AAPS PharmSciTech, Vol. 12, No. 4, December 2011 (© 2011)
`DOI: 10.1208/sl2249-0ll-9644-8
`
`Review Article
`Theme: Sterile Products: Advances and Challenges in Formulation, Manufacturing, Devices and Regulatory Aspects
`Guest Editors: Lavinia Lewis, Jim Agalloco, Bill Lambert, Russell Madsen, and Mark Staples
`
`Radiation and Ethylene Oxide Terminal Sterilization Experiences with Drug
`Eluting Stent Products
`
`Byron J. Lambert,1
`
`3 Todd A. Mendelson,1 and Michael D. Craven2
`'
`
`Received 19 May 2010; accepted 10 June 2011; published online 2 September 2011
`
`Abstract. Radiation and ethylene oxide terminal sterilization are the two most frequently used processes
`in the medical device industry to render product within the final sterile barrier package free from viable
`microorganisms. They are efficacious, safe, and efficient approaches to the manufacture of sterile
`product. Terminal sterilization is routinely applied to a wide variety of commodity healthcare products
`(drapes, gowns, etc.) and implantable medical devices (bare metal stents, heart valves, vessel closure
`devices, etc.) along with products used during implantation procedures (catheters, guidewires, etc.).
`Terminal sterilization is also routinely used for processing combination products where devices, drugs,
`and/or biologics are combined on a single product. High patient safety, robust standards, routine process
`controls, and low-cost manufacturing are appealing aspects of terminal sterilization. As the field of
`combination products continues to expand and evolve, opportunity exists to expand the application of
`terminal sterilization to new combination products. Material compatibility challenges must be overcome
`to realize these opportunities. This article introduces the reader to terminal sterilization concepts,
`technologies, and the related standards that span different industries (pharmaceutical, medical device,
`biopharmaceuticals, etc.) and provides guidance on the application of these technologies. Guidance and
`examples of the application of terminal sterilization are discussed using experiences with drug eluting
`stents and bioresorbable vascular restoration devices. The examples provide insight into selecting the
`sterilization method, developing the process around it, and finally qualifying/validating the product in
`preparation for regulatory approval and commercialization. Future activities, including new sterilization
`technologies, are briefly discussed.
`
`KEY WORDS: combination devices; drug eluting stents; ethylene oxide sterilization; material
`compatibility; radiation sterilization.
`
`INTRODUCTION
`
`Medical device, pharmaceutical, and biologic products
`provide a significant, positive impact to the quality of life
`of patients who receive
`them. Combination devices,
`which utilize technology spanning the medical device,
`pharmaceutical, and biopharmaceutical industries, have
`been growing and evolving. Combination devices are
`products comprised of two or more regulated compo(cid:173)
`nents, i.e., drug/device, biologic/device, drug/biologic, or
`drug/device/biologic, that are physically, chemically, or
`otherwise combined or mixed and produced as a single
`entity (1). More and more companies are creating novel
`
`1 R&D, Abbott Vascular, PO Box 9018 MS T561, Temecula, California
`92589, USA.
`2 R&D, Abbott Vascular, Santa Clara, California, USA.
`3 To whom correspondence should be addressed. ( e-mail: byron.
`lambert@av.abbott.com)
`
`drug delivery devices or are expanding the scope of existing
`devices with the addition of a drug or biologic compound
`(2,3). Abbott Vascular examples of combination devices
`are drug eluting stents (DES) ( 4,5) and bioresorbable
`vascular scaffolds (BVS) ( 6,7). At present, the DES
`market represents 60-70% (as high as 90% in China) of
`the $4B vascular stent industry and is growing at more
`than 7% per year worldwide (8). The use of temperature
`sensitive bioresorbable polymers for timed release of
`active agents is emerging, as are devices that utilize active
`electronics. Common to all of these medical product sectors
`with their sensitive materials as shown in Fig. 1 (9), is the need
`for safe, robust, cost-effective sterilization of product.
`In the world of medical devices, "sterilization" is defined
`as a "validated process used to render product free from
`viable microorganisms." Terminal sterilization is defined as
`the "process whereby product is sterilized within its sterile
`barrier system." (10) The terminal sterilization process is
`considered a manufacturing process step itself and usually
`takes place at, or near, the end of the manufacturing process.
`
`1530-9932/11/0400-1116/0 © 2011 American Association of Pharmaceutical Scientists
`
`1116
`
`Regeneron Exhibit 1049.001
`
`

`

`Terminal Sterilization and Drug Eluting Stent Products
`
`1117
`
`Devices
`
`Vascular
`Scaffolds
`
`Polymers
`
`Fig. 1. Sterilization: a common need across evolving combination
`product sectors with sensitive materials (9)
`
`Sterilizing product within the sterile barrier system is a very
`efficient approach for the manufacture of sterile product.
`Furthermore, terminal sterilization has exceptional process
`control and provides a high assurance of sterility (11). Note
`that sterilization or re-sterilization of products within the
`hospital setting is out of scope of this discussion.
`By definition, and in practice, terminal sterilization
`differentiates itself from aseptic processing where the final
`sterile product is realized over several manufacturing process
`steps. For aseptic processing, the products/components are
`sterilized separately and combined later in a sterile environment
`to produce the final sterile product. Great care must be taken to
`assure control over each process step to maintain sterility of the
`products/components. This involves capital expenditures and
`ongoing quality control expenses to achieve a comparatively
`lower assurance of sterility than terminal sterilization (11- 13).
`However, both sterilization approaches provide for the safe
`sterilization of the final medical product.
`Terminal sterilization is routinely applied to a wide variety
`of implantable medical devices and other medical products that
`are used during implantation procedures (14). Combination
`products with the device as the primary mode of action are
`sterilized using only terminal sterilization; there are no other
`options at this time. The practice of aseptic processing of solid
`combination devices, e.g., drug delivery devices, has only
`recently been considered (15). The application of terminal
`sterilization, apart from steam sterilization, with pharmaceut(cid:173)
`icals has been limited due to material compatibility challenges
`(16). Terminal sterilization of biologic products using radiation
`is also limited with the exception of tissue products for tissue
`banks (17). As the combination product market expands and
`evolves, so does the need to expand and evolve the application of
`terminal sterilization solutions.
`In this article, the authors will:
`
`• Introduce the basic concepts, definitions, benefits, and
`types of terminal sterilization used in the medical
`industry and provide an overview of related interna(cid:173)
`tional sterilization standards
`• Provide guidance and offer strategies for successful
`terminal sterilization process development and product
`sterilization qualifications highlighting case studies
`involving material compatibility challenges with drug
`eluting stents and vascular restoration devices
`• Outline next steps and future opportunities in develop(cid:173)
`ing effective terminal sterilization solutions for combi(cid:173)
`nation devices
`
`OVERVIEW OF TERMINAL STERILIZATION
`
`Terminal sterilization concepts, technologies, and standards
`are reviewed in this section. These perspectives provide a
`foundation for understanding the strong patient safety record
`of industrial terminal sterilization processes.
`
`Terminal Sterilization Concepts
`
`Patient Safety Issues Related to Infection
`
`Hospital acquired infections are a major societal concern.
`It is important to differentiate the sources of this problem. In
`particular, related to the topic of this article, it is important to
`ask the question if product processed by industrial terminal
`sterilization contributes to the problem. The answer appears
`to be a resounding "no."
`The Center for Disease Control (CDC) reviewed sources
`of hospital acquired infections for two sequential decades and
`found no incidents directly linked to terminally sterilized
`product (11,18,19). Why is this? The reasons become clear
`when industrial terminal sterilization processes are under(cid:173)
`stood and compared to hospital sources of infection (20) and
`other methods of manufacturing sterile product, e.g., aseptic
`processing or disinfection/liquid chemical methods.
`Exceptional process control is the primary reason for the
`strong quality record of terminal sterilization. As discussed in
`some detail below, terminal sterilization modalities provide a
`high level of process control to achieve a given sterility
`assurance level (SAL). In practice, while all parts of the
`product in the sterile barrier package confidently achieve the
`SAL, most locations of the product receive considerably
`greater assurance of sterility, often by several orders of
`magnitude (see "Sterility Assurance Level-Exponential
`Decay Curves" below).
`In contrast, aseptic processes are designed to exclude
`microbial contamination during the manufacturing process as
`opposed to killing it after the product is packaged. Process
`control over all variables that could contribute to microbial
`contamination is much more difficult to achieve than process
`control of a robust terminal sterilization process with a
`packaged product. Likewise, despite significant recent advan(cid:173)
`ces with liquid chemical sterilization processes (21), disinfec(cid:173)
`tion of geometrically complex devices followed by liquid
`chemical sterilization cannot match the process control of
`terminal sterilization. The superior patient safety results from
`terminally sterilized product explain the preference of
`regulatory bodies for terminal sterilization whenever possible
`(12) as well as their active participation in the sterilization
`standards development process.
`
`Definition of Sterility for Terminally Sterilized Products
`
`The International Organization for Standardization (ISO)
`definition of sterility is "free from viable microorganisms" (10).
`This definition implies zero microorganisms. A problem
`with this definition is the ability to test for and statistically
`verify achievement of the condition. Even with a practical
`surrogate, such as only one non-sterile unit in 1,000 or one
`million units, testing large quantities of expensive medical
`devices to this level is not practical.
`
`Regeneron Exhibit 1049.002
`
`

`

`1118
`
`Lambert, Mendelson and Craven
`
`Terminal sterilization process validation solves this prob(cid:173)
`lem. Microbial kill rates from ethylene oxide (EO) sterilization,
`radiation sterilization, and other sterilization modalities are
`exponential in nature (22). This allows the sterility of a product
`to be expressed as a probability based on the extent of exposure
`to the sterilization modality and the corresponding microbial log
`reduction. Achievement of a practical surrogate for sterility
`becomes experimentally achievable. This led the medical device
`industry and other industries facing similar challenges to
`quantify the effectiveness of a sterilization process by the
`probability of a non-sterile unit using the term SAL. The basis
`of quantification is microbial inactivation rate data, e.g., D
`values, the time or radiation dose required to achieve inactiva(cid:173)
`tion of 90% of a population of the test microorganism under
`stated conditions (10).
`
`Sterility Assurance Leve"-Exponential Decay Curves
`
`In North America, two healthcare SAL values have been
`used in practice, 10-3 or 10-6
`, the probability of one non-sterile
`unit in 1,000, or one million, units processed, respectively (23).
`Since SAL is a probability of contamination, the smaller
`number, 10-6
`, provides a greater assurance of sterility than the
`larger number, 10-3
`. An SAL of 10-3 has been permitted "if the
`patient risk is negligible, e.g., products not intended to come into
`contact with breached skin or compromised tissue or topical
`products that contact intact skin or mucous membranes."
`Examples include surgical drapes and gowns (14). Most
`combination devices are required to utilize a sterilization
`process that achieves the higher assurance of sterility, an SAL
`of 10-6 or one non-sterile unit in 1,000,000 units.
`An example of the relationship between the extent of the
`sterilization process and the resultant microbial log reduction
`is seen in Fig. 2. In this terminal sterilization example with
`radiation, as radiation dose increases, the number of surviving
`microorganisms drops essentially exponentially. The total
`dose required to get to a target SAL of 10-6 depends on the
`initial bioburden of the product. In this example, a 25-kGy
`
`dose is required to achieve the nine log reduction in
`bioburden from the initial level of 1,000 to an SAL of 10-6
`•
`For product with an initial bioburden level of 10, a seven log
`reduction in bioburden is required to achieve an SAL of 10-6
`,
`which could be achieved with a dose of less than 18 kGy.
`Importantly, the achievement of the one in a million sterility
`assurance level is the minimal requirement. Dose is not delivered
`as a mono-dose, but rather as a distribution of doses. It is the
`minimum portion of the dose distribution curve ( or below, if a
`common statistical safety factor is used) that achieves the SAL of
`10-6
`• The portion of the product that receives the top end of the
`dose distribution may receive a sterility assurance level better
`than one in 10,000,000 (SAL=l0-7 corresponding to the
`maximum dose with a dose uniformity ratio of 1.2; DUR=l.2)
`and more commonly something better than one in 100,000,000
`(SAL=l0-8 corresponding to the maximum dose with DUR=
`1.4) (24). This is an extraordinary margin of safety.
`Similar curves for EO sterilization demonstrate microbial
`log reduction as a function of time of exposure to EO gas for a
`given EO concentration, humidity level, and sterilization
`temperature (25). It is common when utilizing EO sterilization
`to use an overkill method of sterilization validation (26). This
`method essentially assumes that the initial bioburden consists of
`1,000,000 hardest to kill microorganisms. An EO cycle is
`validated to reduce this bioburden all the way to an SAL of
`10-6
`, resulting in a 12 log reduction of bioburden. In practice,
`with a reasonably well-controlled product bioburden of less than
`1,000, the assurance of sterility for all product in an EO sterile
`load is one in 1,000,000,000 (SAL=l0-9
`). Again, this is truly
`overkill and provides exceptional patient safety.
`In light of the very high levels of microbial reduction
`from these standard terminal sterilization processes, the
`strong patient safety record for industrial sterilization is
`indeed not surprising. The technologies that achieve this
`robust assurance of sterility are discussed in the next section.
`This is followed by a discussion of challenges involved in
`qualifying sensitive materials associated with combination
`devices.
`
`~
`
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`E
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`1.E-02
`
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`
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`
`-
`
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`
`Selected SAL
`
`'\ "'
`""
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`
`High Initial Bioburden -
`-
`-
`
`Low Initial Bioburden
`
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`
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`
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`
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`
`15
`Dose(kGy)
`Fig. 2. Log reduction of microorganism as a function of radiation dose
`
`20
`
`25
`
`30
`
`Regeneron Exhibit 1049.003
`
`

`

`Terminal Sterilization and Drug Eluting Stent Products
`
`1119
`
`Terminal Sterilization Technologies: a Brief Introduction
`
`There are several technologies that can provide terminal
`sterilization. Some of these technologies are EO, radiation,
`moist heat (steam), dry heat, hydrogen peroxide, ozone,
`chlorine dioxide, supercritical carbon dioxide, and nitrogen
`dioxide. Ethylene oxide and radiation are the most commonly
`used technologies to terminally sterilize medical devices (27)
`due to their robust microbial kill, broad material compati(cid:173)
`bility, and ability to process high volumes of product at
`reasonable costs. Moist heat and dry heat are most commonly
`applied to pharmaceutical products and components (16);
`they are not applied to combination devices since the devices
`typically have polymeric components that cannot withstand
`the high temperatures.
`
`Ethylene Oxide Sterilization
`
`Fig. 3. Abbott Vascular two-pallet EO chamber
`
`Ethylene oxide sterilization accounts for approximately
`50% of the industrial terminal sterilization market (27) and is a
`conceptually simple terminal sterilization process. A fully func(cid:173)
`tional finished good device is placed into a sealed breathable
`packaging system that allows ingress and egress of EO and
`humidity but is microbially resistant. For most industrial
`applications, packaged product is palletized (approximately
`three cubic meters) in well-defined and validated configurations.
`Based on the size of the EO chamber, one to 40 pallets are
`combined to create an ethylene oxide sterile load. Product must
`be humidified to assure microbial kill; this is sometimes
`accomplished prior to placing product in the EO chamber but
`increasingly it is accomplished in the EO chamber itself through
`dynamic humidity pulsing.
`In the ethylene oxide chamber product is exposed to a
`validated combination of humidity, ethylene oxide gas,
`temperature, and time. Deep vacuum cycles are often used to
`drive humidity and ethylene oxide into palletized product.
`Following the sterilization process, EO levels are brought below
`permissible exposure limits through completion of a validated
`in-chamber vacuum purge process or a post-sterilization aera(cid:173)
`tion process. Product is released for distribution following
`review and documentation of routine monitoring parameters
`and, in many instances, biologic indicator test results (28). Total
`cycle times range from 6 hours to several days.
`Ethylene oxide is a highly reactive cyclic ether with two
`carbons and one oxygen, CH2CH20. It is a gas at room
`temperature with a boiling point of 11 °C. It is pressurized and
`stored as a liquid for use in EO processing plants. The mechanism
`of microbial kill is alkylation of the amine groups of DNA (25).
`Moisture facilitates microbial kill; as noted above, product and
`thus the microbes, must be exposed to a humid environment
`before EO exposure (25). EO kill rate is a function of temper(cid:173)
`ature and concentration of EO gas (29). Shown in Fig. 3 is a two(cid:173)
`pallet EO sterilization chamber used by Abbott Vascular.
`
`Radiation Sterilization
`
`Radiation sterilization accounts for most of the remain(cid:173)
`ing 50% of the industrial terminal sterilization market (27).
`Fully functional finished good devices are placed and sealed
`within a sterile barrier packaging system according to a
`defined product orientation. The product is loaded onto a
`
`conveyor system using a specified orientation and passed
`in front of a radiation source that emits electrons or
`photons that penetrate through the packaging and inacti(cid:173)
`vate the device's microbial load. One parameter, radiation
`dose, correlates directly with microbial kill and is easily
`measured to provide process control. The mechanism for
`microbial kill is radiation induced scission of DNA chains,
`either "direct" (i.e., direct scission of DNA chains) or
`"indirect" (i.e., scission mediated by formed radicals),
`which stops microbial reproduction (25). There are three
`radiation sterilization modalities: gamma, electron beam,
`and X-ray (24).
`
`Gamma Sterilization. Gamma sterilization uses cobalt-
`60, a radioactive element that undergoes nuclear decay
`producing useful gamma radiation. These photons have a
`very large penetration capability, easily penetrating
`through two or more pallets of product (30). Racks of
`cobalt-60 rods provide the radiation source. A conveyor
`system moves many totes of fully packaged product into
`the sterilization chamber and around the racks, often
`passing by multiple times, to sterilize the product. The
`dose is related to
`the amount of exposure time the
`product experiences, typically ranging from 4 to 8 hours.
`
`Electron Beam Sterilization. Electron beam (E-beam)
`sterilization relies on high-energy electrons to accomplish
`sterility. Electrons are commonly accelerated up to 0.2 to
`10 Me V and delivered as a continuous curtain or magnetically
`focused into a 1-5-cm-diameter beam that is magnetically
`scanned at high frequency across the product as it moves
`in front of the beam on the conveyor system. Low energy
`E-beam is used for surface sterilization of pharmaceutical
`packaging whereas high energy E-beams are used for fully
`packaged medical devices. Electrons from accelerators do
`not penetrate nearly as far as photons from gamma
`sources (30), so product is often processed in single
`product cartons or small corrugated shipper boxes. Shown
`in Fig. 4 is an illustration of a self-shielded E-beam
`accelerator and conveyor system. Products packed in
`corrugated shipper boxes are loaded on the conveyor
`system. Product is carried through the electron beam to
`achieve the desired irradiation dose, typically in a few
`
`Regeneron Exhibit 1049.004
`
`

`

`1120
`
`Product L:oa i:I ~I
`
`Fig. 4. Abbott Vascular self-shielded electron beam sterilization
`system
`
`seconds. Product is then returned sterile to an unload/
`product release station.
`
`X-ray Sterilization. X-ray sterilization is a hybrid between
`gamma sterilization and e-beam sterilization. Radiation is
`generated from high-energy electrons from accelerators, typi(cid:173)
`cally using electrons with energies of 5-7.5 MeV The X-ray
`photons behave nearly identical to photons from gamma sources
`in terms of energy deposition and high penetration capabilities.
`Utilization of X-ray sterilization is limited but increasing.
`
`Overview of Standards
`
`A great asset in the application of terminal sterilization to
`combination devices is the availability of clear requirements and
`guidance in the form of national and international consensus
`standards for major sterilization technologies (see Table I).
`These standards are developed cooperatively by regulatory
`authorities, industry users of terminal sterilization, industry
`providers of contract terminal sterilization services or equipment,
`and, as needed, academia. The standards are robust with
`sterilization validation and routine control practices that have
`been in practice for decades. The standards were born out of the
`realization that all parties benefit from having a common
`understanding of best practice. National and international stand(cid:173)
`ard requirements for these important horizontal sterilization
`technologies touch the entire medical device industry and certain
`portions of the pharmaceutical and biopharmaceutical industries.
`
`Lambert, Mendelson and Craven
`
`The standards for each sterilization technology use a
`common template (31) to establish a sterilization process that
`reliably and reproducibly provides the intended sterility assur(cid:173)
`ance level when sterilizing medical products. The concepts in the
`sterilization standards are reviewed below to give the reader a
`sense of their scope which leads to their strong safety
`record. The systematic approach of the standards ensures
`consistency across the sterilization technologies in key
`areas such as utilization of a quality management system,
`characterization and definition of the sterilizing agent,
`sterilization process and equipment, product qualification,
`validation of the process, and monitoring, control, and
`maintenance of the process. This provides for a robust,
`safe approach to sterilize medical products. Although the
`intent to understand and control the process is analogous
`to process analytical technology (PAT), the approach for
`terminal sterilization is concerned with inputs and outputs of the
`sterilization process. Aseptic processing, and PAT, on the other
`hand, involves the characterization and control of inputs,
`outputs, and interactions of multiple processes.
`A typical first step in the application of a terminal
`sterilization process is the identification of a process compatible
`with the product, which includes all product components and
`packaging. Once a suitable process is identified, it is common to
`consider "Product Definition" which includes establishment of
`product families based on product characteristics germane to the
`given sterilization process. This is typically followed by "Process
`Definition" which includes experimental establishment of the
`minimum extent of processing required to assure sterility and
`the maximum extent of processing above which product
`functionality will be compromised. The key challenge for
`combination devices that incorporate pharmaceuticals and/or
`biologics is finding a process window that fits within these
`constraints, as discussed later.
`Once the product and process are defined the process
`can be validated. Each standard provides requirements and
`best practice guidance for installation qualification and
`operational qualification of the sterilization equipment. The
`heart of performance qualification involves the definition of a
`load configuration and experimental verification that the
`proposed production process will achieve sterility (process
`stays above the minimum extent of processing) and avoid
`product functionality concerns (process stays below the
`maximum extent of processing). For radiation sterilization,
`this involves mapping the dose received in the load config(cid:173)
`uration. For ethylene oxide sterilization, this involves assuring
`EO penetration and kill within the load configuration as well
`as mapping product temperature and humidity distributions
`
`Table I. Sterilization Standards and Guidance-References
`
`Radiation sterilization
`
`Ethylene oxide
`
`Moist heat (saturated steam)
`
`Other
`
`EN/ANSI/AAMI/ISO 11137-1 Sterilization of health care products-radiation-part 1: requirements for
`development, validation, and routine control of a sterilization process for medical devices
`EN/ANSI/AAMI/ISO 11135-1 Sterilization of health care products-ethylene oxide-part 1: requirements
`for the development, validation, and routine control of a sterilization process for medical devices
`EN/ANSI/AAMI ISO 10993-7 Biological evaluation of medical devices, part 7:
`ethylene oxide sterilization residuals
`EN/ANSI/AAMI/ISO 17665-1 Sterilization of health care products-moist heat-part 1: requirements
`for the development, validation, and routine control of a sterilization process for medical devices
`AAMI ST67 Sterilization of health care products-requirements for products labeled "STERILE"
`AAMI TIR 17 Compatibility of materials subject to sterilization
`
`Regeneron Exhibit 1049.005
`
`

`

`Terminal Sterilization and Drug Eluting Stent Products
`
`1121
`
`within the product. Demonstrating the reduction or dissipa(cid:173)
`tion of sterilant residuals is also required for EO sterilization.
`Once validated, requirements of a quality management
`system are designed to ensure the process is monitored,
`appropriately controlled and maintained to provide the
`intended sterilization of medical products.
`In summary, terminal sterilization technologies provide
`efficient and robust validated processes to assure patient
`safety. However, relative to combination devices, terminal
`sterilization technologies will provide no benefit to patients if
`sensitive materials are not compatible with them. Avoiding
`this problem is the focus of the next section.
`
`APPLICATION OF TERMINAL STERILIZATION:
`GUIDANCE AND CASE STUDIES
`
`Successful application of terminal sterilization requires the
`selection of an appropriate sterilization modality, qualification
`of materials subject to the sterilization process, optimization of
`the sterilization process, demonstration of stability of the
`product over its shelf-life, and regulatory approval. Combination
`products provide an additional challenge to terminal sterilization
`since these products can incorporate technologies from other
`industries that are not typically terminally sterilized. These topics
`are addressed in this section along with case studies of drug
`eluting stents and bioresorbable vascular restoration devices.
`
`Guidance on Selecting a Sterilization Method
`
`Selecting a terminal sterilization method for a product
`depends on many factors, but two primary factors are central to
`the decision: ability to achieve the desired sterility assurance
`level and compatibility and stability of the associated materials.
`The selected sterilization method must demonstrate the
`required sterility assurance level for the packaged product, and
`the product (and package), once sterilized, must meet intended
`performance requirements, which include lifecycle/shelf-life
`requirements. Secondary factors that may also influence the
`decision include company preferences, sterilization costs, avail(cid:173)
`ability of in-house sterilization technologies, relationships with
`sterilization service providers, knowledge of use, and impact on
`predicate or similar products. In selecting a method the use of
`standards and guidance documents is recommended, especially
`if new materials or sterilization methods are being considered.
`Examples of two such documents are the Technical Information
`Report titled Compatibility of Materials Subject to Sterilization
`(16) (for healthcare manufacturers; covers six sterilization
`modalities and relates to products manufactured from polymers,
`ceramics, and metal with brief discussion of pharmaceuticals and
`biologics) and a Committee for Proprietary Medical Products
`document titled Decision Trees for the Selection of Sterilization
`Methods (32) (for development of pharmaceutics; applies to
`aqueous products, non-aqueous liquids, semi-solids, and dry
`powder products). Sterilization technology review articles
`related to implantable materials and different technologies may
`also be helpful (33- 35).
`Selecting a terminal sterilization method can begin by
`determining if the desired sterility assurance level is achievable
`for the product packaged within the sterile barrier system.
`Product designed, or assembled, such that an interior surface of
`the product is nearly closed off to the external environment
`
`would not be a likely candidate for EO sterilization due to the
`need for moisture and EO gas to reach and interact with
`microbes on that interior surface to destroy their DNA. If EO
`sterilization was desired, based on other factors influencing this
`choice, consideration could be given to how the product is
`assembled and packaged ( e.g., if a stopcock is attached to a
`syringe, can the stopcock be left in an open position to allow
`moisture and EO gas to reach the inner surface of the syringe?).
`On the other hand, if a device includes active electronics, then
`radiation sterilization is not likely to be compatible (16).
`An important and challenging next step in selecting a
`terminal sterilization process would be to understand the
`compatibility of a product subject to a particular sterilization
`process. Product design, materials, and how the product/
`materials are manufactured are key compatibility factors to
`consider (16). For example, if the design or manufacturing
`processes result in residual stresses within the material, one
`sterilization method may be more aggressive than another in
`terms of impact to physical property degradation and the
`resultant product performance. Consideration must be given to
`potential changes in physical properties, chemical properties,
`and the functional performance of the product.
`The most significant part of understanding product com(cid:173)
`patibility with a terminal sterilization modality, once initial
`literature and guidance documents have been reviewed, is
`clinically relevant evaluation of the product performance.
`Regardless of the sterilization method being considered, it is
`important that the effects of that method on the particular
`product being developed are well understood early during the
`design and development phases of the project. Emphasizing this
`point further, consider that