Sterilization by electron beam is rightly perceived as cost effective and fast for processing lightweight polymer-based medical devices in large numbers. The pros and cons of electron beam, when compared to ethylene oxide (EO) and gamma radiation, are well documented and widely known among medical-device manufacturers. But what they may not know is that the science of electron beam sterilization has advanced significantly.
Companies that use electron beam cite a range of plusses. For instance, it is:
FDA approved, and recognized and accepted by international standards organizations;
Penetrates all types of product packaging including foils;
Causes no damage to sterile seals on product packaging;
Allows control of temperature duringirradiation;
Delivers well-controlled (narrow) dose range;
Works quickly (a matter of minutes in small lots) which aids product efficacy and business requirements for immediate access to fully sterilized and shippable product; and
Delivers dose rapidly, which protects a product's function.
What's more, validation guidance documents can assist with its implementation and start-up.
Many manufacturers of specialized healthcare products looking for answers to their sterilization questions find that electron beam (ebeam) sterilization can accommodate critical handling issues inherent to niche products. This relationship between the flexibility of electron beam and requirements of delicate products is rapidly evolving to identify new opportunities for ebeam sterilization.
Medical devices continue to account for most contract sterilization work. By one estimate, 50% of all sterile single-use devices are processed by radiation. In North America, electron-beam sterilization constitutes 12 to 15% of this market. The remainder uses gamma radiation generated from cobalt-60 radioisotopes. Trends, however, show a shift away from gamma radiation to ebeam because of reduced product degradation, specialized processing requirements, and a rapid turnaround.
The ebeam surprise
As electrons scan through a product, they kill its microbial population by directly breaking microbial DNA chains and by creating secondary particles, such as free radicals. These unpaired and highly reactive compounds or atoms further react with the microbes. The damaged DNA keeps microorganisms in the product from reproducing, rendering the product sterile.
While that would be sufficient, ebeam has more up its sleeve. Consider simple devices such as centrifuge tubes, pipette tips, and syringes. These are frequently made of polypropylene, a low-cost polymer that can be sensitive to oxidative degradation during irradiation. However, recent experience shows that a dose delivered rapidly by ebeam reduces the polymer's degradation and embrittlement. This advantage makes ebeam a clear choice over gamma sterilization for several polymers which, until now, were perceived as having marginal radiation stability.
Devices such as surgical dressings, wound care products, electrocautery devices, IV administration kits, dialysers, endoscopy loops, cardiac catheters, and stents are routinely and terminally sterilized by electrons.
Electron beam also works well in an industrial application that uses relatively high doses to modify the molecular structure of bulk polymers. Doing so enhances their heat stability or strength characteristics by enhancing the cross linking of polymer chains. The effect is to increase the polymer's melting temperature and tensile strength. In addition, polymer chain scission may let polymers with normally high elasticity to be ground into fine powers for other tasks. The prevalence of cross linking versus chain scission is polymer dependent.
Some manufacturers that have moved to ebeam after previously using EO, have found similar material changes, even from lower doses, that improve their products' performance. For instance, irradiation may change the surface characteristics of a polymer so as to improve its wetting characteristics and thereby allow for better surface-blood interaction to enhance cell attachment or diffusion characteristics.
New products, new challenges
Combination products incorporate biologics, drugs, and even nano-particles into a single medical device. Examples include simple adhesive bandages that carry antibiotics, complex antimicrobial hydrogel in wound dressings, prefilled syringes, and drug-eluting stents. As expected, combination products bring a greater compatibility issue to any sterilization task. “Combination products tend to be more compatible with ebeam than steam or gaseous sterilants,” said David Liu, World Wide Supply Chain and Operations of Johnson & Johnson, at the September 2008 International Meeting on Radiation Processing in London.
Despite difficulties, there are several ways to reduce radiation-related degradation. These include using specialized chemistry that incorporates free-radical scavengers or antioxidants, freezing or lowering the sterilization temperature, removing water from the device and package, and defining a narrow dose range. These procedures ensure the final sterile product's safety and efficacy. Liu adds that this “customized processing diverges from the current model of high-throughput sterilization systems”.
Successful results from these methods have encouraged companies to install radiation sterilization equipment worldwide to handle economies of scale. That's great if you have lots to sterilize. But what advantage does enormous capacity hold for those with small volumes, specialized devices with tight-dose tolerances, those that need rapid turnaround, or require special processing conditions?
Unlike large cobalt-60 irradiators, processing conditions for ebeam are easily specialized with high throughput due to the speed of the irradiation and the relatively small irradiation volume. At any time in the electron-beam process, only one carrier of product is passing through the electron beam. A 20-ft3 carrier conveys the product and accommodates large boxes as well as many small, single-unit packages. When necessary, jigs can hold products in a particular position. Items can be irradiated individually, thus reducing interference from other product units that might shield the radiation dose. This method delivers a tight maximum-to-minimum dose ratio, thereby providing predictable, consistent product performance — key to sterilizing complex combination devices.
In addition, the product conveyor system's size, path length, and speed control allow processing products in as little as 15 min., thereby handling time-sensitive products while a customer waits. This contrasts with EO gas and gamma which can take many hours.
Since ebeam was commercialized over 40 years ago, a great deal of research has been performed on how it affects pharmaceutical products. With analytical chemistry and sophisticated equipment, byproducts of the process can be identified and compared to those created from conventional sterilization methods such as steam or dry heat. Once identified, the compounds can be assessed for safety. As expected, many complex pharmaceutical products cannot withstand heat or steam sterilization.
The concept and validation of product sterility is complex for products which have been formulated and packaged under aseptic conditions. Maintaining these conditions through automation costs a great deal, as does in-line filtration and barrier technologies in critical production areas. However, such effort and equipment statistically provides less sterility assurance than terminally sterilized medical devices. Regulatory pressures from the FDA encourage manufacturers to adopt terminal sterilization where possible as an alternative to aseptic manufacturing. For products in development, early radiation qualification and process development can offer this alternative. Unfortunately, current sterile pharmaceuticals are not likely candidates because most drug companies would consider it economically unfeasible to convert to terminal radiation sterilization. That's because the company would have to requalify the sterilization's safety and effectiveness to the FDA's satisfaction, a costly and time consuming activity.
The small batch sizes and the process flexibility of ebeam provide tools necessary to mitigate the effects of radiation on drugs. Key to minimizing drug degradation is controlling the overall bioburden in the product. Cleaner raw materials and manufacturing operations need a lower sterilization dose. And the lower the minimum dose, the lower the level of measured chemical change after sterilization. A few clever methods let ebeam broaden its application space. For example, the use of antioxidants, such as ascorbate or compounds with sulphydral or SH bonds, can greatly reduce the effect of free radicals, minimizing their interaction with a drug's critical or active molecular structure. Also, freezing a drug before or during irradiation immobilizes free radicals, thereby reducing their ability to migrate and interact, and thus increasing the probability of recombination instead of degradation. Removing oxygen by purging or displacing it with nitrogen results in reduced oxidative reactions and greater product stability. (Water-based products are often chemically vulnerable due to the direct effect of radiation energy on the compound plus the additional indirect effect from an interaction with the radiolytic byproducts and free radicals from water.) These techniques have successfully converted a range of proprietary pharmaceutical products to sterilization by ebeam.
These require specialized care on many levels. Tissue-based products are used for implants and as surgical aids, and are composed of either human or animal tissue. Such products include demineralized bone, grafting materials, surgical mesh, skin tissue, umbilical-cord tissue, and other materials which are harvested, cleansed, and processed into a final configuration. Of course, they require terminal sterilization. There are many challenges here. For example, there is a:
Short allowable period between manufacturing and sterilization. The sensitive nature of many of these tissue products requires sterilization within hours of manufacturing.
Continuous temperature control. Refrigeration is frequently required to maintain product stability and efficacy during product transport as well as storage before and after processing.
Tight dose range. Doses range between a minimum required for sterility and a maximum allowable to maintain product efficacy. Universally, the range is narrow, often from 1.2 to 1.6.
Wright Medical Technology, a Tennessee-based orthopedic specialty company, uses an ebeam to sterilize demineralized bone products (DBM). “These products stimulate bone formation and are implantable in difficult locations during orthopedic surgery, or where extra assistance is needed to induce bone growth,” says Barbara Blum, senior project engineer in Wright's Biologics Development Department. “Electron beam processing minimizes damage to osteoinductive protein, which is vital to the effectiveness of DBM products.” She adds that EO is inappropriate for this type of product and gamma is more destructive of the critical protein than ebeam.
Similar comments are made by Synovis Surgical Innovations Manager of R&D Sheila Kelly. Her company manufactures products made from bovine pericardium that are sterilized by ebeam. “The company's largest sterilization challenge, especially in the collagen matrix product, is to protect against sterilization-caused tissue damage,” says Kelly. “Steam sterilization cannot be used because of its destructive high temperatures, and EO is inappropriate. Electron beam, however, causes few detrimental effects and allows for individual unit processing, thus ensuring well-controlled and extremely narrow dose ranges.”
Electron beam processing in the medical device, pharmaceutical, and tissue industries has come a long way in the last 15 years. Well into the future, the body of knowledge relative to electron beam technology and its application to niche products will continue to increase.