of customers that want in-house irradiation to sterilize small batches of products. Titan Scan also offered a small batch e-beam system. Other x-ray tube and compact-accelerator manufacturing companies might also be interested if the market were sufficiently large. Varian, for example, indicated an eagerness to develop x-ray systems tailored to the needs of specific applications if a clear and sizable market were apparent. These devices would most likely be, in essence, self-contained irradiators, but they could replace some contract irradiation if the costs of purchase and operation turn out to be competitive. An effective system for irradiating a wider variety of products could be imagined as including a combination contract irradiation facility with a gamma irradiator for moderate- and high-density products and for low-dose-rate irradiation; an e-beam irradiator for low-density products and very-high-dose-rate irradiation; and an x-ray irradiator for high- and very-high- density products and high-dose-rate irradiation. Co-located gamma and e-beam irradiation facilities already exist and are operated in the United States. Utilizing the same accelerator that makes the e-beam to make an x-ray line avoids the cost of another accelerator (one still needs

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PANORAMIC IRRADIATORS 109 the new beam line and x-ray target, the shield, and conveyor), but it is not clear that there is a sufficient market of goods for which x-ray irradiation is sufficiently superior to warrant construction of a separate facility when a gamma irradiator is already available.5 Cost Comparison of Gamma and X-ray Irradiation The clearest comparison of irradiation techniques is between cobalt gamma irradiation and high-energy (7–10 MV) x-ray irradiation. Several cost factors are the same for both: the cost of land, the maze leading into the chamber, the warehouse, and office space. Morrison (1989) notes that the cost of shielding and the conveyor system for cobalt-60 facilities increases with designed hourly throughput because the irradiation chamber must be larger. Accelerators increase throughput by increasing the beam power and conveyor speed, and so the configuration changes little. The factors that more clearly differentiate the cost of cobalt gamma irradiation from x-ray irradiation are listed in Table 6-2. The approximate costs are calculated for irradiators sized to handle roughly 119,000 m3/yr (4.2 million ft3/yr) at 25 kGy. FIGURE 6-6 Depth-dose distribution in a product container irradiated from opposing sides with a cobalt- 60 source. Curve a represents the depth-dose distribution when the product is irradiated by a source rack in positiona. Curve b is for the source rack in position b. Curve a + b shows the sum of doses from irradiation on both sides. SOURCE: Image courtesy of IAEA (2004b). 5 To the committee’s knowledge, one existing gamma irradiation facility was converted to e-beam irradiation for research and development at a company’s headquarters. It is not at all clear that this option is cost-effective for a production operation because the configuration of the shield and the conveyor system for the products are different for the two irradiators. The conversion would also requires cutting holes in the 2-m-thick reinforced concrete shielding to enable the beam line or the radiofrequency energy to pass through.

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110 RADIATION SOURCE USE AND REPLACEMENT TABLE 6-2 Comparison of the Costs of Cobalt Gamma and X-ray Irradiation for Sterilization Expense Category Cobalt Gamma Irradiation X-Ray Irradiation Initial investment Initial loading of cobalt-60 Electron accelerator and targets 130,000 TBq = $7M (assuming 7 MeV, 78.4 kW (x-ray power) = $54/TBq [$2/Ci]) $7M Facility costs including shield, Cost of shield and conveyor conveyor system, hoists, and system = approximately $5M wet-storage pool = Approximately $5M Operating costs Cobalt-60 replenishment Electricity for the accelerator 1,400 kWe = 11,040 MWh /yra or 12.3%/y = $0.86M/yr about $660,000/yrb Regulatory costs = unknown but higher for gamma irradiator Maintenance and operations = Security = unknown but higher perhaps $0.25M/yr more than gamma irradiatorc for gamma irradiator Decommissioning and disposal Final return shipment of cobalt- Disposal of spent targets = costs 60 = $0.25M $0.02M NOTES: Categories with no significant cost difference, such as land, office space, laboratory costs, and tear-down of the facility at decommissioning, are not listed. a Assuming the equipment is 50% efficient for the e-beam and operates 90% of the time b $59.7 per MWh nationwide average for industrial price of electricity based on data from EIA (2006). c Three highly skilled maintenance technicians for the x-ray system versus one for the gamma irradiator. SOURCE: Adapted from Cleland, M. (2006); Smith, M. (2006); and Morrison, R. (1989). These rough calculations suggest that x-ray irradiation is economically viable if the assumptions about performance and costs hold true. Because there is no experience yet with a large-scale x-ray irradiator, the committee cannot state these assumptions with great confidence, and only offers them as the data it has available. Steam or Dry Heat Autoclaves and dry-heat ovens are routinely used in hospitals to sterilize reusable medical devices, but medical devices are increasingly being provided as single-use devices. Autoclaves are essentially pressure cookers used to sterilize devices and equipment. Heating water in a sealed enclosure increases its boiling point as the pressure increases. This enables the water to reach temperatures well above 100°C. Dry-heat ovens operate at higher temperatures, but their heat transfer properties are less efficient, so the sterilization takes longer unless operated in a convection mode by blowing air on the products. Table 6-3 shows sterilizer temperatures, pressures, and times recommended in an article in the Journal of the American Dental Association. Steam is a surface sterilizer, unless the entire device remains for a sufficient time at a temperature that kills pathogens. Chemical vapor sterilizers called chemiclaves are also used. Other emerging technologies have been applied to small-batch sterilization devices for use in hospitals, not for contract irradiation. For example, hydrogen peroxide plasma (Rutala and Weber, 2001) and supercritical carbon dioxide (White et al., 2006) are being marketed as replacements for compact EO sterilizers.

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PANORAMIC IRRADIATORS 111 TABLE 6-3 Autoclave and Dry-Oven Temperature and Time Pressures for Sterilization with EO Included Temperature Pressure Sterilizer (°C [°F]) (kPa [psi]) Time Steam autoclave 121 [250] 100 [15] 15 min unwrapped items 132 [270] 200 [30] 3 min lightly wrapped items 132 [270] 200 [30] 8 min heavily wrapped items 132 [270] 200 [30] 10 min Dry heat, wrapped 170 [340] 60 min 160 [340] 120 min 150 [300F) 150 min 140 [285F) 180 min 121 [250F) 12 h Dry heat (rapid flow) 190 [375F) 6 min unwrapped items packaged items 190 [375] 12 min Chemical vapor 132 [270] 140-280 [20-40] 20 min EO 40–60 6.7-50 [1–7.5] Varies, [100–140] 4–10 hr SOURCE: Courtesy of Journal of the American Dental Association (1991). EO Sterilization More than half of all sterile medical devices sold are sterilized using EO (J. Hadley, Ethylene Oxide Sterilization Association, Inc., personal communication to F. San Martini, 2007; Dever et al., 1994). EO is used for most of the medical products that are incompatible with radiation exposure (Hadley, personal communication, 2007). EO can be used for most current hospital surgical kits, catheters, IV tubing, endotracheal tubing, angiographic balloons, heart kits, cranial and orthopedic implants, pacemakers, and implantable defibrillators. In addition, more than one-third of all reusable devices are currently sterilized with EO (Hadley, personal communication, 2007). Some medical products are not suitable for EO sterilization (Hadley, personal communication, 2007), such as vacuum-pressure-sensitive products; nonvented, sealed products that do not allow for gas diffusion or penetration of EO gas; medical products that retain absorbed EO; products with extremely high densities or challenging physical configurations that would limit the permeation of EO; products with active pharmaceutical ingredients not validated for the effects of EO; and some orthopedic implants where radiation is needed to increase product strength characteristics, in addition to sterilization. EO sterilization typically comprises three stages: preconditioning, sterilization, and aeration. In a conventional sterilization process, these steps are done separately. In some

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112 RADIATION SOURCE USE AND REPLACEMENT cases, however, the three steps are completed together within the sterilization chamber. The four key parameters affecting EO sterilization efficiency are EO concentration, temperature, relative humidity and exposure time. Because of differences in packaging, load density, and other factors, each product type requires a unique treatment cycle. Products to be processed are placed on pallets and then enter the preconditioning phase, which helps ensure EO penetration. Preconditioning consists of exposing products to elevated temperatures (typically between 40ºC and 60ºC) and relative humidity levels (typically between 45 and 75 percent) for up to one day. Sterilization takes place in a stainless steel sterilization chamber. Commercial sterilization chambers vary considerably in size, ranging in capacity from 1 to 30 pallets (Hadley, personal communication, 2007). Typically, the sterilization process is performed under negative pressure conditions (below atmospheric pressure). Once vacuum has been established, EO is pumped into the sterilization chamber.6 This period, during which products are exposed to high EO concentrations, is termed the dwell stage. The EO concentration and cycle times vary greatly depending on the product, cycle conditions, and whether a conventional EO sterilization process is used or the three sterilization stages are performed together in the sterilization chamber. The EO concentrations are highest during the dwell stage and range from about 300 to 1,200 mg/l, with the average at about 650 mg/l (Hadley, personal communication, 2007).7 If the three sterilization stages are performed separately, the chamber time typically ranges from 8 to 12 hours. If the three steps are performed within the chamber, the total chamber time is about 11 to 36 hours (Hadley, personal communication, 2007). After the dwell stage, EO from the chamber is exhausted to air pollution control equipment with successive gas (typically nitrogen) washes. After completion of post-sterilization flushing, the product is transferred to the aeration stage, which removes residual EO. Finally, the products must be tested to verify sterility. EO is extremely flammable, and gas/air mixtures are explosive. The flammability limits in air are 3 percent (30,000 part per million by volume [ppmv]) to 100 percent (Lewis, 2003); pure EO can be ignited in the absence of air. According to the National Institute for Occupational Safety and Health (NIOSH), once ignited, it can flash back to the fuel source with velocities of 1,800 to 2,400 m/s (NIOSH, 2000). The gas is colorless, heavier than air, and may travel along the ground; distant ignition is possible (IPCS, 2001). EO can be detected by odor only when it has already reached the dangerous concentration of 260 ppm (NIOSH, 2000). EO is reactive with strong acids; alkalis and oxidizers; chlorides of iron, aluminum, or tin; and oxides of iron and aluminum (Lewis, 2003). EO is a “known” or “probable” human carcinogen, depending on the classifying body.8 Repeated or prolonged inhalation exposure may cause asthma; it may have effects on the nervous system, liver, and kidneys, or cause cataracts; and it may cause heritable genetic damage to human germ cells. There are reports of EO-induced anaphylaxis from sterilized 6 Most commercial sterilization facilities currently use pure EO (Hadley, personal communication, 2007). Previously, mixtures of EO and chlorofluorocarbons (CFCs) were used to reduce flammability and the risk of explosions. EO–CFC mixtures were phased out following the Montreal Protocol. 7 Assuming sterilization occurs at approximately 0.67 atm and room temperature (298.15 K), the range of EO concentration during the dwell stage is approximately 250,000 to 999,700 ppmv, with an average of approximately 540,000 ppmv (i.e., 25–99.97 percent, with an average of 54 percent). 8 The National Toxicology Program recently upgraded EO to a known human carcinogen. In 1985, the U.S. Environmental Protection Agency classified it as a Group B1 (probable) carcinogen; a new draft evaluation of the carcinogenicity of EO was being evaluated at the time of this writing. The International Agency for Research on Cancer (IARC) classified it as a Group 1 carcinogen. NIOSH (2004) found that persons exposed to very high levels of EO may be at an increased risk of developing blood cancers among men and breast cancers among women.

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PANORAMIC IRRADIATORS 113 membranes used in hemodialysis (Ebo et al., 2006). Both chronic and acute exposures may cause miscarriages. Because of its environmental, safety, and occupational hazards, EO is regulated by federal and state agencies. Oxidizing emission control devices are generally used to remove EO from low-concentration emission streams; acidified wet scrubber systems are typically used when emissions contain high EO concentrations. The Occupational Safety and Health Administration (OSHA) permissible exposure limit for EO is 1 ppmv and the NIOSH recommended exposure limit for EO is 0.1 ppmv, both as an 8-hour time-weighted average, and a short-term exposure limit of 5 ppmv, time-weighted over 15 minutes (29 CFR § 1910.1047). NIOSH has determined that 800 ppmv is the EO concentration that is immediately dangerous to life and health. OSHA also requires: • monitoring employees to determine actual exposure to EO during work shift, • restricting access to EO areas to authorized personnel, and • implementing a system to provide emergency warning in the event of a release. In addition to the requirement to meet the sterility assurance level described above, FDA regulations specify permissible residual concentrations of EO on sterilized medical products. Safety and Security and EO To educate users of EO, five chemical companies produced and make freely available (http://www.ethyleneoxide.com) a guide that summarizes essential information for safely handling EO (Buckles and Chipman, 1999). The summary of incidents involving EO given in Section 5 of the guide illustrates EO’s hazards. These range from a railcar9 explosion that caused major damage over a 300-m radius and broke windows up to 5 km away; and an incident in which 0.27 kg of EO decomposed in a pump, causing the upper part of the pump and its motor (weighing approximately 450 kg) to break free of the 12 steel bolts that held them in place and shoot over 18 m into the air (Buckles and Chipman, 1999). More recent examples of accidents at EO sterilization facilities confirm that process safety concerns remain. An explosion at an EO sterilization facility in California in 2004 injured four workers and severely damaged the facility. The explosion sheared the hinges off both of the 1,800-kg (4,000-lb) sterilization chamber doors and propelled them outward. One door came to rest approximately 25 m from the chamber after striking and fracturing the south wall of the building, while the other came to rest approximately 5 m away, after colliding with and damaging a steel column (U.S. Chemical Safety and Hazard Investigation Board, 2006). A similar explosion occurred at a sterilization facility in 1997. The explosion occurred during a test of a newly installed oxidizing emission control device that replaced an acidified wet scrubber system. The explosion blew off the sterilizer door and moved the 22,700-kg (50,000-lb) sterilization chamber off its foundation. About 7 to 9 kg (15 to 20 lb) of EO is believed to have been in the sterilizer at the time of the explosion (NIOSH, 2004). 9 This incident involved an EO shipment from a European EO producer to a customer. In North America, all EO sterilization companies receive their EO supply in gas drums that are shipped via truck from ARC Specialty Products. These drums comply with current Department of Transportation requirements. They are double-walled stainless steel drums that provide protection for all valve openings. The drums are regularly inspected, pressure tested, and drop tested (Hadley, personal communication with F. San Martini, 2007).

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114 RADIATION SOURCE USE AND REPLACEMENT EO Summary EO gas sterilization has been used for more than seven decades.10 Less than 1 percent of all EO produced in the United States is used as an industrial sterilant or fumigant (LaMontagne and Kelsey, 1998). Therefore, concerns over its hazards should be viewed in context. It is a technology that has been used for many years to sterilize medical products effectively. There have been no accidents or incidents involving mass casualties due to the use of EO. However, there are substantial health and safety concerns surrounding the use of EO and encouraging substitution to EO just replaces one kind of risk with another. FOOD IRRADIATION Foods such as spices, fresh fruit, vegetables, and grains can be irradiated to slow the ripening process, prevent sprouting, extend shelf-life, and kill bacteria, parasites, and mold. Meat and poultry can be irradiated to 4.5 kGy for similar purposes. Table 6-4, taken from Deeley (2001), lists the typical doses required for different food irradiation applications, and Table 6-5 lists the approved uses of radiation for treatment of food. Food irradiation, which can use the same kinds of equipment as sterilizer irradiators (cobalt-60, e-beam, or x-ray), is not common in the United States, but it may increase in the future. TABLE 6-4 Typical Radiation Doses for Various Food Applications Application Food Product Typical Dose (kGy) Reduction or elimination of Spices 3–10 microbial populations in dry food Starch ingredients Enzyme preparations Pasteurization Meat 2–7 Poultry Shellfish Frogs’ legs Herbs/spices Extend shelf–life Fruits 0.5–5 Vegetables Meat, poultry Fish Parasite disinfection Meat 0.1–3 Pork Fish Insect de-infestation Grain 0.2–0.8 Flour Dried fruits Inhibition of sprouting Onions 0.03–0.14 Garlic Potatoes NOTE: The necessary radiation dose depends on the application and the bacteria being treated. Moisture reduces the necessary dose. Absorbed dose is measured in Gray (Gy). 1 Gy is 1 J of energy absorbed per kilogram of food irradiated. SOURCE: Adapted from Deeley (2001). 10 Application for a patent for sterilization using EO was made as early as 1933 by Gross and Dixon (1937).

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PANORAMIC IRRADIATORS 115 TABLE 6-5 Approved Uses of Radiation for Treatment of Food in the United States Year Approved Food Dose (kGy) Purpose 1963 Wheat flour 0.2–0.5 Control of mold 1964 White potatoes 0.05–0.15 Inhibit sprouting 1986 Pork 0.3–1.0 Kill Trichina parasites 1986 Fruit and vegetables 1.0 Control Insects, increase shelf life 1986 Herbs and spices 30 Sterilization 1990, FDA Poultry 3 Reduce bacterial pathogens 1992, USDA Poultry 1.5–3.0 Reduce bacterial pathogens 1997, FDA Meat 4.5 Reduce bacterial pathogens 1999, USDA Meat 4.5 Reduce bacterial pathogens (pending) SOURCE: Courtesy of CDC (2005). The largest food irradiator in the United States, SureBeam, declared bankruptcy in 2004, and its facilities, which handled large quantities of ground beef, shut down. Since then, a company called BeamOne, LLC, has operated the former SureBeam facilities in San Diego, California, Denver, Colorado, and Lima, Ohio for sterilization of medical products and for polymer processing. Sadex purchased SureBeam’s e-beam irradiator in Sioux City, Iowa. Currently, two commercial facilities in the United States routinely irradiate food: one is in Florida (Food Technology Service, Inc., a gamma irradiator) and the other is in Hawaii (Hawaii Pride; an e-beam facility rated at 15 kW). In August 2007, Hawaii Pride received a license to build another facility in Hawaii, this one using cobalt-60. In addition, the U.S. Department of Agriculture (USDA) has one gamma irradiation facility dedicated to food irradiation research, Iowa State University operates the Linear Accelerator Facility for food irradiation, and Texas A&M University operates the National Center for Electron Beam Food Research, a semi- commercial, semi-research facility for e-beam and x-ray food irradiation. A few other irradiation facilities can be contracted to irradiate foods, but do not do so routinely (aside from spices) and do not have a refrigerated storage warehouse for receiving products. As noted earlier, the same kinds of equipment can be used for irradiation of food as for sterilization irradiation. E-beam irradiators compete with gamma irradiators in this market today. X-ray irradiators face the same economic uncertainties for food irradiation as for sterilization applications. While fumigation and chlorine rinses are possible for produce, there is no direct replacement for irradiation of ground beef, which is currently the biggest market for U.S. food irradiators. MATERIALS PROCESSING USING PANORAMIC IRRADIATORS Although the majority of irradiators are devoted to medical device sterilization, contract irradiators (gamma and e-beam) are also used in a number of materials processing applications. These range from the irradiation of PTFE (Teflon®) to create PTFE micropowders, useful in inks and lubricants, to the treatment of polymer strips to enhance their lubricity). These applications depend on ionizing irradiation to break chemical bonds in polymers and to decrease their molecular weight. Because the density of polymers is low, this can be accomplished by ionizing radiation produced by x-ray, e-beam, or gamma rays.

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116 RADIATION SOURCE USE AND REPLACEMENT Doses cited for materials processing range from 200 kGy for cross-linking of polymers to well over 500 kGy for degradation of PTFE. High dose rates are desirable for such high doses, and so e-beam irradiation is the preferred approach for some of these applications. Indeed, it is the primary application of e-beam irradiators and, for very thin targets, of high-dose-rate kilovoltage x-ray sources. Many of these materials processing applications appear to be proprietary processes and it is not clear to the committee how extensively gamma irradiation facilities are used for these purposes. Chemical cross-linking is the predominant technique used by polymer manufacturers, and so those using irradiation have specifically sought out the features peculiar to irradiation. INSECT STERILIZATION USDA operates about a half-dozen irradiators for sterilization of male insects, called the sterile insect technique. This practice is carried out extensively outside the United States (see, e.g., Enserink, 2007a,b), which constitutes a larger market for the irradiation devices. USDA facilities breed the pests (e.g., the Caribbean fruit fly) in isolated facilities and sterilize live specimens by irradiation with a dose of 100–150 Gy, then load them into transport containers and release them in areas of potential infestation to compete with the infesting populations for breeding. This suppresses the reproduction rate and inhibits infestation. The gamma irradiators USDA uses are decades old and are loaded only with their original cesium-137 sources. As these sources age, the time needed for irradiation lengthens and eventually the devices will need to be replaced. Some irradiation devices utilizing x-rays for sterile insect release have been sold outside the United States (Kirk, 2006). As noted above, too, foods may be irradiated to reduce the threat from pests, such as fruit flies. FINDINGS For some applications, alternative technologies to gamma irradiators are already preferred and in use. The primary reason to consider encouraging the sterilization of medical products with EO rather than by irradiation is a reduction of security risk. The risks of EO should be judged relative to those associated with the use of radiation sources in panoramic irradiators. EO poses no area-denial radiological dispersal device risk, but the accidents and potential security risks, health risks associated with exposure, and pressures to encourage EO users to switch away from EO because of its toxicity indicate that encouraging a shift from irradiation to EO sterilization may not be desirable. A direct replacement for gamma irradiators is available and technologically feasible in the form of x-ray irradiators. Whether these replacements are economically competitive with gamma irradiators is not clear. The committee’s incomplete calculation shows that the costs could be comparable, but the actual cost differences depend on variable factors such as the cost of electricity and the reliability and throughput of the equipment in the x-ray facility.