From the Publishers of

www.medicaldesignbriefs.com September 2012

Viewing Metabolic Alterations of Disease as They Occur

Using NO2 to Sterilize Disposable andImplantable Devices

Color Compensation TechnologyWithstands Sterilization with Color Intact

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Sterilization with Nitrogen Dioxide Gas: A New Tool for

Designers and Manufacturers

Noxilizer has developed a room tem-perature sterilization process formedical devices that is based on

nitrogen dioxide (NO2) gas. Currently,industrial sterilizers and contract sterili-zation services using NO2 gas are beingoffered to medical device manufacturersfor terminal sterilization during the man-ufacturing process. A hospital model isalso being developed for use in the clini-cal setting as a means of sterilizingreusable medical devices. As such,designers should be aware of this tech-nology today for disposable andimplantable devices, and also in thefuture for reusable devices sterilized inhospitals using NO2 gas sterilizers. Atpresent, the terminal sterilization marketfor medical devices is primarily servicedby ethylene oxide (EO) gas or radiationprocesses, with gamma accounting forthe majority of radiation sterilization. Inthis article, NO2 sterilization is discussedin the context of other gas sterilizationprocesses, but it may also be applicableto devices that are sterilized with gamma.NO2 is a rapid and effective sterilant,

as demonstrated using a broad range ofmicroorganisms. The most resistantorganism is the spore-former, Geo bacillusstearothermophilus, which is also the bio-logical indicator for both steam andvapor hydrogen peroxide sterilization. Itis a well-characterized biological indica-tor organism and, as can be seen inFigure 1, NO2 provides a log-linear pop-ulation reduction as exposure time isincreased. This log-linear responseallows for a model around which the ster-ilization cycle for a given device may bedeveloped. With most medical devices, asterility assurance level (SAL) of 10-6 canbe achieved with 20 to 40 minutes ofexposure time to the NO2 sterilant.All gas sterilizers face challenges in

addressing the wide variety of medicaldevices that are being produced today,or will be developed in the future. Thefirst challenge is the fact that thegaseous sterilant needs to contact all ofthe device surfaces that require steriliza-

Fig. 1 – NO2 provides a log-linear population reduction as exposure time is increased.

Fig. 2 – Lethality with NO2 gas sterilization proceeds quickly on films of common bioresorbable materials and col-

lagen.

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tion. Therefore, the packaging anddevice design must permit gas access.For the device, this means avoidingclosed spaces and mated surfaces. Forthe packaging, gas access is typicallyachieved through the use of porouspackaging that provides a sterile barrierfor the finished device. Tyvek® has beenan industry standard in sterile barrierpackaging for years because it allowsready gas diffusion in and out of thepackage. Tyvek pouches are compatiblewith EO, hydrogen peroxide (H2O2),steam, and NO2 sterilization. Add i tion -ally, EO can diffuse through polymers inorder to sterilize within non-porouspolymeric packaging.Sterilant access to all device surfaces

can be ensured during the designprocess by allowing for paths throughwhich the NO2 can flow, either undervacuum or by diffusion, into complicat-ed geometries such as lumens andmated surfaces. With H2O2 (boilingpoint, Tb = 150 °C) condensation of thesterilant can occur prior to reaching theinnermost regions of a device as the ster-ilant concentration approaches the satu-rated vapor pressure. This condensationcan result in localized sub-lethal condi-tions leading to non-sterile devices. WithNO2 (Tb = 21 °C) this is not an issuebecause of the high saturated vaporpressure at the sterilization tempera-ture. Diffusion into lumens occurs with-out the driving force for condensation.EO sterilization relies on diffusion of thegas without the aid of vacuum to reachcomplicated geometries, which resultsin longer cycle times. EO can sterilizeclosed volumes within devices via diffu-sion through polymers given longenough exposure times. Removal of residual sterilant is another

challenge posed by gas sterilizers.Concern has been expressed over theresiduals left behind by EO sterilization,which have been shown to be both cyto-

toxic and carcinogenic. Much of the pro-cessing time with EO sterilization is takenup by the lengthy aeration phase that isrequired to ensure adequate removal ofresidual sterilant from the devices andpackaging materials. Furthermore, EOwill diffuse into materials like polymersand paper over the long exposure timethat is required to achieve sterility. Inorder to remove the residual sterilantfrom the devices, one must wait for theEO to diffuse back out of the materials.This aeration process is carried out overmany hours or even days in order toensure that the devices are safe. Unlike EO, most polymers are rather

impermeable to NO2, particularly overthe relatively short exposure requiredwith NO2 gas sterilant. This makes aera-tion a faster process. Since NO2 has avapor pressure of 1 atm at room temper-ature, aeration can be carried out usingeither vacuum-assisted air exchanges ora steady flow of air at ambient pressurethrough the sterilization chamber. Theaeration process with NO2 sterilization isgenerally about 15 minutes in duration,and this is built into an overall cycle timethat usually runs about 60 to 90 minutesfor the large industrial sterilizers. NO2 sterilant is supplied as a liquid,

from which vapor is dosed into thechamber during the cycle. This is aspace saving alternative to large gascylinders. NO2, while a toxic gas, is non-explosive and non-carcinogenic. At theend of the cycle, NO2 is removed fromthe exhaust gas via a scrubber systemthat is built into Noxilizer’s industrialsterilizers, which can allow an NO2 ster-ilizer to be vented safely, without releas-ing NO2. The spent scrubber material isa non-hazardous solid waste product(considered landfill-safe in the US) thatcan be disposed of in accordance withlocal regulations. This makes NO2 steril-ization a safer and more cost-effectiveoption to bring sterilization activities in-

house and make it a real part of themanufacturing process.NO2 sterilization is a truly room tem-

perature process, which provides design-ers and developers a good choice for thesterilization of temperature-sensitivematerials such as bioresorbable polymers.Some of the formulations of biore-sorbable polymers, particularly thosebased on polylactides, have glass transi-tion temperatures that approach, orreside below, the elevated processing tem-peratures for EO and H2O2 gas steriliza-tion. With the EO process, there is often along preconditioning phase in order tobring the entire load up to the requiredtemperature and relative humidity, whichincreases the amount of time thatimplants are exposed to high humidity. Ascan be seen in Figure 2, lethality with NO2gas sterilization proceeds quickly on filmsof common bioresorbable materials andcollagen. The shorter overall cycle timesin NO2 sterilization means the biore-sorbable materials are exposed to humid-ity for shorter periods of time.While temperature is not controlled,

relative humidity (%RH) is a critical pro -cess variable. Lethality proceeds morerapidly with increasing humidity, but anSAL of 10-6 can still be achieved atreduced %RH with increased cycle dura-tion. A cycle with 80%RH will typicallyrequire a sterilant exposure time of 20 to40 minutes, while an exposure with <25%RH will be on the order of severalhours. This allows one to balance shortexposures with high humidity againstlonger exposures with low humidity inorder to maximize device compatibilitywith the NO2 sterilization process. If%RH is not critical to device integrity,then the higher humidity cycles minimizethe overall exposure to the NO2 gas. Each sterilization method has a

unique set of materials with which theyare compatible. EO is recognized as having the widest compatibility withdevice materials, including most metalsand polymers. However, the elevatedtemperatures and humidities associatedwith EO may limit the ability to processsome bioresorbables or electronicdevices. While not a gas, it is worthy tonote that gamma radiation often causescross-linking or oxidation of polymers,which can result in changes in materialproperties that must be accounted forduring engineering. Discoloring bygamma radiation can be combated withmore expensive, gamma-stable materials.H2O2 is oxidative, and is compatible with

Sterilization with Nitrogen Dioxide Gas

Incompatible Material Design Alternative

Delrin® (polyacetal) Polyetherimide, polysulfone, PEEK

Nylon® Polyester or polyolefins

Polyurethane Thermoplastic elastomers (TPE)

Cellulosics (paper) Polystyrene or polyester label stock

Copper (and alloys) Stainless steel

Nitinol Depends upon application

Table 1. Noxilizer proposes that a suitable design alternative exists for each material that is incompatible with NO2

sterilization. Of course, suitability is dependent on the properties desired.

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Sterilization with Nitrogen Dioxide Gas

most materials with the exception ofthose that absorb or decompose H2O2such as polyurethane, nylon, cellulosics(paper), and copper-based alloys. Again,H2O2 sterilization is carried out at elevat-ed temperatures due to the need to keepthe sterilant in the vapor phase, whichmay limit its ability to sterilize some tem-perature-sensitive materials. NO2 sterili-zation is compatible with many medicaldevice materials as well. Notable incom-patible materials for NO2 are similar tothose of H2O2. Additionally, devices thatinclude nitinol and polyacetal (Delrin®)should not be processed through NO2sterilization. For each incompatible mate-rial, Noxilizer believes there is a suitabledesign alternative depending on theproperties required. Table 1 outlinesthese alternatives.As NO2 sterilization is not compatible

with cellulosic materials like paper andcardboard, the sterilization step must beperformed prior to final packaging. Theproduct would be packaged in the sterilebarrier packaging, sterilized with NO2,and then sent to final packaging, whichmay include paper inserts. This may rep-resent a shift in manufacturing philoso-phy, but in order to realize cost savings orroom temperature processing with NO2,it is one that is quite feasible particularlywhen sterilization is brought in-house.Procedural kits or devices that include

a prefilled syringe represent an ideal can-didate product for sterilization withNoxilizer’s NO2 process. The ability ofNO2 to diffuse into packaging at ambientpressure allows the syringe to be steril-ized without moving the stopper becauseno pressure is exerted upon it by thehead space in the syringe. The low per-meability of most polymers to NO2means that the sterilant will not interactwith, or contaminate, the drug productcontained within the syringes. A shortcycle time at room temperature reducesthe likelihood of degradation of temper-ature-sensitive drug products. NO2 steril-ization is compatible with many commonsyringe materials such as glass, cyclicolefins, polypropylene, silicone, mostrubbers, and thermoplastic elastomers.In fact, NO2 can be used to sterilizesyringe parts after manufacturing, as wellas decontaminate syringe tubs prior toentering the filling line.

Most manufacturers pre-fer to use contract steriliza-tion services for EO gas.The EO sterilization processis inherently lengthy due tothe preconditioning, expo-sure, and aeration phases.The process time is oftencompounded with the timerequired to accrue sufficientinventory and to transportthe product to the sterilizer.As a result, manufacturerscan lose inventory to thesterilization process for sev-eral days up to one month,which adds inventory carry-ing costs to the equation.This factor seems to impactsmall- and medium-sizedmanufacturers the most, asthey will not always produceenough to fill a commercialEO sterilization chamberand must wait to accumu-late enough product to fill achamber before their prod-uct is processed. NO2 sterilization is a new

option for medical device manufacturers.Designers of medical products can havethe option of NO2 sterilization efficien-cies through material selection anddesign choices. The advantage of theNO2 sterilization is in-house sterilization,which can save time and money by elimi-nating transportation and inventory car-rying costs associated with contract steril-ization. Man ufacturers are often reluc-tant to bring EO or gamma sterilizationin-house because of the substantial capi-tal investments and safety issues that areassociated with the technologies. Gammaunits are capital intensive, and requirecooling water or other facilities modifica-tions. Large EO units also require facili-ties modifications, such as abaters andexplosion-proof walls, owing to the explo-sive and carcinogenic nature of the gas. Noxilizer’s patented NO2 sterilization

process provides a solution to some of the challenges and inefficiencies posed by other sterilization methods with theRTS 360 industrial NO2 sterilizer, shownin Figure 3. It is a self-contained unit(requiring only a power connection)that provides a usable sterilization load

volume of 25" × 25" × 36". This is rough-ly equivalent to one fifth of a pallet ofproduct. With a typical cycle time of 60to 90 minutes, approximately one palletof product can be sterilized in an eight-hour shift. The product is safe to handleafter the cycle and can be returned toinventory immediately. For manufactur-ers who wish to bring sterilization inhouse, this allows the sterilization step tobecome an integral part of the produc-tion line. The fast cycle turnaround ofthe RTS 360 is capable of supportingsmall, medium, and large companies’lean manufacturing philosophies suchas “just-in-time.” Noxilizer can alsodesign and build custom in-line systemsfor manufacturers with high volumesthat would see a greater financial benefitfrom a continuous sterilization process,as well as provide a contract service forNO2 sterilization.

This article was written by Evan Goulet,Ph.D., Technical Applications Manager, andDavid Opie, Ph.D., Senior Vice President ofResearch and Development for Noxilizer(Baltimore, MD). For more information, visithttp://info.hotims.com/40437-162

Fig. 3 – RTS 360 Industrial NO2 Sterilizer.

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

Maura O. KahnVice President, Business Development & Marketing443-543-5783 • mokahn@noxilizer.com • www.noxilizer.com

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