Mark Crawford, Contributing Writer02.17.16
Sterilization is one of the most important parts of the entire medical device manufacturing process. An MDM can have an innovative, top-line product, but if it can’t be sterilized properly, it won’t make it very far into the marketplace. MDMs rely on their suppliers to be up to speed on the latest developments in sterilization and to deliver the right process for their products. As a result, the sterilization industry is robust, with providers building new locations or increasing capacity to meet customer demands. Consolidation is also going on—for example, Sterigenics’ acquisition of Nordion in 2014 and Synergy Health Plc in 2015. A few larger companies are bringing traditional technologies such as ethylene oxide sterilization (EO) and gamma radiation in-house to gain efficiencies; most smaller companies and startups continue to outsource sterilization.
Large-scale industrial sterilization, which relies on the well-established EO and gamma radiation processes, hasn’t changed much in decades. MDMs, following the “if it ain’t broke, don’t fix it” mindset, are reluctant to try new technologies if they don’t have to. This, however, is starting to change—as products become more complex, more companies are considering newer processes such as super-critical carbon dioxide and nitrogen dioxide. Combination products, for example, with narrower specifications, complex geometries, and multi-modality sterilization requirements, present unique sterilization challenges. Inner spaces are harder to reach and some devices may have to be disassembled to be properly sterilized. New devices may also contain advanced electronics, which can complicate sterilization.
“With the upswing of technologies in electronics, robotics, and plastics, more complex devices are being designed, packaged, and submitted for ethylene oxide sterilization,” said Bill South, EO Tech Team manager for STERIS Applied Sterilization Technologies, a Mentor, Ohio-based provider of contract radiation and ethylene oxide sterilization. “Some contain hazardous components such as live batteries and capacitors that must be closely monitored, with safeties devised to assure they remain inactive during the sterilization process.”
Another challenge is increased regulatory scrutiny, especially for more complex devices. For example, sterilization methods and processes came into question during the recent antibiotic-resistant "superbug" outbreak that was linked to improper cleaning of duodenoscopes. The multiple patient deaths that resulted now have many leaders in healthcare considering alternative sterilization processes. Because of these and other concerns, the effectiveness of sterilization methods is being closely examined by the U.S. Food and Drug Administration (FDA), especially for validation testing.
“There is a greater need for additional aspects of validation, like dry time and thermal profiling, in order to have greater confidence that the sterilization methods and parameters being provided to hospitals will truly sterilize all devices within the sets,” said Meredith May, vice president of Empirical Consulting, a Colorado Springs, Colo.-based provider of sterilization and contamination validation and testing quality/regulatory consultation.
Speed and Flexibility
OEMs are pushing their sterilization partners for more speed and flexibility, and lower costs. They also want more of their devices to be compatible with different types of sterilization modalities, reducing the potential for disruption with their critical supply chain vendors. There is also increased emphasis on just-in-time manufacturing and expedited sterilization.
“OEMs continue to focus on supply chain efficiencies related to faster turn times,” said Tim Skordahl, reusable devices program manager for Biotest Laboratories, a subsidiary of STERIS. “The demand for expedited processing has increased. Efficiencies related to faster product release to market, such as conversion from sterility test release to parametric release in EO, continues to be prevalent.”
Another recent trend is the production of smaller lots of product. In the past, device manufacturers had very little choice if they produced lots with small volumes; these devices were basically included with large device batches already being sterilized by contract sterilization companies. “However, 3M has recently come out with a newly FDA 510(k)-cleared EO sterilizer, and also released its GSX series of EO sterilizers, which are a perfect fit for life science applications and sterilization of smaller lots of components and medical devices by the OEM manufacturer themselves,” said Gary Socola, president of HIGHPOWER Validation Testing and Lab Services Inc., a Rochester, N.Y.-based provider of testing and consulting services to medical device manufacturers.
Almost all manufacturers have conducted reviews of their supply chains and costs in recent years. When considering a switch to a newer sterilization technology, not only do they want proof of effectiveness and cost compared to EO or gamma radiation, they also want to know turnaround speed—especially for just-in-time manufacturing. For example, nitrogen dioxide sterilization, which is gaining in popularity, has a very short cycle time—typically about two to four hours—which also includes aeration.
“If product arrives on day one, it is inspected immediately and processed through one of the sterilization units the next day,” said Maura O. Kahn, vice president of business development and marketing for Noxilizer Inc., a Baltimore, Md.-based provider of nitrogen dioxide sterilization. “While the customer still has the transportation costs, the turnaround time is only two to three days—much shorter than the two to four weeks typically required for the large contract sterilization companies.”
Another way to reduce costs is by installing sterilization equipment on-site in an existing manufacturing facility. This eliminates transportation costs for the customer. Inventory carrying costs are also minimized because the sterilization cycle is completed in hours instead of days with a process like EO. “In the financial analyses we have done with customers comparing in-house versus contract sterilization, we find that purchasing NO2 sterilizers reduces sterilization costs by 50 percent, with a payback on the investment of 16 months,” said Kahn.
More Complexity, More Challenge
As new materials and more complex delivery systems come into the market, contract sterilizers must be ahead of the game in finding and implementing effective sterilization solutions. Top challenges include combination materials and 3D-printed devices.
“Combination materials, such as hydroxylapatite (HA)-infused polyether ether ketone (PEEK), titanium-coated PEEK, and HA-coated titanium raise questions about the effect of the chemicals and temperatures on the coating-to-substrate bond,” said May. “In addition, 3D-printed devices with complex interior features make cleaning, and confirmation of the effectiveness of the cleaning, nearly impossible. Therefore, most of these devices must be delivered terminally sterile.”
Heat-sensitive products and materials, such as many drug/device combination products, are especially challenging to sterilize. Many of these cannot safely and effectively go through EO or radiation sterilization processes. Ideally the process needs to take place at room temperature or sub-room temperature with short cycle times. Suitable low-temperature gas sterilization methods include carbon dioxide, nitrogen dioxide, and hydrogen peroxide (these can also sometimes be used in conjunction with a standard process).
“For device sterilization by users in healthcare facilities, steam is the most popular sterilization process that our OEM customers ask our laboratory to validate sterilization efficacy studies for,” said Socola. “However, low-temperature sterilization processes like hydrogen peroxide continue to gain more popularity each year. These two sterilization processes combined are the one-two punch in healthcare facilities.”
From an operational perspective, manufacturers want to know the pricing and turnaround time from a contract sterilization provider are competitive and reliable—they don’t want any surprises that slow down the process. Therefore, most MDMs want to follow “standard” sterilization methods; however, sterilization challenges related to more advanced materials and complex designs are forcing them to consider alternative methods.
“With the status quo as entrenched as it is, alternative sterilization methods typically aren’t asked for until an R&D project comes to a halt because of limitations of legacy sterilization methods,” said Matt Conlon, general manager of REVOX Sterilization Solutions, a Minneapolis, Minn.-based provider of a room-temperature vaporized peracetic acid (VPA) sterilant process. “Then it becomes an urgent issue, which either requires a novel approach to sterilization or a product re-design to accommodate legacy sterilization methods.”
The REVOX technology is a true room-temperature (18-30 degrees Celsius) process utilizing vaporized peracetic acid. Because the chemical components break down into simple carbon dioxide, oxygen, and water, VPA requires no special ventilation, blast-proof walls, or large capital investment to use on-site. “Over the past 18 months, we’ve successfully processed the most complex and delicate devices, and are introducing a two-pallet industrial system to match its technical ability with industrial scale throughput requirements,” said Conlon.
EO and Radiation Still Strong
Medical devices are becoming more sophisticated. From implantable drug delivery or monitoring devices to biologic therapies or combination drug-device products, the inclusion of new materials and more sophisticated designs brings new challenges to the sterilization field, which has not seen an industrial breakthrough in over 20 years. In most cases, an effective sterilization method can still be found for most categories of products, but each sterilization method has its limitations in terms of being able to accommodate both simple “widgets” as well as complex or delicate assemblies. Finding the right sterilization solution takes in-depth know-how and innovative thinking.
“On the ‘delicate’ side of the sterilization equation are products like biologics, enzyme-coated devices, or tissue that may be affected by increased temperatures associated with sterilization,” said Conlon. “On the ‘complex’ side are products like long lumen stents or implantable drug-delivery devices, where sterilization needs to occur across or down lumens, while not adversely impacting the drug or device itself. This creates the need for a patchwork of various methods to accommodate each product design in the most effective, efficient manner.”
OEMs seek more creative solutions with respect to sterilization methods or sterilization cycles. As their products become more complex, traditional sterilization methods and cycles must be improved/enhanced to assure product functionality post-sterilization. For example, Martell Winters, senior scientist and consulting manager for Nelson Laboratories, a Salt Lake City, Utah-based provider of testing and consulting services, continues to see new versions of tissue products and new combination products that often require something “out of the ordinary” with respect to sterilization cycles. “The typical radiation doses of 25 kGy and the EO cycles with typical high humidity and temperature sometimes need to be adjusted to allow for sterilization to 10-6 without causing significant degradation to the product functionality,” he said.
Sterilization cycles can be made more efficient through dynamic aeration and all-in-one processing. Sterilization providers are also upgrading to new controller and monitoring technologies and integrating outputs into new IT platforms, which make it easier to monitor the sterilization process and extract processing, supply change, and quality data. Novel cycles involving temperature, pressure, and gas dynamics are also evolving to address complex devices and a demand for lower product EO gas residuals.
“Parametric release, all-in-one processing, cold temperature processing, and custom cycle development using dynamic conditioning and aeration reiterations are becoming more commonplace for ethylene oxide,” confirmed South. “The industry and manufacturers are working to develop a common strategic approach to sensors used for parametric release processing.”
Nelson Labs has also worked with customers to validate low-temperature, low-humidity EO methods for products that are sensitive to both temperature and humidity. “This requires many qualification cycles to determine the happy medium between microorganism reduction and product functionality,” said Winters.
Sometimes a new or improved technology isn’t always the solution to a sterilization issue—it may just require an adjustment or two to the mechanics of the process itself. For example, many sterilization failures can be mitigated through careful evaluation of the caddies and trays that are used to house implants and instruments during sterilization and transportation. “The fit between the brackets and the instruments is critical to the success of both sterilization validation and distribution testing,” said May. “If the fit is too tight, the area will not receive enough steam to sterilize. If the fit is too loose, the instruments will come out during shipping.”
Regulatory Changing Too
Although the FDA has maintained a steady position on industrial and healthcare sterilization of single-use and reusable medical devices in recent years, it has dramatically changed its requirements for “cleaning validations” being performed on reusable medical devices. For example, its March 2015 guidance document placed more emphasis on cleaning validations than device sterilization.
“If the device is going to be delivered non-sterile with cleaning and sterilization instructions, the FDA will expect to see proof that your cleaning validation is complete and that your steam sterilization validation plan meets the expectations of all the guidance documents,” said May. “This is a shift from previous years, when the FDA accepted a promise that these validations would be complete prior to commercialization.”
Standards and guidance documents continue to evolve to assure sterilization method effectiveness, reproducibility, and safety. Revisions of ISO standards on sterilization are being written to clarify that the manufacturer owns all aspects of the sterilization process—even when sterilization is performed at an off-site contractor facility. FDA audits also tend to be more in-depth than ever before.
“Notified bodies have requested that they have the ability to perform unannounced audits and are requiring that the manufacturers insert statements to that effect into sterilization quality contracts,” said South. “The use of detailed quality contracts, in addition to statements in business contracts with sterilizers, is on the rise.”
Kahn reports that FDA reviewers have been requesting that the exterior surfaces of syringes used in the sterile field be sterilized as a final manufacturing step—especially for ophthalmic products. In response, manufacturers have been asking for a process that will sterilize the exterior of the syringe, while leaving the contents, which have been aseptically filled, unaffected—a perfect application for nitrogen dioxide sterilization.
“This process offers an important benefit for drug delivery systems—a low-temperature sterilization process that can be applied at near-ambient pressures,” she said. “Owing to the relatively short duration of contact with the NO2 sterilant, the risk of diffusion of NO2 past the container-closure barrier is minimized, if not eliminated.”
The sterilization method is as important to the regulatory process as any other criteria for product clearance, and testing and documentation of efficacy and safety are critical. As expected, increased regulatory scrutiny associated with new industrial sterilization methods, whether by the FDA or other international regulatory bodies, can be daunting.
“While a new sterilization method brings with it increased regulatory scrutiny, when the fundamentals of efficacy and safety are thoroughly demonstrated, it can receive regulatory approval, as we’ve shown,” said Conlon. “REVOX is the first new sterilization technology to be used for FDA-cleared devices in more than two decades. It was also used for Class-II clinical trial products in two European countries.”
Nelson Labs also works with companies to help them understand future Association for the Advancement of Medical Instrumentation (AAMI) and ISO expectations for sterilization testing. AAMI document ST67 helps address the selection of appropriate sterility assurance levels (SAL) for products. This document has been an FDA consensus standard, which is applicable for all products that need to be sterilized. It allows a company to rationalize use of an alternate SAL (e.g., 10-3, 10-4, or 10-5) if the sterilization process to an SAL of 10-6 renders the product nonfunctional.
“These rationalizations are meant to include significant product testing and a risk-based assessment,” said Winters. “Currently, AAMI is revising this document in an effort to provide some additional guidance and clarification on the rationale. ISO Working Group 15 has also been established to address the same issue of SAL for healthcare products on an ISO level.”
Moving Forward
The rate of change in the sterilization market tends to be slow; it is, however, starting to accelerate, thanks to more complex medical devices, new materials, and regulatory expectations. Although there are opportunities for new technologies and new players, the barriers for getting a new sterilization method into the market are still high—including convincing medical device manufacturers of their worth.
“The largest medical device and pharmaceutical companies in the world aren’t going to move away from traditional modes of sterilization unless the new sterilization processes have been thoroughly validated, are reproducible, and have been investigated by their regulatory affairs and quality assurance, production, and validation teams,” explained Socola.
That said, there is a definite need for more economical sterilization processes that allow the processing of a wider range of complex instruments and materials in the shortest amount of time—but development and approval is not an easy process either.
“Any new nontraditional sterilization process looking to be sold to the U.S. healthcare market requires an immense amount of test data, which is compiled and reviewed by the FDA during the 510(k) clearance process,” said Socola. “New processes can take years to get through the FDA’s Office of Device Evaluation.”
Forward-thinking contract sterilizers are starting to redesign their sterilization platforms to provide more options. Manufacturers must approach sterilization with an eye for flexibility and not be locked into a single sterilization method.
“Plan early and build in options with respect to sterilization,” advised Thad Wroblewski, vice president of sales for STERIS Applied Sterilization Technologies. “Build in redundant processing ability into products. Manufacturers with a broad vision will be able to position their businesses with sterilization options in the future, providing a competitive edge.”
Contract sterilizers will be expected to fulfill more needs in the future, and their OEM customers will expect them to have the answers. This need for integrated thinking is why contract sterilizers should work with their customers very early in the design process. Product development teams that do not consider sterilization increase the risk that the materials selected and/or the design will not be compatible with any sterilization method.
“Considering sterilization as early as possible in the design and development process is ultimately a cost-saving procedure,” said Kahn. “It cuts down on the need to modify drawings, tooling, and work instructions to accommodate late changes for sterilizability.”
Conlon notes that the real breakthroughs resulting from technologies such as REVOX will come when, at the materials science level, new substances that previously could not withstand the sterilization process, become materials of choice that broaden the possibilities of product design.
“These new materials may be the difference in the technical or commercial feasibility of the next life-saving device or therapeutic—which had been limited in the past by such a rudimentary process as sterilization,” he said.
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders. He also writes a variety of feature articles for regional and national publications and is the author of five books. Contact him at mark.crawford@charter.net.
Large-scale industrial sterilization, which relies on the well-established EO and gamma radiation processes, hasn’t changed much in decades. MDMs, following the “if it ain’t broke, don’t fix it” mindset, are reluctant to try new technologies if they don’t have to. This, however, is starting to change—as products become more complex, more companies are considering newer processes such as super-critical carbon dioxide and nitrogen dioxide. Combination products, for example, with narrower specifications, complex geometries, and multi-modality sterilization requirements, present unique sterilization challenges. Inner spaces are harder to reach and some devices may have to be disassembled to be properly sterilized. New devices may also contain advanced electronics, which can complicate sterilization.
“With the upswing of technologies in electronics, robotics, and plastics, more complex devices are being designed, packaged, and submitted for ethylene oxide sterilization,” said Bill South, EO Tech Team manager for STERIS Applied Sterilization Technologies, a Mentor, Ohio-based provider of contract radiation and ethylene oxide sterilization. “Some contain hazardous components such as live batteries and capacitors that must be closely monitored, with safeties devised to assure they remain inactive during the sterilization process.”
Another challenge is increased regulatory scrutiny, especially for more complex devices. For example, sterilization methods and processes came into question during the recent antibiotic-resistant "superbug" outbreak that was linked to improper cleaning of duodenoscopes. The multiple patient deaths that resulted now have many leaders in healthcare considering alternative sterilization processes. Because of these and other concerns, the effectiveness of sterilization methods is being closely examined by the U.S. Food and Drug Administration (FDA), especially for validation testing.
“There is a greater need for additional aspects of validation, like dry time and thermal profiling, in order to have greater confidence that the sterilization methods and parameters being provided to hospitals will truly sterilize all devices within the sets,” said Meredith May, vice president of Empirical Consulting, a Colorado Springs, Colo.-based provider of sterilization and contamination validation and testing quality/regulatory consultation.
Speed and Flexibility
OEMs are pushing their sterilization partners for more speed and flexibility, and lower costs. They also want more of their devices to be compatible with different types of sterilization modalities, reducing the potential for disruption with their critical supply chain vendors. There is also increased emphasis on just-in-time manufacturing and expedited sterilization.
“OEMs continue to focus on supply chain efficiencies related to faster turn times,” said Tim Skordahl, reusable devices program manager for Biotest Laboratories, a subsidiary of STERIS. “The demand for expedited processing has increased. Efficiencies related to faster product release to market, such as conversion from sterility test release to parametric release in EO, continues to be prevalent.”
Another recent trend is the production of smaller lots of product. In the past, device manufacturers had very little choice if they produced lots with small volumes; these devices were basically included with large device batches already being sterilized by contract sterilization companies. “However, 3M has recently come out with a newly FDA 510(k)-cleared EO sterilizer, and also released its GSX series of EO sterilizers, which are a perfect fit for life science applications and sterilization of smaller lots of components and medical devices by the OEM manufacturer themselves,” said Gary Socola, president of HIGHPOWER Validation Testing and Lab Services Inc., a Rochester, N.Y.-based provider of testing and consulting services to medical device manufacturers.
Almost all manufacturers have conducted reviews of their supply chains and costs in recent years. When considering a switch to a newer sterilization technology, not only do they want proof of effectiveness and cost compared to EO or gamma radiation, they also want to know turnaround speed—especially for just-in-time manufacturing. For example, nitrogen dioxide sterilization, which is gaining in popularity, has a very short cycle time—typically about two to four hours—which also includes aeration.
“If product arrives on day one, it is inspected immediately and processed through one of the sterilization units the next day,” said Maura O. Kahn, vice president of business development and marketing for Noxilizer Inc., a Baltimore, Md.-based provider of nitrogen dioxide sterilization. “While the customer still has the transportation costs, the turnaround time is only two to three days—much shorter than the two to four weeks typically required for the large contract sterilization companies.”
Another way to reduce costs is by installing sterilization equipment on-site in an existing manufacturing facility. This eliminates transportation costs for the customer. Inventory carrying costs are also minimized because the sterilization cycle is completed in hours instead of days with a process like EO. “In the financial analyses we have done with customers comparing in-house versus contract sterilization, we find that purchasing NO2 sterilizers reduces sterilization costs by 50 percent, with a payback on the investment of 16 months,” said Kahn.
More Complexity, More Challenge
As new materials and more complex delivery systems come into the market, contract sterilizers must be ahead of the game in finding and implementing effective sterilization solutions. Top challenges include combination materials and 3D-printed devices.
“Combination materials, such as hydroxylapatite (HA)-infused polyether ether ketone (PEEK), titanium-coated PEEK, and HA-coated titanium raise questions about the effect of the chemicals and temperatures on the coating-to-substrate bond,” said May. “In addition, 3D-printed devices with complex interior features make cleaning, and confirmation of the effectiveness of the cleaning, nearly impossible. Therefore, most of these devices must be delivered terminally sterile.”
Heat-sensitive products and materials, such as many drug/device combination products, are especially challenging to sterilize. Many of these cannot safely and effectively go through EO or radiation sterilization processes. Ideally the process needs to take place at room temperature or sub-room temperature with short cycle times. Suitable low-temperature gas sterilization methods include carbon dioxide, nitrogen dioxide, and hydrogen peroxide (these can also sometimes be used in conjunction with a standard process).
“For device sterilization by users in healthcare facilities, steam is the most popular sterilization process that our OEM customers ask our laboratory to validate sterilization efficacy studies for,” said Socola. “However, low-temperature sterilization processes like hydrogen peroxide continue to gain more popularity each year. These two sterilization processes combined are the one-two punch in healthcare facilities.”
From an operational perspective, manufacturers want to know the pricing and turnaround time from a contract sterilization provider are competitive and reliable—they don’t want any surprises that slow down the process. Therefore, most MDMs want to follow “standard” sterilization methods; however, sterilization challenges related to more advanced materials and complex designs are forcing them to consider alternative methods.
“With the status quo as entrenched as it is, alternative sterilization methods typically aren’t asked for until an R&D project comes to a halt because of limitations of legacy sterilization methods,” said Matt Conlon, general manager of REVOX Sterilization Solutions, a Minneapolis, Minn.-based provider of a room-temperature vaporized peracetic acid (VPA) sterilant process. “Then it becomes an urgent issue, which either requires a novel approach to sterilization or a product re-design to accommodate legacy sterilization methods.”
The REVOX technology is a true room-temperature (18-30 degrees Celsius) process utilizing vaporized peracetic acid. Because the chemical components break down into simple carbon dioxide, oxygen, and water, VPA requires no special ventilation, blast-proof walls, or large capital investment to use on-site. “Over the past 18 months, we’ve successfully processed the most complex and delicate devices, and are introducing a two-pallet industrial system to match its technical ability with industrial scale throughput requirements,” said Conlon.
EO and Radiation Still Strong
Medical devices are becoming more sophisticated. From implantable drug delivery or monitoring devices to biologic therapies or combination drug-device products, the inclusion of new materials and more sophisticated designs brings new challenges to the sterilization field, which has not seen an industrial breakthrough in over 20 years. In most cases, an effective sterilization method can still be found for most categories of products, but each sterilization method has its limitations in terms of being able to accommodate both simple “widgets” as well as complex or delicate assemblies. Finding the right sterilization solution takes in-depth know-how and innovative thinking.
“On the ‘delicate’ side of the sterilization equation are products like biologics, enzyme-coated devices, or tissue that may be affected by increased temperatures associated with sterilization,” said Conlon. “On the ‘complex’ side are products like long lumen stents or implantable drug-delivery devices, where sterilization needs to occur across or down lumens, while not adversely impacting the drug or device itself. This creates the need for a patchwork of various methods to accommodate each product design in the most effective, efficient manner.”
OEMs seek more creative solutions with respect to sterilization methods or sterilization cycles. As their products become more complex, traditional sterilization methods and cycles must be improved/enhanced to assure product functionality post-sterilization. For example, Martell Winters, senior scientist and consulting manager for Nelson Laboratories, a Salt Lake City, Utah-based provider of testing and consulting services, continues to see new versions of tissue products and new combination products that often require something “out of the ordinary” with respect to sterilization cycles. “The typical radiation doses of 25 kGy and the EO cycles with typical high humidity and temperature sometimes need to be adjusted to allow for sterilization to 10-6 without causing significant degradation to the product functionality,” he said.
Sterilization cycles can be made more efficient through dynamic aeration and all-in-one processing. Sterilization providers are also upgrading to new controller and monitoring technologies and integrating outputs into new IT platforms, which make it easier to monitor the sterilization process and extract processing, supply change, and quality data. Novel cycles involving temperature, pressure, and gas dynamics are also evolving to address complex devices and a demand for lower product EO gas residuals.
“Parametric release, all-in-one processing, cold temperature processing, and custom cycle development using dynamic conditioning and aeration reiterations are becoming more commonplace for ethylene oxide,” confirmed South. “The industry and manufacturers are working to develop a common strategic approach to sensors used for parametric release processing.”
Nelson Labs has also worked with customers to validate low-temperature, low-humidity EO methods for products that are sensitive to both temperature and humidity. “This requires many qualification cycles to determine the happy medium between microorganism reduction and product functionality,” said Winters.
Sometimes a new or improved technology isn’t always the solution to a sterilization issue—it may just require an adjustment or two to the mechanics of the process itself. For example, many sterilization failures can be mitigated through careful evaluation of the caddies and trays that are used to house implants and instruments during sterilization and transportation. “The fit between the brackets and the instruments is critical to the success of both sterilization validation and distribution testing,” said May. “If the fit is too tight, the area will not receive enough steam to sterilize. If the fit is too loose, the instruments will come out during shipping.”
Regulatory Changing Too
Although the FDA has maintained a steady position on industrial and healthcare sterilization of single-use and reusable medical devices in recent years, it has dramatically changed its requirements for “cleaning validations” being performed on reusable medical devices. For example, its March 2015 guidance document placed more emphasis on cleaning validations than device sterilization.
“If the device is going to be delivered non-sterile with cleaning and sterilization instructions, the FDA will expect to see proof that your cleaning validation is complete and that your steam sterilization validation plan meets the expectations of all the guidance documents,” said May. “This is a shift from previous years, when the FDA accepted a promise that these validations would be complete prior to commercialization.”
Standards and guidance documents continue to evolve to assure sterilization method effectiveness, reproducibility, and safety. Revisions of ISO standards on sterilization are being written to clarify that the manufacturer owns all aspects of the sterilization process—even when sterilization is performed at an off-site contractor facility. FDA audits also tend to be more in-depth than ever before.
“Notified bodies have requested that they have the ability to perform unannounced audits and are requiring that the manufacturers insert statements to that effect into sterilization quality contracts,” said South. “The use of detailed quality contracts, in addition to statements in business contracts with sterilizers, is on the rise.”
Kahn reports that FDA reviewers have been requesting that the exterior surfaces of syringes used in the sterile field be sterilized as a final manufacturing step—especially for ophthalmic products. In response, manufacturers have been asking for a process that will sterilize the exterior of the syringe, while leaving the contents, which have been aseptically filled, unaffected—a perfect application for nitrogen dioxide sterilization.
“This process offers an important benefit for drug delivery systems—a low-temperature sterilization process that can be applied at near-ambient pressures,” she said. “Owing to the relatively short duration of contact with the NO2 sterilant, the risk of diffusion of NO2 past the container-closure barrier is minimized, if not eliminated.”
The sterilization method is as important to the regulatory process as any other criteria for product clearance, and testing and documentation of efficacy and safety are critical. As expected, increased regulatory scrutiny associated with new industrial sterilization methods, whether by the FDA or other international regulatory bodies, can be daunting.
“While a new sterilization method brings with it increased regulatory scrutiny, when the fundamentals of efficacy and safety are thoroughly demonstrated, it can receive regulatory approval, as we’ve shown,” said Conlon. “REVOX is the first new sterilization technology to be used for FDA-cleared devices in more than two decades. It was also used for Class-II clinical trial products in two European countries.”
Nelson Labs also works with companies to help them understand future Association for the Advancement of Medical Instrumentation (AAMI) and ISO expectations for sterilization testing. AAMI document ST67 helps address the selection of appropriate sterility assurance levels (SAL) for products. This document has been an FDA consensus standard, which is applicable for all products that need to be sterilized. It allows a company to rationalize use of an alternate SAL (e.g., 10-3, 10-4, or 10-5) if the sterilization process to an SAL of 10-6 renders the product nonfunctional.
“These rationalizations are meant to include significant product testing and a risk-based assessment,” said Winters. “Currently, AAMI is revising this document in an effort to provide some additional guidance and clarification on the rationale. ISO Working Group 15 has also been established to address the same issue of SAL for healthcare products on an ISO level.”
Moving Forward
The rate of change in the sterilization market tends to be slow; it is, however, starting to accelerate, thanks to more complex medical devices, new materials, and regulatory expectations. Although there are opportunities for new technologies and new players, the barriers for getting a new sterilization method into the market are still high—including convincing medical device manufacturers of their worth.
“The largest medical device and pharmaceutical companies in the world aren’t going to move away from traditional modes of sterilization unless the new sterilization processes have been thoroughly validated, are reproducible, and have been investigated by their regulatory affairs and quality assurance, production, and validation teams,” explained Socola.
That said, there is a definite need for more economical sterilization processes that allow the processing of a wider range of complex instruments and materials in the shortest amount of time—but development and approval is not an easy process either.
“Any new nontraditional sterilization process looking to be sold to the U.S. healthcare market requires an immense amount of test data, which is compiled and reviewed by the FDA during the 510(k) clearance process,” said Socola. “New processes can take years to get through the FDA’s Office of Device Evaluation.”
Forward-thinking contract sterilizers are starting to redesign their sterilization platforms to provide more options. Manufacturers must approach sterilization with an eye for flexibility and not be locked into a single sterilization method.
“Plan early and build in options with respect to sterilization,” advised Thad Wroblewski, vice president of sales for STERIS Applied Sterilization Technologies. “Build in redundant processing ability into products. Manufacturers with a broad vision will be able to position their businesses with sterilization options in the future, providing a competitive edge.”
Contract sterilizers will be expected to fulfill more needs in the future, and their OEM customers will expect them to have the answers. This need for integrated thinking is why contract sterilizers should work with their customers very early in the design process. Product development teams that do not consider sterilization increase the risk that the materials selected and/or the design will not be compatible with any sterilization method.
“Considering sterilization as early as possible in the design and development process is ultimately a cost-saving procedure,” said Kahn. “It cuts down on the need to modify drawings, tooling, and work instructions to accommodate late changes for sterilizability.”
Conlon notes that the real breakthroughs resulting from technologies such as REVOX will come when, at the materials science level, new substances that previously could not withstand the sterilization process, become materials of choice that broaden the possibilities of product design.
“These new materials may be the difference in the technical or commercial feasibility of the next life-saving device or therapeutic—which had been limited in the past by such a rudimentary process as sterilization,” he said.
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders. He also writes a variety of feature articles for regional and national publications and is the author of five books. Contact him at mark.crawford@charter.net.