Section 5.1.2 of ANSI/AAMI/ISO 11137-1 states that “the potential for induced radioactivity in product shall be assessed.” This article describes how compliance with this requirement may be achieved using qualified test methods. Materials of consideration are conceptually discussed, and results of testing conducted on products processed with a 7.5-MeV X-ray irradiation process are provided. As X-ray becomes more widely used in healthcare sterilization, having standard assessment protocols for activation coupled with a shared database of material test results will benefit manufacturers seeking to utilize this innovative technology.
Radioactive material of natural origin is ubiquitous in nature, with wide variations in type and amount. Energy from these materials, plus radiation of cosmic or cosmogenic origin, is collectively called background radiation. Artificial radioactivity occurs when a human operation results in radioactivity being created, generally as a nuclear fission product in a reactor or activation from bombardment by photons or particles. Activation also is called “induced radioactivity.” Assessment of induced radioactivity in radiation-sterilized healthcare products must determine whether such activity is present at a level higher than background. In terms of medical device manufacturing and sterilization, induced radioactivity must be considered from the perspective of safety for all individuals who may come in contact with the irradiated product.
Two broad categories of exposure pathways can be considered for potential risk to individuals1 :
External exposure (i.e., radiation from sources outside the person's body) may be of concern for individuals working in the irradiator facility or distribution warehouse; those involved in transporting materials; and healthcare workers (e.g., physicians, nurses) who handle the product.
Internal exposure (i.e., radiation from sources inside the person's body) might occur for patients into whom irradiated products would be placed.
In previous evaluations of induced radioactivity in radiation-sterilized healthcare products,1–3 the estimated or measured concentrations of induced radioactivity was small and generally not distinguishable from background in terms of external exposure. As such, hazards from external radiation would not exist from induced radioactivity in radiation-sterilized healthcare products. Section 5.1.2 of ANSI/AAMI/ISO 11137-1 requires evaluation of potential activation of materials with X-ray irradiation exceeding 5 MeV.4
When a photon strikes a nucleus, a particle can be ejected from the nucleus if its binding energy is less than the absorbed photon energy. The remaining nucleus may be radioactive. The primary major reactions that can lead to photon-induced activities are as follows:
Photon-neutron reaction: absorption of a photon and expulsion of a neutron
Photon-proton reaction: absorption of a photon and expulsion of a proton 1H+
Photon-deuterium reaction: absorption of a photon and expulsion of a nucleus of deuterium 2H+
Photon-tritium reaction: absorption of a photon and expulsion of a nucleus of tritium 3H+
Photo-alpha reaction: absorption of a photon and expulsion of an alpha particle (the nucleus of helium 4H++)
For incident photon energies of 10 MeV and below, the photoneutron reactions are most probable, while the emission of other particles become important at higher energy.5 In a 7.5-MeV X-ray irradiator, the energy of the high-energetic photons can generate a low neutron radiation during interaction in the matter (photonuclear effect X,n; Figure 1).
For a photon-neutron reaction to occur, the photon must strike a nucleus with more energy than the binding energy of the atom. This reaction requires at least 2.22 MeV (for hydrogen) and about 10 MeV for the heaviest nuclei. Figure 2 shows the photonuclear cross-section as a function of the energy of the photon. The blue area indicates the X-ray's energy spectrum in a 7.5-MeV irradiator.
Cross-section is defined as the probability that a particular interaction will occur. The photoneutron production cross-section (Figure 2) is the probability that a photon will interact with a nucleus in such a way as to cause a neutron to be ejected from the nucleus. The probability is expressed in units of area (e.g., cm2), representing the theoretical size of a target for the interaction, though cross-section is not an actual area measurement.
Photon-neutron activation is the process in which neutron radiation induces radioactivity in some materials; it occurs when atomic nuclei capture free neutrons, become heavier, and enter excited states. The excited nucleus (Figure 3) begins to decay immediately after the reaction by emitting particles and gamma rays.
Assessment of Activation Based on Material Composition
An activation reaction produces a new isotope of a new element (if a proton was emitted) or the original element (if a neutron was emitted). Each isotope has a unique threshold energy for such reactions and a particular cross-section that determines the probability of the reaction occurring. A list of energy thresholds and an activation risk-based approach according to material composition, X-ray energy, and activation reaction is discussed by Grégoire et al.2
To evaluate the level of concern posed by potential activation by an X-ray beam, a list of elements most likely to be found in medical devices was assembled (Table 1). This list was cross-referenced with information found in the International Atomic Energy Agency's (IAEA's ) TECDOC-1287 (specifically Tables 7–9).5 The TECDOC tables list all naturally occurring isotopes of these elements, the daughter isotope from both (γ,p) and (γ,n) reactions, and the threshold energies for each.
If a daughter product of a reaction is stable, or the threshold for such a reaction is above 7.5 MeV, then no concern exists regarding activation of that isotope by the primary X-ray beam. In Table 1, the cell for that element is indicated by boldface text, if all isotopes met that criterion. If not, the cross-section for the (γ,p) or (γ,n) reaction was evaluated to determine whether any reason for concern existed. In all remaining cases, the cross-section was too small to be of concern or the threshold of the reaction was below, but very close to, 7.5 MeV. The percentage of X-rays in this energy range was very small and, when coupled with the small cross-section, was most likely of negligible concern. These are indicated by italicized text in Table 1.
Table 1 does not examine neutron-capture reactions. A small number of neutrons can be generated in the X-ray target: H-2, C-13, and O-17 (0.015%, 1.11%, and 0.04% natural abundance, respectively). The capture of these neutrons, resulting in activation, is a second-order effect. As such, these reactions result in barely measurable activation that is below action levels, as shown in Tables 2 and 3.
In evaluating potential radiation risk to individuals, the IAEA Basic Safety Standard (BSS)6 applies the term “exemption” to a practice, as well as sources within that practice, that has been determined a priori to meet criteria that would free it from the requirements of the BSS.7 This exemption is based on an individual dose that would have no health significance, regardless of the route of exposure, such that the exemption level applies to healthcare workers, members of the public, and patients.
The IAEA has published derived concentration levels for a wide range of radionuclides that based on distribution and uptake models, would be low enough to be considered exempt. Similarly, the U.S. Nuclear Regulatory Commission (USNRC) has published a table of exempt concentrations for a variety of radionuclides,8 though the number is more limited in scope than that exempted by the IAEA. To determine whether induced radioactivity exists in sufficient quantities to be a safety concern, the IAEA exempt concentrations provide a sound basis.
Assessing the potential for induced radioactivity in irradiated products should follow a logical sequence, as depicted in the flow chart of Figure 4. The first assessment is simple: If the X-ray irradiator energy does not exceed 5 MeV, then no further evaluation is required. In a higher energy irradiator, the assessment should determine whether any metal components or constituents are present. Based on published literature1,2,9 and previous measurements, the probability of nonmetals being activated at levels exceeding the exemption limit is negligible.
Of important note, although a product may not contain a metal component (i.e., a part made of metal), it may still contain metal. Various polymers may contain metal constituents, such as (1) certain dyes that may contain metals, including cadmium, chromium, nickel, cobalt, and/or copper,10 and (2) metal-containing polymers used as drug delivery vehicles, as biosensors, and in bioimaging,11 which need to be included in the assessment. For this step and each of the subsequent steps in the assessment, if it is not possible to answer the questions definitively, a conservative conclusion should be assumed and the next step in the assessment should be taken as though the answer is “yes.”
Induced radioactivity in an irradiated product generally will not present undue risk to individuals if the half-life of the radionuclide is short. For example, a radionuclide with a three-hour half-life would decay to 0.4% of its initial activity during a 24-hour period. During that same period, the activity of a radionuclide with a two-hour half-life would reduce to 0.02% of its initial value. For the assessment described in this article, if the induced radioactivity half-life is less than two hours, then the potential for exceeding the exemption limit was considered negligible.
The final step of the initial evaluation is to determine whether, based on published literature or previous measurements, irradiation of the product may result in induced radioactivity greater than the exemption limit. If a reasonable expectation exists, further evaluation should be made to determine if irradiation of a particular product results in elevated induced radioactivity. This evaluation may consist of a more detailed search of available data or case histories, calculations specific to the circumstances, or more detailed mathematical modelling. If a significant probability remains that induced radioactivity could exceed the exemption level, then empirical evidence should be gathered by irradiating the device, its packaging, and its labeling and measuring induced radioactivity.
Methodology of Activation Assessment
Empirical evaluations or measurements of the presence of induced radioactivity in irradiated products may involve two approaches:
Performing a screening measurement of the product to determine whether radiation emissions exceed background radiation levels, which would indicate the presence of radioactivity. This requires that protocols for using the screening instrument allow radioactivity at the exemption level to be detected.
Performing qualitative and quantitative analysis of the product to determine which radionuclides are present and in what quantity. Values for the radionuclides can be compared with the specific exemption level for the radionuclides detected in the sample.
The activation of elements is proportional to the absorbed dose received. This means that if the absorbed dose received (in gray [Gy]) doubles, the activity of an activated radioelement (in becquerel [Bq]) also doubles.
The Ludlum Model 54A Small Article Monitor shown in Figure 5 is a self-contained radiation detection instrument designed to detect radioactive contamination on objects small enough to fit into the chamber. The active portion is a cubic chamber lined on six sides with plastic scintillators, providing 4-π counting geometry. Figure 6 shows the monitor with an internal sample holder designed to position a check source in the center of the counting chamber.
The minimum detectable activity for this method was established as the critical level (LC), which is the signal level above which an observed instrument response may be reliably recognized as “detected above background.”12 This minimum detectable activity must be compared with a target value from the IAEA and USNRC tables of exempt radionuclide concentrations.8 Taking the lowest value for any exemption level in the tables and assuming a minimum mass for the product being irradiated, the activity target for the screening instrument can be calculated. Figure 7 depicts results of an experiment to establish the LC as a function of count time. The independent variable is the ratio of the LC to the derived exemption limit. For this situation, a count time of approximately eight minutes gives an LC equal to the exemption limit.
Based on validation tests conducted on the instrument, which were derived from a similar program for assessing induced radioactivity during e-beam irradiation,10 a routine procedure was established to assess the potential for induced radioactivity in products irradiated in X-ray. The important steps are:
Irradiate the sample to a dose higher than the maximum acceptable dose of the device, giving a probability of creating induced radioactivity in the assessment as high or higher than might be expected during routine operation.
Use a default count time of 10 minutes, corresponding to an LC approximately 14% below the exemption level.
Prior to making an irradiated product measurement, conduct a 10-minute empty-chamber count to monitor consistency and reproducibility of local background, similar to a statistical process control chart.
Prior to making an irradiated-product measurement, perform a count of a radioactive source of known low activity (i.e., activity similar to levels that might occur for induced radioactivity).
Count the irradiated product as soon as practicable following irradiation. If the count exceeds LC, conduct another count after an interval equivalent to the expected operational time between irradiation and product shipment, in order to determine whether the radioactivity is short lived. Generally, this time interval will be no more than a few hours, depending on the irradiation facility's normal schedule for processing and shipping.
Assess the potential risk from any induced radioactivity, accounting for the level of activity present and the length of its half-life.
Qualitative and Quantitative Approach
From a regulatory point of view, there is no requirement to know which radionuclide is present in the tested device. However, it may be interesting to use this method to determine the radionuclide that results in an activation level higher than the authorized limit when using the screening method. Qualitative identification may provide information through which design changes might be made to eliminate the induced radioactivity or to make a direct comparison with the radionuclide-specific exemption level.
Germanium detectors (Figure 8) are used to determined which radionuclides are present and in what quantity. Because of the complexity of the setup and cost of the spectrometer, the following measurement usually is done by an approved laboratory, and a certificate is delivered as an output of this measurement.
Expose the sample to a dose at least higher than the maximal acceptable dose of the device, giving a probability of creating induced radioactivity in the assessment as high or higher than might be expected during routine operation.
After the process, send the sample to the approved laboratory as soon as possible to ensure short-lived activity can be detected. The time between end of process and start of measurement should not exceed 24 hours. Note: The start and end exposure times must be recorded, as well as minimum and maximum doses received by the sample.
The laboratory performs the activation measurement.
If activation level is detected, the laboratory will define which radionuclides are present and calculate the level of activation at the time the process is completed.
Case Study Results
The case studies shown in Table 2 are based on qualitative and quantitative methods. The activity (in Bq) has been recalculated at the time of irradiation, following a measurement in laboratory with a Germanium Hyper-Pure detector. Of note, it is unlikely to detect an activated radioelement in polymer products, such as vials, syringes, or bottles. Therefore, case study 3 was an exception because activation was detected in polymer products. Most likely, this was due to a metal constituent in inks or dyes used in packaging or in the product. Such composition should be considered in evaluating potential for induced radioactivity during irradiation.
Summary of Results at STERIS Däniken
Table 3 lists all the radionuclides that were detected in product samples, as well as their associated regulatory limit and half-life. These measured activity levels are very low. For comparison purposes, some natural activities are as follows:
A human body has an average natural activity of 8,000 Bq
1 kg granite has a natural activity of approximately 4,000 Bq
A 150 g banana has a natural activity of about 21 Bq
These natural activities come from radioelements with extremely long half-lives, such as uranium-238 (4.5 billion years) or potassium-40 (1.25 billion years).
Results Using a Screening Method
The screening method currently is being implemented; therefore, a minimal number of measurements have been collected. In absence of data to establish patterns or trends, the instrument performance can be compared with values reported in Table 3.
All of the radionuclides shown in Table 3 had photon yield levels well below the exemption limit. Comparing the calculated activity to the screening instrument LC, five radionuclides at the activity listed would have resulted in an instrument measurement above an LC of 7.5 Bq. These results would be considered detection of induced radioactivity from 24Na, 60Co, 64Cu, 135mBa, and 187W. All other listed radionuclides would have insufficient activity to have exceeded LC using the screening instrument.
If induced radioactivity is detected, further evaluation would be needed to assess the potential impact, specifically to determine whether activity exceeds the exemption limit. The first step would be to identify constituents of the material in which induced radioactivity was detected. Grégoire et al.2 provided a basis for this evaluation. For example, 24Na would be expected in glass, particularly borosilicate glass. 135mBa may also occur in glass, as well as certain types of coloring agents. For others, 64Cu is expected in brass, while 60Co could be in stainless steel and 187W in coatings for metallic blades. Based on the number and type of measurements reported above, it could be assumed that if induced radioactivity was detected in these materials, then the identified radionuclide is most likely the detected activity. As such, comparison of the activity measured by the screening instrument with the exemption limit for the particular radionuclide would be an evaluation of risk from irradiating that product. In some situations, conducting qualitative measurements, such as gamma spectroscopy, may be necessary to determine the specific radionuclide.
Assessment of induced radioactivity, as required by 11137-1, requires a methodical approach based on an understanding of the mechanisms through which induced radioactivity might occur in a product. The assessment must be based on potential risk to individuals from the radioactivity of the product, which can be based on comparison with established exemption limits.
Although much of the assessment can be based on theoretical considerations, thereby eliminating many materials from consideration because of the low probability of induced radioactivity occurring, some means of measuring the presence of radioactivity may be necessary. This measurement may be a screening method to determine if radioactivity exists above background levels or a method that provides both qualitative and quantitative analysis of the sample product.
A history of making such measurements at an operating X-ray irradiator shows that most products exhibit no induced radioactivity, while radioactivity that has been measured in a limited number of products has been well below the exemption limits.
The authors thank the Kilmer Collaboration Modalities group for collaborating to consider how additional sterilization modalities may be deployed and adopted by the healthcare products manufacturing industry, for the benefit of patient care.
About the Authors
Hervé Michel is the director of Radiation Technology EMEA-A at STERIS in Däniken, Switzerland. Email: firstname.lastname@example.org
Thomas Kroc is an applications physicist for technology development at Fermilab in Batavia, IL. Email: email@example.com
Brian J. McEvoy is senior director of global technologies at STERIS in Tullamore, Ireland. Email: firstname.lastname@example.org
Deepak Patil is a senior director of radiation technology at STERIS in Libertyville, IL. Email: email@example.com
Pierre Reppert is a validation manager at STERIS in Däniken, Switzerland. Email: firstname.lastname@example.org
Mark A. Smith is the managing director of Ionaktis in Charlotte, NC. Email: email@example.com