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www.medicaldesignbriefs.com September 2012

Viewing Metabolic Alterations of Disease as They Occur

Using NO2 to Sterilize Disposable and Implantable Devices

Color Compensation Technology Withstands Sterilization with Color Intact

From the Publishers of 30604:Layout 1 10/4/12 11:00 AM Page 4

Sterilization with Dioxide : A New Tool for Designers and Manufacturers

oxilizer has developed a room tem- perature sterilization process for Nmedical devices that is based on nitrogen dioxide (NO2) gas. Currently, industrial sterilizers and contract sterili- zation services using NO2 gas are being offered to medical device manufacturers for terminal sterilization during the man- ufacturing process. A hospital model is also being developed for use in the clini- cal setting as a means of sterilizing reusable medical devices. As such, designers should be aware of this tech- nology today for disposable and implantable devices, and also in the future for reusable devices sterilized in hospitals using NO2 gas sterilizers. At present, the terminal sterilization market for medical devices is primarily serviced by ethylene oxide (EO) gas or radiation processes, with gamma accounting for the majority of radiation sterilization. In this article, NO2 sterilization is discussed in the context of other gas sterilization processes, but it may also be applicable Fig. 1 – NO2 provides a log-linear population reduction as exposure time is increased. to devices that are sterilized with gamma. NO2 is a rapid and effective sterilant, as demonstrated using a broad range of microorganisms. The most resistant organism is the spore-former, Geo bacillus stearothermophilus, which is also the bio- logical indicator for both steam and vapor peroxide sterilization. It is a well-characterized biological indica- tor organism and, as can be seen in Figure 1, NO2 provides a log-linear pop- ulation reduction as exposure time is increased. This log-linear response allows for a model around which the ster- ilization cycle for a given device may be developed. With most medical devices, a sterility assurance level (SAL) of 10-6 can be achieved with 20 to 40 minutes of exposure time to the NO2 sterilant. All gas sterilizers face challenges in addressing the wide variety of medical devices that are being produced today, or will be developed in the future. The first challenge is the fact that the

gaseous sterilant needs to contact all of Fig. 2 – Lethality with NO2 gas sterilization proceeds quickly on films of common bioresorbable materials and col- the device surfaces that require steriliza- lagen. 30604:Layout 1 10/4/12 11:00 AM Page 6

Sterilization with Nitrogen Dioxide Gas

house and make it a real part of the Incompatible Material Design Alternative manufacturing process. Delrin® (polyacetal) Polyetherimide, polysulfone, PEEK NO2 sterilization is a truly room tem- perature process, which provides design- ® Nyl on or polyolefins ers and developers a good choice for the Polyurethane Thermoplastic elastomers (TPE) sterilization of temperature-sensitive Cellulosics () Polystyrene or polyester stock materials such as bioresorbable polymers. Some of the formulations of biore- Copper (and alloy s) Stainless steel sorbable polymers, particularly those Niti nol Depends upon application based on polylactides, have transi- tion temperatures that approach, or

Table 1. Noxilizer proposes that a suitable design alternative exists for each material that is incompatible with NO2 reside below, the elevated processing tem- sterilization. Of course, suitability is dependent on the properties desired. peratures for EO and H2O2 gas steriliza- tion. With the EO process, there is often a tion. Therefore, the packaging and toxic and carcinogenic. Much of the pro- long preconditioning phase in order to device design must permit gas access. cessing time with EO sterilization is taken bring the entire load up to the required For the device, this means avoiding up by the lengthy aeration phase that is temperature and relative humidity, which closed spaces and mated surfaces. For required to ensure adequate removal of increases the amount of time that the packaging, gas access is typically residual sterilant from the devices and implants are exposed to high humidity. As achieved through the use of porous packaging materials. Furthermore, EO can be seen in Figure 2, lethality with NO2 packaging that provides a sterile barrier will diffuse into materials like polymers gas sterilization proceeds quickly on films for the finished device. ® has been and paper over the long exposure time of common bioresorbable materials and an industry standard in sterile barrier that is required to achieve sterility. In collagen. The shorter overall cycle times packaging for years because it allows order to remove the residual sterilant in NO2 sterilization means the biore- ready gas diffusion in and out of the from the devices, one must wait for the sorbable materials are exposed to humid- package. Tyvek pouches are compatible EO to diffuse back out of the materials. ity for shorter periods of time. with EO, hydrogen peroxide (H2O2), This aeration process is carried out over While temperature is not controlled, steam, and NO2 sterilization. Add i tion- many hours or even days in order to relative humidity (%RH) is a critical pro - ally, EO can diffuse through polymers in ensure that the devices are safe. cess variable. Lethality proceeds more order to sterilize within non-porous Unlike EO, most polymers are rather rapidly with increasing humidity, but an -6 polymeric packaging. impermeable to NO2, particularly over SAL of 10 can still be achieved at Sterilant access to all device surfaces the relatively short exposure required reduced %RH with increased cycle dura- can be ensured during the design with NO2 gas sterilant. This makes aera- tion. A cycle with 80%RH will typically process by allowing for paths through tion a faster process. Since NO2 has a require a sterilant exposure time of 20 to which the NO2 can flow, either under vapor pressure of 1 atm at room temper- 40 minutes, while an exposure with <25 vacuum or by diffusion, into complicat- ature, aeration can be carried out using %RH will be on the order of several ed geometries such as lumens and either vacuum-assisted air exchanges or hours. This allows one to balance short mated surfaces. With H2O2 (boiling a steady flow of air at ambient pressure exposures with high humidity against point, Tb = 150 °C) condensation of the through the sterilization chamber. The longer exposures with low humidity in sterilant can occur prior to reaching the aeration process with NO2 sterilization is order to maximize device compatibility innermost regions of a device as the ster- generally about 15 minutes in duration, with the NO2 sterilization process. If ilant concentration approaches the satu- and this is built into an overall cycle time %RH is not critical to device integrity, rated vapor pressure. This condensation that usually runs about 60 to 90 minutes then the higher humidity cycles minimize can result in localized sub-lethal condi- for the large industrial sterilizers. the overall exposure to the NO2 gas. tions leading to non-sterile devices. With NO2 sterilant is supplied as a liquid, Each sterilization method has a NO2 (Tb = 21 °C) this is not an issue from which vapor is dosed into the unique set of materials with which they because of the high saturated vapor chamber during the cycle. This is a are compatible. EO is recognized as pressure at the sterilization tempera- space saving alternative to large gas having the widest compatibility with ture. Diffusion into lumens occurs with- cylinders. NO2, while a toxic gas, is non- device materials, including most metals out the driving force for condensation. explosive and non-carcinogenic. At the and polymers. However, the elevated EO sterilization relies on diffusion of the end of the cycle, NO2 is removed from temperatures and humidities associated gas without the aid of vacuum to reach the exhaust gas via a scrubber system with EO may limit the ability to process complicated geometries, which results that is built into Noxilizer’s industrial some bioresorbables or electronic in longer cycle times. EO can sterilize sterilizers, which can allow an NO2 ster- devices. While not a gas, it is worthy to closed volumes within devices via diffu- ilizer to be vented safely, without releas- note that gamma radiation often causes sion through polymers given long ing NO2. The spent scrubber material is cross-linking or oxidation of polymers, enough exposure times. a non-hazardous solid waste product which can result in changes in material Removal of residual sterilant is another (considered landfill-safe in the US) that properties that must be accounted for challenge posed by gas sterilizers. can be disposed of in accordance with during engineering. Discoloring by Concern has been expressed over the local regulations. This makes NO2 steril- gamma radiation can be combated with residuals left behind by EO sterilization, ization a safer and more cost-effective more expensive, gamma-stable materials. which have been shown to be both cyto- option to bring sterilization activities in- H2O2 is oxidative, and is compatible with 30604:Layout 1 10/4/12 11:00 AM Page 8

Sterilization with Nitrogen Dioxide Gas

most materials with the exception of Most manufacturers pre- those that absorb or decompose H2O2 fer to use contract steriliza- such as polyurethane, nylon, cellulosics tion services for EO gas. (paper), and copper-based alloys. Again, The EO sterilization process H2O2 sterilization is carried out at elevat- is inherently lengthy due to ed temperatures due to the need to keep the preconditioning, expo- the sterilant in the vapor phase, which sure, and aeration phases. may limit its ability to sterilize some tem- The process time is often perature-sensitive materials. NO2 sterili- compounded with the time zation is compatible with many medical required to accrue sufficient device materials as well. Notable incom- inventory and to transport patible materials for NO2 are similar to the product to the sterilizer. those of H2O2. Additionally, devices that As a result, manufacturers include nitinol and polyacetal (Delrin®) can lose inventory to the should not be processed through NO2 sterilization process for sev- sterilization. For each incompatible mate- eral days up to one month, rial, Noxilizer believes there is a suitable which adds inventory carry- design alternative depending on the ing costs to the equation. properties required. Table 1 outlines This factor seems to impact these alternatives. small- and medium-sized As NO2 sterilization is not compatible manufacturers the most, as with cellulosic materials like paper and they will not always produce cardboard, the sterilization step must be enough to fill a commercial performed prior to final packaging. The EO sterilization chamber product would be packaged in the sterile and must wait to accumu- barrier packaging, sterilized with NO2, late enough product to fill a and then sent to final packaging, which chamber before their prod- may include paper inserts. This may rep- uct is processed. Fig. 3 – RTS 360 Industrial NO2 Sterilizer. resent a shift in manufacturing philoso- NO2 sterilization is a new phy, but in order to realize cost savings or option for medical device manufacturers. volume of 25" × 25" × 36". This is rough- room temperature processing with NO2, Designers of medical products can have ly equivalent to one fifth of a of it is one that is quite feasible particularly the option of NO2 sterilization efficien- product. With a typical cycle time of 60 when sterilization is brought in-house. cies through material selection and to 90 minutes, approximately one pallet Procedural kits or devices that include design choices. The advantage of the of product can be sterilized in an eight- a prefilled syringe represent an ideal can- NO2 sterilization is in-house sterilization, hour shift. The product is safe to handle didate product for sterilization with which can save time and money by elimi- after the cycle and can be returned to Noxilizer’s NO2 process. The ability of nating transportation and inventory car- inventory immediately. For manufactur- NO2 to diffuse into packaging at ambient rying costs associated with contract steril- ers who wish to bring sterilization in pressure allows the syringe to be steril- ization. Man ufacturers are often reluc- house, this allows the sterilization step to ized without moving the because tant to bring EO or gamma sterilization become an integral part of the produc- no pressure is exerted upon it by the in-house because of the substantial capi- tion line. The fast cycle turnaround of head space in the syringe. The low per- tal investments and safety issues that are the RTS 360 is capable of supporting meability of most polymers to NO2 associated with the technologies. Gamma small, medium, and large companies’ means that the sterilant will not interact units are capital intensive, and require lean manufacturing philosophies such with, or contaminate, the drug product cooling water or other facilities modifica- as “just-in-time.” Noxilizer can also contained within the syringes. A short tions. Large EO units also require facili- design and build custom in-line systems cycle time at room temperature reduces ties modifications, such as abaters and for manufacturers with high volumes the likelihood of degradation of temper- explosion-proof walls, owing to the explo- that would see a greater financial benefit ature-sensitive drug products. NO2 steril- sive and carcinogenic nature of the gas. from a continuous sterilization process, ization is compatible with many common Noxilizer’s patented NO2 sterilization as well as provide a contract service for syringe materials such as glass, cyclic process provides a solution to some of NO2 sterilization. olefins, , silicone, most the challenges and inefficiencies posed This article was written by Evan Goulet, rubbers, and thermoplastic elastomers. by other sterilization methods with the Ph.D., Technical Applications Manager, and In fact, NO2 can be used to sterilize RTS 360 industrial NO2 sterilizer, shown David Opie, Ph.D., Senior Vice President of syringe parts after manufacturing, as well in Figure 3. It is a self-contained unit Research and Development for Noxilizer as decontaminate syringe tubs prior to (requiring only a power connection) (Baltimore, MD). For more information, visit entering the filling line. that provides a usable sterilization load http://info.hotims.com/40437-162

Reprinted from Medical Design Briefs, September 2012. On the web at www.techbriefs.com. © 2012. All Rights Reserved. Foster Service: 866-879-9144, www.marketingreprints.com.

Maura O. Kahn Vice President, Business Development & Marketing 443-543-5783 • [email protected] • www.noxilizer.com