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Modernizing Sterlization Standards  



Re-evaluating current requirements could boost drug/device combinations.



Jerry Fireman



As the orthopedic industry develops more advanced and complex products, the sterilization industry is adapting to meet challenges by developing new processes to help ensure the safety of novel devices. New sterilization methods are playing a critical role in helping to deliver emerging clinical technology that offers functional improvements in nearly every class of orthopedic device.

Current FDA and international standards require a sterility assurance level (SAL) of 10-6 for orthopedic
devices as well as other terminally sterilized invasive medical devices. The 10-6 requirement was established arbitrarily and sterilization specialists have noted that there is no evidence that a 10-6 SAL is any safer than, for example, an SAL of 10-3, which is acceptable for pharmaceutical products manufactured under aseptic processing. Working Group 90 of the Association for the Advancement of
Medical Instrumentation (AAMI) is in the process of establishing a task force charged with considering the possibility of reducing the SAL requirement to 10-3. According to industry experts who spoke with Orthopedic Design & Technology, re-evaluating current requirements could lead to significant dose reductions, as well as greater device material options, without sacrificing safety.

“Lowering the current sterility assurance level requirement of 10-6 to 10-3 has the potential to reduce sterilizing doses by as much as 40% to 50%,” said John Masefield, an industry veteran with extensive experience in field of radiation sterilization. “Most important, this change would enable the terminal
sterilization of a range of radiation-sensitive products such as drug/device combination products and thereby increase their safety by making it possible to switch from less-reliable aseptic processing
to terminal sterilization.”

Current SAL Standard’s Origin


The concept of SAL originally was derived from the food industry, which had to inactivate large populations of clostridium botulinium spores using moist-heat sterilization. In the 1970s the FDA incorporated an SAL of 10-6 into its regulations for the sterilization of medical devices. In 1979, AAMI
Working Group TC 198—charged with developing guidelines for the radiation sterilization of single-use medical devices—urged the FDA to sanction the use of an SAL of 10-3 for non-invasive
medical products.


Cobalt 60 Source Rack used in gamma processing submersed under water glows blue exhibiting the "Cerenkov" effect, which is produced when the velocity of beta particles emitted exceeds the speed of light in a vacuum and related to the index of refraction as the particles travel through water. Photo courtesy of Steris Corporation.
“These SAL levels were then linked to a set of rational radiation dose-setting methods that take into account the total microbial population on the product, its distribution and its resistance to radiation,” Masefield said. The Centers for Disease Control and Prevention (CDC) maintains that there is no evidence that a medical product subjected to a radiation sterilization dose established by using an SAL of 10-6 is any safer than one established using an SAL of 10-3. There have been differing interpretations of the meaning of an SAL of 10-6, including:

• Starting with 10-6-resistant spores, the sterilization procedure results in a 10-6 probability that one
spore survives
• There is a 10-6 probability that a contaminant will survive on a product after sterilization
• Less than one non-sterile item exists in a million items sterilized

The industry is moving toward developing rational methods for selecting SALs in order to facilitate the selection of minimum radiation doses that would render products safe for their intended use. Masefield’s involvement comes from his position as an industry pioneer. His influence is a result of his
position as an industry pioneer. He founded Isomedix in 1972 and led it to become one of the world’s largest providers of contract irradiation services. Masefield stepped down from an executive role after Isomedix merged with Mentor, OH-based Steris Corp. in 1997, but still serves as executive advisor
to the company. He also serves as chairman of the International Irradiation Association (iiA). In addition, Masefield served on the board of directors of AAMI and spent more than 20 years as co-chairman of the international standards committee that developed the world standard for radiation sterilization of medical products.


Drug/Device Combinations Spur New Standard


Masefield noted that reconsideration of SAL standards has become more important than ever with the increasing use of radiation-sensitive medical devices to deliver drugs. For example, orthopedic
drug/device combination products are being used to combine recombinant protein therapeutics with tissue-specific scaffolds to actively stimulate tissue healing and regeneration for patients suffering from injuries to bones, cartilage, ligaments and tendons.

By next year, the global market for drug/device combination products is forecasted to reach $9.5 billion. The inherent radiation sensitivity of many drug molecules makes it impossible to radiation sterilize many of the important emerging combination drug/device products using the minimum radiation sterilization doses established on the basis of achieving an SAL of 10-6.

“Regulators, when comparing aseptic processing to terminal sterilization, are saying wherever possible terminal sterilization is preferred,” Masefield said. “This is because it lowers the chance of error and risk of a contaminated product causing infection or transmitting a disease to the patient.
So every effort should be made to determine the lowest possible dose required to make products ‘safe for their intended use.’”

Should it be shown that setting minimum doses that achieve an SAL of 10-3 renders products safe for their intended use, then, in most cases, sterilizing doses have the potential to be lowered by as much as 40% to 50%.

Lower doses would allow:

• Potential development of products that benefit patients that otherwise wouldn’t have been developed
• Radiation sterilization of a wide range of drug/device combinations and other products
• More flexibility in the choice of materials used in many products
• More flexibility and efficiency in product packaging configurations
• Reduced risk of over-dosing valuable advance drug/device combinations
• Terminally sterilizing products that might otherwise need to be aseptically manufactured

Broad Industry Support


Masefield cited a recent iiA survey that shows wide support for a change in the SAL to 10-3. Of the 144 healthcare manufacturing companies responding to the survey, 134 indicated their support for the proposed change. A total of 118 of the 147 individuals who responded said that the industry would
benefit from the increased flexibility in product design from the wider acceptable dose ranges resulting from establishing lower acceptable minimum doses. In addition, 101 of the 147 respondents manufacture products that currently can’t be radiation sterilized because of unacceptable physical material degradation at the sterilizing doses required to achieve an SAL of 10-6.

Considerable progress has been achieved with respect to gaining support for the proposed initiative, according to Masefield. Two workshops sponsored by the iiA on the sterilization of advanced drug/device products gained FDA and industry support, while a third iiA workshop was held in conjunction with the International Meeting on Radiation Processing 2008 in London in September. Eight recognized scientific leaders in the field of radiation sterilization have agreed to update a seminal 1992 paper titled “Sterility and Safety Assurance of Medical Devices.” Importantly, the FDA and CDC have agreed to participate on the AAMI Working Group 90 taskforce that has accepted the SAL issue as a work item.

Thad Wroblewski, sales director for Steris Isomedix Services, also supports the proposed refinement of standards. He agreed that as orthopedic products become more complex they also become more difficult to sterilize.


If 10-3 SAL was approved, a device would require a process time (dose in radiation or cycle changes in ethylene oxide) as much as 40% to 50% less than that needed for 10-6. This chart depicts that, for such a device, a 6-log reduction would be needed versus a 9-log reduction. Image courtesy of Steris Corporation.
“Some recent devices designed to cut bone are so complex that they incorporate RFID [radio frequency identification] chips to provide the proper settings to make the proper surgical cut,”
Wroblewski said. “Conventional chips would be destroyed by radiation, but semiconductor manufacturers have already developed radiation-resistant chips for the application. Another interesting
area of evolution is the advancement of soft- and hard-tissue implants. De-mineralized bone is being fabricated to form screws or plates that are used to provide support in a trauma situation. Soft tissues are being implanted to treat tendon injuries.”

These advancements create new challenges such as the need to avoid chemical residuals from ethylene oxide sterilization or the inability to withstand gamma radiation doses used on earlier generations of products, according to Wroblewski.

“There are many parental and injectable drugs that cannot be sterilized and so are produced in an aseptic fill process in which 10-3 is typically the best SAL that can be achieved,” Wroblewski continued. “An SAL of 10-3 is also used for many non-invasive medical devices. The current standard
SAL of 10-6 has never been shown to be superior to 10-3 in terms of reducing infection or a particular disease. No one wants to make a rash decision, but lowering the SAL offers a cascade of advantages. We will be able to substantially reduce the radiation dose, say from 25 kilograys to 15 kilograys for a
typical product. This opens the door to using new materials and different processing cycle options, increases processing efficiencies, and means that, over time, less radioactive isotopes need to
be installed in facilities around the country. It might also become possible to use less ethylene oxide gas in new processing cycles.”

Using the Current Standard


Trabue Bryans, vice president and general manager of the Atlanta, GA-based division of Wuxi Apptec, a China-headquartered contract sterilizer that works with many orthopedic device manufacturers, said sterilizers are able to work within the current standard to meet the needs of a new generation of
orthopedic products.

“The heat involved in steam sterilization is detrimental to the new biologics used in drug/device combinations, while the residuals left by ethylene oxide can also cause problems,” Bryans said. “And
many of these products are not able to withstand the dose that is normally required to achieve the current SAL standard of 10-6. Typically, a maximum dose of from 40 to 45 kilograys is required to achieve a minimum value of 25 kilograys throughout the device load.”

Bryans said that devices that are unable to withstand this dosage may still be sterilized to an SAL of 10-6 by using ultraclean processing methods that reduce the bioburden on the product prior to the sterilization process.

“When the bioburden on the product is significantly reduced, we can reduce the typical sterilization dose needed to achieve an SAL of 10-6 to a maximum of 25 kilograys to achieve a 15 kilogray
minimum dose. The bioburden on the device prior to sterilization is quantitated with culture methods. The radiation dosage is calculated from the bioburden using theoretical methods and then validated experimentally. It’s worth noting that the AAMI/ISO 11137 standard has a method that substantially
reduces the cost and time involved in validating a low radiation dosage for ultraclean products. The
new method typically reduces the number of samples that need to be run from 125 to 130 in the past to 25 to 30 now.”

The Role of Electron Beam


Tom Stephan, vice president of Business Development for San Diego, CA-based Beam One, which specializes in electron beam sterilization, said that this method can help address the special
sterilization challenges of tissue banks.

“A few years ago, the FDA ordered a tissue-processing firm to recall all distributedhuman allograft tissues after fungal and bacterial contamination was associated with the death of a patient who received a soft-tissue implant during reconstructive knee surgery,” Stephan said. “In the past, human tissue processors have assumed that the harvesting process itself could be conducted in a way that would eliminate transfer of bacteria to the harvested tissues. But this incident demonstrated the possibility of transferring bacteria on the outer skin or elsewhere to the harvested tissues.”

As a result of this incident, many tissue processors began using terminal sterilization. Organic tissues are susceptible to heat damage, which makes it impossible to use steam sterilization. The tissues have a high level of moisture that react with ethylene oxide to produce residuals that impact the performance
of the tissue. The majority of these products currently is sterilized with gamma radiation; however, the
time required with this method may produce tissue damage, Stephan said.

“Electron beam sterilization reduces the total sterilization time from hours to minutes so it minimizes oxidative degradation that can cause problems with gamma irradiation,” Stephan said. “Electron beam sterilization is also well suited to delivering tightly controlled doses to very small batches of material which makes it ideal for the tissue processors. It also allows the use of special jigs that may be needed to use dry ice.”

Working With Ethylene Oxide


Interesting developments also have occurred in the field of ethylene oxide sterilization, according to Dick Malo, vice president of Contract Sales for Ethox Corporation in Buffalo, NY.

“Ethylene oxide sterilization is normally done at temperatures that can be damaging to certain materials such as polyvinyl chloride and ethyl vinyl acetate,” Malo said. “These materials also don’t lend themselves to gamma radiation because the radiation tends to discolor the plastic. These and other polymers are being used more frequently today largely because of the industry trend towards the use of disposable products which in turn tend to be made of more delicate materials.”

Malo explained that this problem is being addressed by a move toward cooler ethylene oxide sterilization cycles. He said that while the normal ethylene oxide sterilization cycle might involve
temperatures of 48.9 degrees Celsius (120 degrees Fahrenheit), his firm has validated and uses in production cycles with temperatures as low as 30 degrees Celsius (86 degrees Fahrenheit). He said that Ethox is able to achieve the same SAL at the lower temperature by lengthening the time over which the product is exposed to ethylene oxide.He said that cold cycles are subject tothe same validation methods as thetraditional hot cycles by running testcycles to validate the ability to of the
process to kill spore strips.

Early Involvement Is Key


No matter what kind of technology is used to sterilize an orthopedic device, the success of the process often hinges on the relationship between manufacturer and sterilization provider. According to Brenda Sparks, director of Corporate Accounts for Centurion Sterilization Services (a division of Tri-State Hospital Supply Corporation), in Howell, MI, orthopedic device manufacturers are getting sterilization providers involved earlier  in the development cycle.

“Sterilization is the last step in the manufacturing process so traditionally device manufacturers got us involved only towards the end of the development process,” Sparks said. “The problem with this approach is that any hiccups or problems with sterilization can delay the introduction of the product. It
may even require changes to the device design or packaging. Device manufacturers are much more knowledgeable and are seeking input much earlier in the process to prevent any potential issues that may arise.”

Sparks said her company begins by performing basic confidence testing to determine the best cycles. “The cycle includes temperature, humidity, cycle duration, vacuum depth, load configuration and density, and many other factors,” she explained. “Once we have an idea on the cycle needed, we can get started on the validation. The validation involves several cycles processed under the worst-case conditions for both parameters and load configuration. Variations to the cycle parameters will be made if required during this process.”

* * *

As orthopedic manufacturers—and their contract manufacturing partners and suppliers—work on the next generation of implants and instruments, sterilization standards (and possible changes) are critically important to clinical and market outcomes. 

Jerry Fireman is based in Lexington, MA, and is president of Structured Information, a company that produces articles and other technical documents for publications and companies in the medical device field as well as a wide range of other technologies. He  has been writing since 1984 and has
published more than 9,000 articles.




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