The requirements for the irradiation of healthcare products have been well established and implemented across the globe for several decades. The ISO 11137 series of standards gives the user the road map for designing a radiation process that will routinely deliver the required sterility assurance level so that product consistently meets specifications. The latest addition to the ISO 11137 series of standards should provide much-needed guidance around establishing a highly reproducible process based on a statistical analysis of the validated state of control. Most industries refer to this as “process control.”
What is process control?
Process control is “activities involved in ensuring a process is predictable, stable, and consistently operating at the target level of performance with only normal variation.”1 Are radiation processes used for the sterilization of healthcare products predictable, stable, and consistently operating at a target level of performance?
To determine whether a radiation process is stable and predictable, it is essential to first understand all components of the process that can have a direct impact on the output of the process. For this application, the primary output of the process is the delivered dose to product.
Three main components are critical to process control for a radiation process—the product, the dose measurement system (dosimetry), and the irradiator (including product conveyance or exposure to the radiation source). Each of these inputs operate independently, but each can have a direct impact on the outcome of the process and therefore must be well characterized, separately and in combination.
Radiation Process Components
The product is the first component critical to process control. Characterizing the product and packaging is referred to as “product definition.” Items addressed in the product definition should include: a) the density (typically expressed as g/cc), b) orientation within the primary, secondary, and tertiary packaging, and c) other items included in the package that might impact the overall density (e.g., instructions for use documents and trays or bindings that hold product in desired orientation). These items may have an impact on the absorption of dose during a radiation process.
This product definition—in conjunction with a defined loading pattern within the irradiation container or on the conveyor, including the way it is presented to the radiation source—is called a “loading configuration.” The product definition and loading configuration are both critical for radiation process control.
The measurement system is the second critical component that can impact the radiation process control. Dosimetry is the primary measurement system used to determine the amount of radiation dose absorbed by the product or process loading configuration. Absorbed dose is measured through a dosimetry system that is calibrated and traceable to a national standard of absorbed dose. The process for calibrating a dosimetry system, as defined by ISO/ASTM 51261,2 characterizes the uncertainties associated with the response and measurement of a dosimeter as they relate to the true estimate of dose. All measurements have an associated uncertainty and the magnitude of the measurement uncertainty is important for assessing the quality of the results of the measurement system (see ISO/ASTM 517073 ). Thus, a calibrated dosimetry system provides the best measurement of absorbed dose and, therefore, values from dose measurements should not be corrected by associated measurement uncertainty (see ISO 11137-3: 2017, section 4.1.3).4
Dosimetry systems have several components of uncertainty that may manifest during routine radiation processing (i.e., uncertainties due to dose rate or temperature) and must be characterized for the conditions of use.
The overall reproducibility of the irradiator is the final critical component for process control. An irradiator delivers the dose to products and has several critical components (e.g., source, conveyance, irradiation pathways, etc.) that also must be characterized to determine the appropriate processing parameters and conditions for processing a product. This process characterization, or operational qualification, requires the operator to understand the processing limits, expected variability (common cause variability), and overall reproducibility of the radiation process. This characterization uses a calibrated dosimetry system to measure the process output; therefore, the user must be careful not to confuse measurement system uncertainty with radiation process variability and vice versa. A lack of understanding of the sources of variability and whether they manifest during the process may lead to double counting in the assessment of process variability.
Radiation Process Control
Routine dosimetry is used to determine whether a radiation process is predictable, stable, and consistently operating at the target level of performance. Dosimeters are placed at defined locations within irradiation containers at predefined frequencies, and measured to evaluate whether the qualified process delivered the predicted range of absorbed dose for a predetermined loading configuration. A term that is typically used for a radiation process is target dose. This is the dose that the radiation process parameters are set to deliver at a specified monitoring location. If the irradiator operates as expected and the resulting measured dose is within the predicted limits of the target dose, the process can then be considered in control. The measured doses are used as a means for determining process acceptance and releasing the product. This is referred to as “dosimetric release.”
Radiation Processing Measurements
The analysis of a routine monitoring dosimeter(s) can be used to indirectly determine whether a product has received the required sterilization dose without exceeding the maximum acceptable dose determined for that product. The purpose of the new ISO/TS 11137-45 standard is to provide guidance on how to analyze and interpret this measurement.
A single, routine dosimeter measurement in isolation can be interpreted several ways. Repeated measurements provide some information on the range of doses that can be expected over time. Routine dose measurement made in the context of a desired target dose range provides information on whether the process is in a state of control. In industrial radiation sterilization, the interpretation of these individual dose measurements in relation to product is used to set up target doses and establish and monitor an ongoing radiation process. There is potential for confusion due to variations that are observed and whether they are related to what is going on in the product.
ISO/TS 11137-4 provides information on the sources of variation that may contribute to the range of doses seen during a routine process (Figure 1). These sources relate to both the process itself as well as our ability to measure the process.
Variation is caused both by things we actively control and things that are beyond our control, and can be anticipated (i.e., common cause) or unanticipated (i.e., special cause). The factors that affect the output of a radiation process will depend on whether it is gamma, electron beam, or X-ray, but ultimately, three factors are at play:
The intensity of the radiation activity or energy (the activity of the source or the power of the beam)
The distribution of the radiation (the shape of a scanned beam or placement of sources)
The path of exposure of the product to the source of radiation (conveyor speed or shuffle and dwell timing and positions)
Based on these factors, key parameters can be identified that have a direct effect on dose to product if they are varied during the radiation process.
ISO/TS 11137-4 Table 2 provides a list of process parameters that are critical to radiation sterilization, the effect of the variation of these parameters, and how they are monitored as part of the process. The table provides a starting point for guidance on monitoring process parameters, in addition to dosimetry, to ascertain that product has been processed according to the specifications stipulated in ISO 11137-1:2006/(R)2015, A.10.6.6
There are components of measurement uncertainty that will contribute to variability seen in a routine dosimetry measurement. These include variability inherent in the measurement of dose due to the equipment used to measure it or the dosimeter itself, and variations in the dosimeter placement or products surrounding it.
Additional components of measurement uncertainty may or may not be apparent, including components relating to calibration, as well as influence quantities such as temperature, which may only be observed seasonally.
Establishing Radiation Process Parameters
Minimum and maximum doses to product for the process and their expected variation are determined through replicate direct dose measurements made during process qualification (e.g., product dose mapping). A radiation process can be established based on these dose measurements. Each measurement of dose made during dose mapping is made with a calibrated dosimetry system and a known level of uncertainty.
In order to determine appropriate processing parameters, the variations determined from the dose mapping data are used in conjunction with other information on expected variability to establish minimum and maximum process dose targets designed to verify that a process is in control. ISO/TS 11137-4 describes the following three different approaches that may be used based on the level of information that the operator has about the overall process.
First, in a new site, where there is little to no operating history, components of uncertainty may be estimated based on known or calculated values to account for unknown factors that could contribute to overall process variability. For example, machine variability for an electron-based system may be added to the observed variability from dose mapping if it is not known how this may vary over time. Additional uncertainties can also be added to account for shifts in calibration or to accommodate a wide range of applicable temperatures or other environmental changes that could happen. This is a conservative approach and assumes that all these components add in quadrature. It is anticipated that this starting point is refined over time as more operational history with the system is gained.
Second, at a site that has been operating for years, the variation observed during dose mapping can be compared with past data to see whether a standard process buffer (i.e., level of variation) can be used to set up the range of processing parameters. This is most useful at sites that have a well-documented history of operation and products with dose requirements that allow for this approach, which may also be conservative.
A third method is to design the dose mapping study in such a way that it fully captures both the expected variation of the process—whether it be through additional replicates or replicates made over long time intervals—and the extremes that are expected to be encountered in normal processing. This measured variability, along with any additional variability or uncertainty expected to occur, may then be used to set the targets. The goal is to make an accurate estimate of the true variability of the system.
Additional components related to special causes may be added to account for foreseeable events such as process interrupts or transitions between different products.
During routine processing, the dosimeter locations representing the loading configuration minimum and maximum dose zones may or may not be accessible. In the case where these locations are accessible, process monitoring is straightforward as the routine dose measurement provides a direct measurement that dose specifications are being met. When direct measurements are not available, a routine monitoring location can be used to determine whether the output of a process was delivered as expected or to calculate an indirect measurement of dose to the product.
One of the purposes of the ISO/TS 11137-4 document is to consider how to interpret the routine monitoring location dose results. There are two methods of interpreting this value: 1) as an indirect measurement of minimum and maximum dose to product, or 2) as a monitor to verify the process ran as expected.
Measurement of Product Dose
When routine monitoring dose measurements are used as an indirect measurement of the minimum and maximum dose, there is additional uncertainty associated with the indirect measurement, including the uncertainty associated with the ratio calculation and use of a ratio to make the indirect dose measurement.
The use of a ratio to make this calculation based on a few measurements assumes that the normal variations seen at the routine monitoring position correspond to the same variations seen in dose to product. Often, variation seen in monitoring dosimetry is caused by factors that do not include actual changes to the process, including normal dosimeter variation, environmental influences, and positioning. Even when variations in the monitoring dosimeter are process related (e.g., due to normal variation in dose delivery or conveyance), this does not mean that they are covariant with variations at the maximum or minimum dose to the product.
Therefore, when a maximum or minimum dose is calculated from a routine dose measurement, the uncertainty associated with this calculated measurement needs to account for the extremes in the relationships. Therefore, when the uncertainty associated with this indirect measurement is used to establish process parameters, which ensures that the minimum and maximum doses to the product are achieved, the process can become extremely conservative and restrictive.
There is nothing wrong with an approach that is conservative and provides a high level of confidence; however, when you have tight process specifications or where there is a requirement to optimize a process, there is an equally acceptable alternative.
Measurement of Process Dose
Routine dose measurements can also be used as a process monitor where the expected variation of the routine dose measurement can be utilized to determine whether a process ran as expected, is in a state of control, and delivers the specified product dose. When interpreting the replicate dose measurements made during the process qualification, rather than looking at the ratios of the individual measurements of dose, a probability distribution function associated with measurements of routine, maximum, and minimum doses can be developed to establish a predictable range of expected dose measurements for a given set of process parameters.
The measured dose in routine processing becomes a verification that the process ran as expected rather than a means to calculate an indirect measurement of maximum or minimum product dose.
Case Study: Product Dose Measurement vs. Process Dose Measurement
The following is an example of data from a performance qualification study (i.e., dose mapping) needed to establish routine radiation processing parameters for a medical device. The data (Table 1) represents the variation that is expected (i.e., common cause or planned variation) during routine processing. The data was evaluated to determine minimum and maximum routine dosimetry locations and to establish the baseline expectations for the radiation process (Figure 2).
Product Dose Measurement
During routine processing, a reference dose location—which is neither the minimum nor maximum dose location—will be monitored and measured. A calculation of the dose to product (indirect measurement) will be made using reference dose ratios (including their uncertainty) and the reference location dose measurement to determine conformance to the product specifications.
The reference ratios, along with other components of variability and uncertainty, are then used to evaluate and establish process target doses that will ensure a process can routinely deliver the required minimum and maximum doses to the product.
In this example, a coverage factor (k) of 2, representing a 95% confidence for a two-sided distribution, was used. The expected range of maximum, minimum, and monitoring doses for this process are shown in Figure 3.
The indirect measurement considers the largest potential uncertainty that may have occurred in the ratio and applies it in each indirect measurement, whether it occurred or not. The resultant calculations are used to determine whether the processed product meets the product specifications:
These calculations are used to: a) set a process target dose, b) determine whether your process is capable; and c) evaluate routine processing runs and determine acceptance for release. In the example, the target dose of 31.0 kGy yields an acceptable product dose. This target dose can then be adjusted to determine the appropriate target dose processing range.
Process Dose Measurement
Using the same data set, another acceptable means of determining whether your product met its acceptance criteria is to verify the process ran as expected and was under a state of control. In evaluating the output of a process, a statistical analysis of various parameters from the process can provide a high degree of confidence the radiation process was executed as planned. For this example, the process establishment utilized five replicate process runs, and the dose delivered to product (the absolute minimum and absolute maximum) and a routine monitoring location were monitored. The variability in the dose measurements was assessed and an expected range of doses from future processing runs (under the same process conditions) can be predicted and establishes the baseline for determining whether the process is reproducible and repeatable.
Again, a coverage factor (k) of 2, representing a 95% confidence for a two-sided distribution, was used.
This statistical evaluation can then be used to establish a process target that in turn ensures the product doses are within specification. The expected ranges of maximum, minimum, and monitoring doses for this process are shown in Figure 4.
Process measurement considers the largest potential variability that may occur in each of the three measured locations and establishes a range of predictable doses based on the variability associated with each independent location. The resultant calculations are used to determine whether the process ran as expected and in turn, whether the product met its dose specifications. In this case a target dose between 28.4 kGy and 36.6 kGy can be selected.
Product specifications: 25–40 kGy
Processing target dose: 32.5 kGy
Process monitoring: no special cause variations occurred during processing
Direct measurement of the routine monitoring dose: 32.0 kGy
Expected routine monitoring dose range: 31.0–34.0 kGy
Process conformance: Routine monitoring dose (direct measurement) is within the predicted range for that location, indicating the process delivered an expected dose at the monitoring location, and verifying the process ran as expected and is in a state of control.
Product conformance: As a result of the processing being in a state of control, the qualified process predicts a product dose equal to or greater than 27.3 kGy (lowest dose in the predicted range for minimum dose) and product dose equal to or less than 36.7 kGy (highest dose in the predicted range for maximum dose) will be achieved. Thus, the product is acceptable
Using a statistical analysis, the user can determine whether the output of the radiation process (i.e., dose) was delivered as expected and, in turn, confirm whether the product processed met its acceptance criteria. Thus, if the routine monitoring dose is within the expected range of doses for that location, the user can infer the product received doses between the lowest expected minimum dose (from the calculated range) and the highest expected maximum dose (from the calculated range).
For both methods, statistics calculations are the basis for setting a process target dose. The difference in the methods are whether an indirect measurement of minimum or maximum dose to the product is calculated or the process output is verified to be within the range predicted for the monitoring location.
ISO/TS 11137-4 provides several examples for evaluating and setting radiation process targets when using a product dose measurement or a process dose measurement acceptance process.
Process Optimization Using ISO/TS 11137-4
One of the main advantages of this new guidance document is that it provides a framework for process characterization and optimization by identifying the sources of variation in a process and providing guidance on how to reduce them. Less variation means that lower process target doses can be set, allowing for more efficient process utilization and less risk of process failure for products that have tight dose specifications.
Additionally, methods that use measured variation in setting up a process, as opposed to estimating overall uncertainty or standard process buffers, provide an opportunity to improve overall process efficiency.
In all cases, process data should be analyzed and reviewed to ensure that a process remains in a state of control, and opportunities for improvement are realized (Figure 5).
The industry collaboration that has resulted in the creation of ISO/TS 11137-4 has provided guidance and tools that can be used to set up, monitor, and optimize radiation sterilization processes. Clarity in understanding and interpreting direct and indirect measurements of dose in process control can lead to:
More consistent application and interpretation across the industry.
Reduced potential for accounting for an uncertainty multiple times.
Options to choose the process control approach based on the amount of information known about the irradiator.
The ability to accommodate innovative products that may require a tighter dose range.
The use of process measurements provides an acceptable alternative to traditional methods that require an indirect or direct measurement of minimum and maximum dose as a measure of conformance. Identifying sources of variability provides an avenue to improve and optimize these processes. Either method described in this article provides the acceptable dose range for the product to meet its specification, but there are advantages of the process dose approach for the industry utilizing ISO/TS 11137-4. Overall, this new guidance document can be used to broaden the application of radiation sterilization for products with challenging dose specifications and allow more efficient operation for irradiators.