The Case for Qualifying More Than One Sterilization Modality

The International Irradiation Association (iia) has estimated that contract sterilization volume is distributed at approximately 40.5% gamma, 4.5% electron beam (E-beam), 50% ethylene oxide (EO), and 5% via a variety of modalities (e.g., steam, X-ray).¹  Sterilization modalities are not selected by happenstance; one can expect that a medical device company is using a sterilization modality that is compatible with the material of composition, product configuration, and packaging configuration for a given healthcare product, in order to meet regulatory requirements.

When evaluating sterilization modalities for a line extension, new product development, or business continuity plan (BCP), it is practical for these same companies to look at the modality they are most familiar with or a modality that is already used for similar products in the industry. Therefore, for product development, a speed-to-market approach typically will utilize a sterilization modality already in use. This will reduce the time for validation and follow a known regulatory pathway. BCP approaches may include qualifying a cycle in more than one sterilization chamber at the same site, validating their established process at an alternate sterilization site(s), or qualifying and approving another vendor to deliver their process. In addition, a company may qualify a sterilization process to be performed two or three times as a BCP approach.

Material selection and product configuration often are the drivers for modality selection. Due to an extensive history of well-characterized effects on materials with EO and gamma, as well as the dominance of both modalities in relation to contract sterilization volumes (90.5% per iia report¹ ), stakeholders may make the incorrect assumption that EO and gamma are the only available sterilization modalities that can be used for their products. Considering these factors, new product development teams within companies may perceive the advantage of selecting EO or gamma to be greater than any benefits gained from using an alternate modality as a primary mode of sterilization or using an alternate modality as part of business continuity planning.

Several initiatives in the industry indicate an increased interest in exploring novel sterilization technologies. One driver is innovation surrounding additional combination products that may introduce new drugs, biologics, or materials that are sensitive to heat, moisture, and oxidation.²  These innovative products introduce material compatibility challenges with widely used sterilization modalities. AAMI TIR17, Compatibility of materials subject to sterilization, was updated in 2017 to include guidance on, for example, vaporized peracetic acid, liquid peracetic acid, and nitrogen dioxide sterilization modalities.³  In addition, the International Organization for Standardization (ISO) working group (WG) 16 is developing ISO/CD 22441, Sterilization of health care products—Low temperature vaporized hydrogen peroxide—Requirements for the development, validation and routine control of a sterilization process for medical devices. These initiatives are not happening in isolation; rather, they are influenced by the demands of the industry and the growing pressures facing current sterilization modalities.

EO is used worldwide to sterilize medical devices and has an established history of effectiveness. In the United States, regulatory changes have been proposed at both the national and state levels to reduce EO emissions, including efforts by the Environmental Protection Agency (EPA)⁴  and Texas Commission on Environmental Quality.⁵  As directed by the Illinois Environmental Protection Agency, multiple sterilization facilities were temporarily closed in 2019 because of issues with EO emissions.⁶  Also in 2019, the Food and Drug Administration (FDA) introduced a challenge focused on finding ways to reduce EO emissions.⁷ 

Potential changes to EPA regulations and the FDA's challenge to reduce EO emissions have prompted contract sterilizers and medical device manufacturers that perform sterilization in-house to evaluate improvements to their EO emission controls systems and explore ways of optimizing their processes to reduce the amount of EO used. The FDA also issued a challenge related to identifying new sterilization methods and technologies.⁸  Although the device industry may have developed the impression that selecting only “traditional” sterilization modalities (i.e., EO, gamma, E-beam, moist heat, dry heat) would be accepted by regulators, the FDA's challenge clearly indicated its willingness to review alternate sterilization modalities.

The absence of capacity, or limited capacity, at a contract sterilizer can have a significant impact on the industrial sterilization network. For example, multiple site closures in the United States in 2019 had a direct impact on the industrial EO sterilization network, as it reduced the available capacity to sterilize medical devices.⁶  The closure of contract sites prompted a series of disruptions that led medical device manufacturers to discontinue production, immediately validate at a new location, or activate their BCP to continue supplying product to customers.

In cases where validation was required, the supply of medical devices was affected because validation efforts can take several weeks or even months depending on the availability of sterilization equipment, resources to execute the validation, and incubation times for the microbiological quality testing needed for validation. In the event that a medical device manufacturer determines that it must validate at an alternate supplier for contract sterilization services, one would expect the company to review its approved supplier network, thereby avoiding the necessary time and resources required to qualify a new supplier. Closures of contract sites also bring inherent challenges at the remaining contract sites, as the influx of additional customers can have a direct impact on the turnaround time for previously existing customers. For a medical device manufacturer that previously validated a secondary site for business continuity planning, that secondary site becomes the primary sterilization site and the manufacturer must now develop a backup to this new primary sterilization site.

Gamma sterilization is considered effective and reliable and is conducted by a large network of facilities worldwide. However, gamma sterilization has faced challenges in the sourcing of cobalt-60 (Co-60), as described in the 2019 report from the iia.⁹  In addition to shortages, Co-60 poses safety and security risks, as reported by the International Atomic Energy Agency.¹⁰ 

The perpetually increasing market for medical devices has burdened the available gamma sterilization capacity. For example, data presented at the 2019 International Meeting on Radiation Processing provided an estimated average compound annual growth rate of 5% for Europe and Asia across EO, gamma, E-beam, and X-ray modalities.⁹  E-beam is a good complement to gamma but has inherent limitations with penetration related to high-density products. X-ray is known to have a penetration capability comparable with gamma, and approximately five facilities worldwide offer industrial X-ray sterilization services. In addition, expansion projects have been announced recently, with more X-ray sterilization facilities under construction in North America, Europe, and Asia.

Shortages of available EO sites and Co-60 have placed challenges on the supply chain and, in turn, affected healthcare delivery organizations (HDOs) and other users of medical devices. Given this situation, the manufacturing of additional products might provide a buffer for the additional time needed to deliver products to HDOs (i.e., to accommodate increased processing time). If this action is taken, the healthcare industry also must be aware of the burden that an influx of additional product would place on the available sterilization capacity. Therefore, the question becomes: “Is the supply chain prepared for a disruption?”

Shifting all products from a primary to a backup sterilization site does not imply that product volume (cubic footage) can be processed in the same amount of time. A change from one sterilization site to another also affects regulatory agencies. Does the regulatory agency have the capacity to handle the influx of submissions with a sudden disruption in network capacity? This change is not instantaneous and involves an added layer of complexity within the supply chain to manage product distribution as regulatory approval is obtained in different markets.

If bias is removed related to designing a product for sterilization, what approach should be taken? A product development team could move the exploration of multiple sterilization modalities to earlier in the design control/product design process. Following product launch, product development resources to support exploration of alternate sterilization modalities might be limited due to availability. Depending on the state of product inventory, waiting to explore an alternate sterilization modality at the time of need could result in supply issues and, therefore, affect access to medical devices by health professionals and patients. The time it takes to react to a disruption could come at the cost of patient care.

The current challenges could be overcome in a variety of ways. The evaluation/development of multiple sterilization modalities could occur during the product design phase or after the product is available in the market. (These options are further explored below.) The timing for addressing the exploration of modalities might depend on the number and types of products (e.g., device classification) already in the market, as well as the number of new products envisioned to be developed in the future. If the process is designed to speed products to market, a company might choose to address the development of one sterilization modality during product design and commit resources to developing an additional sterilization modality after the product reaches market.

However, if a company has potential products in its pipeline that might be incompatible with current sterilization modalities, the initial exploratory studies evaluating additional sterilization modalities should occur as part of the research-and-development (R&D) process. If alternate sterilization modalities are evaluated during the R&D process, a body of knowledge would be available to support future products.

Having more than one sterilization modality option will provide a medical device company with flexibility when responding to industry capacity constraints and future product needs. Validating multiple modalities allows a company to be agile and dynamic, helping it deliver products quickly to customers and respond to current and future challenges. It also can help expand a company's materials compatibility database, which may speed up material selection during product development.

Keeping an open mind and eliminating sterilization modality bias when selecting the path forward may not be common practice. Biases often can direct an organization down the path of least resistance, resulting in short-term gains but limited long-term benefits. The following two scenarios describe the benefits of exploring multiple modalities (1) during new product development and (2) for a predicate device with a preselected modality.

The FDA guidance on design controls contains common phases, such as design planning, design verification, and design validation. The selection of sterilization modality and validation was included in a list of examples to be considered as part of design inputs.¹¹  Value can be added by involving sterilization subject matter experts (SMEs) at the onset of the design phase. Sterilization SME input can help expand the options of available and compatible modalities. For example, materials that have detrimental effects resulting from sterilization conditions during design verification may force manufacturers to adjust sterilization parameters, such as using a relatively low maximum acceptable dose to accommodate product specifications. This can limit processing range, cause inefficient loading configurations, or restrict resterilization capabilities.

This scenario considers sterilization modality selection during the development of a new product. Early collaboration can help make the connections between the materials selected and their respective product functionality requirements, thereby eliminating certain options immediately. A product that is not heat or moisture sensitive may be compatible with dry heat, moist heat, gaseous sterilants (e.g. EO, vaporized hydrogen peroxide, nitrogen dioxide), and even radiation. A product that is not prone to radiation degradation may work with either gamma, E-beam, or X-ray.

Most of this work can be outlined with a sterilization SME up front to minimize validation efforts following product launch. Speed to market commonly is a high priority. Therefore, one may select and establish one method as the primary mode and explore an alternate method in parallel as a backup. When engaged early, the sterilization SME can provide valuable insight, including material selection recommendations, package design recommendations, and recommendations that allow for supply chain optimization.

Based on information available in TIR17, peer-reviewed articles, and experience, a sterilization SME can combine his/her understanding of product functionality and knowledge of the sterilization processes to identify the optimal material for a robust product design. For example, a predetermined radiation dose may be used to cross-link a polymer used in a device for which the functional requirement is tensile strength. A heated sterilization process (e.g., dry heat, EO) may enhance the performance of a component by further curing of an adhesive.

The selection of materials should not be focused solely on the functionality of the materials. How the materials will respond to the sterilization modality in the final finished design should also be considered. Functionality of materials might change based on the extrusion properties for plastics and the specific heat of metals. Product functionality is tested following initial exposure to the sterilization process and following a shelf-life study that might incorporate accelerated aging studies. However, initial exploratory studies may direct product design engineers in the appropriate direction prior to finalizing the materials selected.

Equipped with an understanding of the available sterilization modalities, a sterilization SME can provide packaging material and configuration recommendations compatible with the selected modality or multiple sterilization modalities. If the product requires nonporous packaging to maintain product integrity or moisture, a sterilization modality that does not require porosity for access of the sterilant to the product should be explored (e.g., radiation). If the product requires a tray for the presentation of the product to the operating field, final packaging design should be developed with sterilization in mind. As with product materials, the selection of appropriate packaging designs and materials can limit or expand the options that might be explored for sterilization modalities. The use of initial exploratory studies might support the selection of multiple sterilization modalities.

A sterilization SME can determine the appropriate sterilization modalities that might be selected with an understanding of the future anticipated product volume, product/packaging materials and designs, and results of initial exploratory studies. This information may also provide the data needed to decide between internal sterilization and external contract sterilization services. If internal sterilization is selected, the current internal capacity can be compared with the time to procure, install, and validate additional sterilization equipment. If internal sterilization is selected and capacity is constrained, external contract sterilization might be used while additional equipment capacity is installed. If external sterilization is selected, the options for contract sterilization can be evaluated for location, capacity, and compatibility. This would allow for multiple sites to be selected for validation and provide the BCP necessary for the chosen sterilization modalities.

Validating a secondary sterilization modality may not be feasible because of a product's materials of construction, because of the need for getting a new product to market quickly, or if a product (or product line) has been on the market for a long period of time and the original validation was conducted using only one sterilization modality.

Evaluating alternate sterilization modalities may indicate the need to change materials of construction or include additives to the materials to allow for the use of an alternate sterilization method. For example, adding antioxidants to plastics might allow a radiation sterilization method to be used. However, several products might not allow for a secondary modality and may require business continuity planning of the single sterilization modality. If the product is a legacy product or if a secondary sterilization modality was not evaluated during the product development phase because of a need to reach market quickly, this testing can be conducted as part of the product's life cycle management and may/may not require changes to support an alternate sterilization modality.

This scenario considers a portfolio of legacy products that were previously validated using only one sterilization modality: gamma. Products that have a legacy of being qualified using gamma might have a convenient pathway for qualifying a secondary radiation modality, such as converting to X-ray and/or E-beam. For this scenario, two areas need to be considered: the microbiological qualification and the physical/process qualification. The validation of a second radiation modality can be straightforward if the sterilization dose and the maximum acceptable dose allowed (i.e., validated dose range) remain the same and if one satisfies certain conditions following guidance provided in ANSI/AAMI/ISO 11137-1:2006/(R)2015.¹² 

For the sterilization dose (microbiological qualification), a successful repeat of the verification dose experiment with the new radiation modality might be the extent of additional work required for transferring the sterilization dose from one radiation modality to the second radiation modality. For the maximum acceptable dose allowed, the testing to support this portion of the qualification might require considerably more work, as it deals with material compatibility. The primary area of concern could be the potential impact on product materials if the doses that might be observed during routine sterilization with X-ray or E-beam exceed those approved for gamma. However, testing may be minimized if the doses observed during routine sterilization can be maintained below the qualified maximum dose for gamma processing. Product packaging and product loading patterns might be adjusted to allow for processing within the validated dose range.

For this example, the selection of a secondary radiation modality might be easily qualified for X-ray. X-ray has similar penetration capability to gamma, which may support maintaining the current load configuration (as presented during routine sterilization processing). Minimal qualifications are required when transferring from a low-dose rate (e.g., gamma) to high-dose rate (e.g., E-beam), as described in 11137-1 when considering the transfer of maximum acceptable dose between radiation sources.¹²  The AAMI sterilization standards WG 2 is drafting TIR104, which will provide additional guidance on converting radiation technologies.

For this scenario, given his/her understanding of the future anticipated product volume and additional testing of alternate radiation sterilization modalities (e.g., X-ray, E-beam), a sterilization SME can determine the secondary sterilization modality that might be selected. Qualifying E-beam or X-ray sterilization as a second modality opens the possibility for in-house sterilization. The decision to select E-beam or X-ray will rely on volume, product density, and loading configuration. In-house sterilization can be the new primary source, with gamma as backup, thereby allowing for just-in-time sterilization, reduced turnaround time, and a decrease in product inventory.

When selecting external contract services, factors that should be considered include vendor competency in managing complex equipment and speed to market (utilizing existing infrastructure).

For product supply chain sustainability, more than one sterilization modality should be validated for products that are compatible with multiple modalities. The validation of more than one sterilization modality will provide medical device companies with flexibility when responding to high product demand and sterilization supply chain interruptions. A BCP that includes validating and maintaining validation of both sterilization modalities should be considered. In addition, the BCP also should take into account the potential to validate multiple sterilization sites for supply chain flexibility. For products designed to allow for multiple sterilization modalities, the BCP becomes more robust and allows for constructive conversations regarding turnaround time, processing flexibility, and resources. These advantages are possible with a best-in-class sterilization program that allows for sterilization SME engagement in the early stages of product development.