Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
  • A61L2/08—Radiation
  • A61L2/087—Particle radiation, e.g. electron-beam, alpha or beta radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
  • A61L2/08—Radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/24—Apparatus using programmed or automatic operation

Definitions

• the present invention relates to a medical device; more particularly, this invention relates to methods of sterilizing the medical device by irradiation of the medical device.
• Such a system may operate as a conveyor in which products are carried pass a radiation source where the product is subjected to a predetermined dose of radiation, e.g., X-ray, gamma or electron radiation, at a predetermined level or intensity. Careful and continuous control of the dose delivered to a product is critical. If a product receives too little radiation, the desired sterilization, pasteurization, and/or chemical modification is not obtained. If a product receives too much radiation, the treatment is damaging to the product.
• a predetermined dose of radiation e.g., X-ray, gamma or electron radiation
• U.S. Pat No. 6,806,476 discloses a radiation conveyor system operated to cause a product on the conveyor to make two passes before the radiation source, e.g., an electron beam.
• the product is flipped 180 degrees between first and second passes.
• the system exposes the product to a predetermined level of radiation defined by, among other things, a dose level, beam width, speed of conveyor selected and electron energy spread spectrum.
• Sterilization of implantable medical devices by exposure to radiation is known. Sterilization is typically performed on implantable medical devices, such as stents and catheters, to reduce the bioburden on the device. Bioburden refers generally to the number of microorganisms that contaminate an object. The degree of sterilization is typically measured by a Sterility Assurance Level ("SAL"), referring to the probability of a viable microorganism being present on a device unit after sterilization. A sterilization dose can be determined by selecting a dose that provides a required "SAL". The required SAL for a device is dependent on the intended use of the device. For example, a device to be used in the body's fluid path is considered a Class III device.
• SAL Sterility Assurance Level
• SALs for various medical devices can be found in materials from the Association for the Advancement of Medical Instrumentation (AAMI) in Arlington, Va.
• the SAL for biodegradable stents is at a radiation dose from about 20 kGy to about 30 kGy.
• the required dosage depends upon the starting bioburden in the medical device, which can vary based on the degree of sterility maintained when the medical device is fabricated.
• Medical devices composed in whole or in part of polymers can be sterilized by various kinds of radiation, including, but not limited to, electron beam (e-beam), gamma ray, ultraviolet, infra-red, ion beam, and x-ray
• e-beam electron beam
• gamma ray ultraviolet, infra-red, ion beam
• ion beam x-ray
• a sterilization dose can be determined by selecting a dose that provides a required SAL.
• One problem faced in the art is how to apply sufficient radiation to achieve the SAL without causing degradation to bio-absorbable polymers and/or therapeutic agents contained within a polymer coating.
• High- energy radiation tends to produce ionization and excitation in polymer molecules, as well as free radicals.
• These energy-rich species undergo dissociation, abstraction, chain scission and cross-linking in a sequence leading to chemical stability.
• the stabilization process can occur during, immediately after, or even days, weeks, or months after irradiation which often results in physical and chemical cross-linking or chain scission.
• Resultant physical changes can include embitterment, discoloration, odor generation, stiffening, and softening, among others.
• the deterioration of the performance of polymeric materials and drugs due to e-beam radiation sterilization has been associated with free radical formation in a device during radiation exposure and by reaction with other parts of the polymer chains. The reaction is dependent on, e.g., e-beam dose and level of temperature.
• sterilization procedures for medical devices containing polymers and/or radiation-sensitive drugs specify an upper limit to the dose levels that the medical device may accept without degrading the
• the lower dose range and upper dose range often includes safety factors, which narrows the operating range for sterilization. This complicates the sterilization process and limits the range of designs or materials available for medical devices.
• the invention provides methods and systems for radiation sterilization of a medical device formed in whole, or in part, by a polymer material and medical devices containing radiation-sensitive therapeutic agents.
• a medical device formed in whole, or in part, by a polymer material and medical devices containing radiation-sensitive therapeutic agents.
• e- beam sterilization is used, however other radiation sterilization sources may be used without departing from the scope of the invention.
• the method and systems described herein are especially adapted for improving a sterilization process for implantable medical devices.
• the methods and systems are particularly relevant to implantable medical devices having a polymeric substrate, a polymer-based coating, and/or a drug-delivery coating.
• a polymer-based coating may contain, for example, an active agent or drug for local administration at a diseased site.
• An implantable medical device may include a polymer or non-polymer substrate with a polymer-based coating.
• One example of an implantable medical device particularly suited for radiation sterilization according to the invention is a drug-eluting polymer stent.
• Typical upper ranges for a drug-eluting bio-absorbable polymer stent are now 30 kGy or less. This significantly reduces the available operating range, which increases the complexity of the sterilization procedure because greater control over the speed of the device as it passes through the radiation source, and beam parameters is required. Similarly, the more narrow range required now makes it more difficult to maintain a sufficient level of throughput, i.e., time required to sterilize each device. Moreover, when operating within more narrow ranges, even assuming more precise control is feasible, there is greater risk that the maximum allowable dose will be exceeded since dose levels approach upper limits more often than in the past.
• methods are provided to reduce variance in radiation dosages received over a medical device by adjusting dosage levels with orientation of the medical device relative to a radiation source. For example, for a first pass the medical device is disposed in a first orientation, e.g., front facing the radiation source, and then exposed to radiation at a first dose level. For a second pass the medical device is disposed in a second orientation, e.g., back facing the radiation source, and then exposed to radiation at a second dose level, different from the first dose level.
• first orientation e.g., front facing the radiation source
• second orientation e.g., back facing the radiation source
• the dose levels are selected so as to arrive at a total radiation exposure, meaning the sum total of radiation received when the first dose is administered and the radiation received when the first dose is administered, for the medical device that best minimizes differences between doses received at different locations on the medical device. With variance in dose minimized over the device, there is a greater operating range made available, which simplified the sterilization process and reduces instances where does levels approach maximum allowable limits for the device.
• a process for radiation sterilization may achieve higher throughput by obviating or reducing the need to undertake special measure to reduce radiation damage.
• the upper range of the radiation dose is close to the upper limit for the medical device, more control is needed in order to assure that no damage occurred, even if the upper limit is not reached, which makes the sterilization process for each medical device more time consuming.
• temperature controls have been proposed as a measure to avoid glass transition temperatures from being reached within the polymer material due to radiation, see e.g., US Pub. No.
• a method for sterilizing a medical device by irradiation includes the steps of obtaining a first dose map and a second dose map for the medical device based on exposure of the medical device to a nominal dose level.
• the dose maps are obtained,
• the method includes the steps of selecting a first dose level and a second dose level based on a distribution of dose levels described by each of the first dose map and the second dose map; and sterilizing the medical device including the steps of disposing the medical device in the first orientation and then exposing the medical device to the first dose level and disposing the medical device in the second orientation and then exposing the medical device to the second dose level, wherein a total radiation received at a location on the medical device is the sum total of the radiation received at the location after exposure to the first dose and the second dose.
• the first dose level and the second dose level are selected so that the difference in total radiation throughout the product is minimized.
• the method may further include the step of disposing the medical device in additional orientations relative to a radiation source and exposing the medical device to different dose levels to obtain a additional dose map, and the sterilizing step further includes disposing the medical device to the additional orientations and then exposing the medical device to the corresponding dose level.
• the first dose level may be reduced relative to the second dose level when a first density of material in a high dose area for the first orientation is higher than a second density of material in a high dose area for the second orientation.
• a system for sterilizing a medical device by irradiation includes a radiation source; a conveyor system for moving a plurality of devices before the radiation source in conjunction with the dose levels of radiation desired per device; providing a first and second dose level to use when the device is respectively, orientated in a first and second orientation on the conveyor before the radiation source, the dose levels be different from each other; and sterilizing a plurality of such medical devices including the steps of disposing the medical devices in the first orientation on the conveyor and then exposing the medical devices to the first dose level and then disposing the medical device in the second orientation on the conveyor and then exposing the medical devices to the second dose level.
• a method for sterilizing a medical device by irradiation includes the steps of obtaining a first dose map, a second dose map and a third dose map for the medical device based on exposure of the medical device to a nominal dose level; sterilizing the medical device including the steps of disposing the medical device in the first orientation and then exposing the medical device to a first dose level, disposing the medical device in the second orientation and then exposing the medical device to a second dose level and disposing the medical device in the third orientation and then exposing the medical device to a third dose level.
• the method may include selecting a first dose level, second dose level and a third dose level based on a distribution of dose levels described by each of the first dose map, second dose map and third dose map. The first, second and third dose levels may also be the same.
• a method for sterilizing a medical device by irradiation includes the steps of
• the N dose level and/or N directions are selected so that the difference in total radiation throughout the medical device is minimized.
• the N dose level and/or N directions may be chosen to minimize the differences between a minimum and a maximum dose, e.g., difference between two dosimeter readings, as opposed to an overall minimization of differences.
• the N dose levels may be the same.
• both the dose levels and the orientations are adjusted to produce a minimal variance.
• the integer N may be less than 10, or 2, 3, 4 or 6.
• the dose levels may be adjusted for one or more of the N orientations according to the density of material in a high dose zone for the respective orientation relative to the other orientations.
• FIG. 1 is depth-distribution curve which depicts the relationship between the dose level received for a material having a first density (D1 ) and a second density (D2).
• FIG. 2 is a schematic illustrating a density profile for a medical device having a circular cross-section.
• the areas of high density are modeled as a triangle, i.e., three high density sides.
• the shaped formed by the majority of the mass is more important than the overall shape.
• three passes are made before a radiation source. Each pass orients the device at 120 degree increments relative to the radiation source.
• FIGS. 3A-3C and 4A-4C illustrate the distribution of dose levels for a device having a two-sided density profile.
• FIGS. 3A-3C show radiation levels when the same dose level is used for each pass.
• FIGS. 4A-4C shows the radiation dose level when dose levels according to the invention are used to minimize the variance in dose levels over the device.
• FIGS. 5A-5C and 6A-6B illustrate the distribution of dose levels for the device of FIG. 2 having a three-sided density profile.
• FIGS. 5A-5C show radiation levels after two passes when the same dose level is used for each pass.
• FIGS. 6A-6C shows radiation levels when the device is oriented in three different directions for three different passes before the radiation source.
• FIG. 1 depicts a depth dose distribution curve illustrating the
• the curve shows the dose versus the depth of a material that the electrons travel through for two different densities, a higher density D1 and lower density D2.
• the dose initially rises, then drops off, in each case.
• the material is more dense, e.g., D1
• the ramp up is more rapid and the decline in dose level verses depth is more rapid.
• the peak dose is at 44 kGy, and eventually drops down to, for example, 25 kGy and finally to 0 kGy upon further permeation through a material.
• the sharp ramp-up near the front face of the material having the higher density may be explained, at least in part, by the increased frequency of collisions between the incoming electrons and the denser material near the front face. This rapidly increases the dosage until it reaches a peak (44 kGy) then drops off sharply as the number of electrons penetrating through to deeper depths decreases.
• a peak 44 kGy
• the peak is reached more gradually and the distribution of dosage more uniform since there is less collisions with the material initially, so that there are a greater number of electrons penetrating deeper into the material.
• a method according to the invention may include the following steps. First, the device is characterized by a density profile, which describes the distribution of mass, or density for the device. The density profile indicates the number of passes before the radiation source, e.g., 2, 3 or more, and the orientation of the device relative to the radiation source for each pass. Next, an independent dose map is made for each pass. Then, after obtaining the dose maps, a dose level is derived for each pass. The dose levels are selected to minimize the difference, or variance between the sum total of the radiation levels received at different locations on the medical device after all passes before the radiation source. In some embodiments, the density profile determination step or dose level determination step is not needed, or they are readily apparent.
• a density profile for a device is illustrated in FIG. 2.
• a density profile is a polygon, generally, where each side indicates the direction in which the body should face the radiation source, to account for its mass distribution.
• the density profile is rectangular, indicating that two passes at 180 degrees orientations would most likely provide adequate reduction in variance in dosage over the device.
• a density profile may be understood, or expressed in terms of the number of passes for a device before a radiation source and the orientation of the device for each of these passes.
• a density profile may be explained by way of example with a catheter product.
• This type of medical device includes a polymer balloon, a bio-absorbable stent mounted to the balloon, and a composite delivery catheter portions including distal and proximal shaft portions. These components are all packaged within a sealed bag.
• the most dense parts of the catheter are typically the distal end (where the balloon and stent are placed, and the proximal end of the catheter shaft, assuming no parts are laid on top of another when facing the radiation source.
• the density distribution of the device may be characterized has a two-sided, rectangular shape or density profile.
• FIG. 3 depicts a density distribution for a body that has the physical dimensions of a disc but, due to the arrangement of the denser components within the device, its density profile for radiation sterilization is a three-sided polygon.
• the density profile for purposes of facilitating a more uniform exposure to radiation is a three- sided body, or triangle. Accordingly, each of the three sides define three passes before the radiation source, where each pass has the device oriented at 120 degree increments, in the case of an equilateral triangle, for each pass before the radiation source.
• the next step is to dose map the device for each pass before the radiation source.
• dosimeters are placed at locations over the device to measure the radiation dose received when the device is exposed to a nominal level of radiation.
• a monitoring dosimeter is placed upstream of the device to measure the level of radiation in the incoming beam.
• the dose map provides an indication of the relative levels of radiation, relative to the monitoring dosimeter level, that the device will receive when exposed to radiation.
• a dose map is constructed for each orientation of the device relative to the radiation source.
• two dose maps are constructed for a two-sided density profile (e.g., the catheter example, above) two dose maps are constructed. The first with the device facing with its front face facing the radiation source and the second with the device flipped 180 degrees around.
• three dose maps are constructed, with each dose map showing the
• Dosimeters should be located in places where variances in dose levels can be best realized, e.g., behind a dense component and a less dense component. Dosimeters should also be placed behind more radiation-sensitive material, e.g., a bio-absorbable polymer so that accurate information is available to ensure that maximum dosage levels are not exceeded. After constructing the dose maps, comparison between one dose map and another might indicate that the density profile was improperly constructed. In these cases, different orientations or more orientations / passes of the device before the radiation source may be chosen.
• an iterative process of dose mapping, followed by comparison of the distribution of dose levels detected by the dosimeters may alternatively be used to selected the best orientations of the device for radiation sterilization.
• the next step in the process is determining the dosage level to apply for each pass before the radiation source, so that the variance after all passes is minimized.
• Existing methods of radiation sterilization use the same dose when two passes before a radiation source is used, e.g., U.S. Pat No. 6,806,476.
• these systems are not suitable for irradiation of medical devices that require more narrow dose ranges, because the variance in dose levels using the existing methods is too great. It is necessary to reduce this variance so that there is a greater working range made available for sterilizing medical devices containing radiation sensitive material.
• FIGS. 3 and 4 it is shown that when e-beam dose levels are selected depending on the specific orientation of the device relative to the beam, there is a reduction in the overall variance as compared to using the same dose for each pass.
• FIGS. 5 and 6 show how a reduction in variance may be achieved by selecting a more appropriate density profile for the device. In this example the variance is dramatically reduced when the device is irradiated in three directions, as opposed to two.
• FIGS. 3A-3C and FIGS. 4A-4C depict the dose-depth distribution for a catheter (two-sided density profile) which is twice passed before the radiation source.
• the direction of the radiation beam is illustrated in FIGS. 3A and 4A and is the same for subsequent views FIGS. 3B 3C, 4B and 4C.
• the locations x1 , x2, x3, and x4 indicate the depth-wise coordinates of a mass of material, e.g., a distal end of a catheter, corresponding to the indicated dose levels, e.g., in FIG. 3A location x1 has a dose level after the first pass of 25 KGy.
• the figures also identify low dose zones and high dose zones, as described earlier in connection with FIG. 1 . For the first pass, location x1 is in a high dose zone, whereas in the second pass x4 is in the high dose zone.
• FIGS. 3A-3C illustrate the dose levels received at depths x1 , x2, x3, and x4 when the component of, or the device is irradiated by a 25 KGy dose for both passes.
• FIGS. 4A-4C illustrate the dose levels received at depths x1 , x2, x3, and x4 when the same device is irradiated, but with a 30 KGy dose for the first pass and a 20 KGy dose for the second pass (the first dose level is reduced relative to the second dose level because a first density of material in a high dose area for the first orientation is higher than a second density of material in a high dose area for the second orientation).
• FIGS. 3A and 4A show the dose levels after the first pass.
• the dose levels received when the device is flipped 180 degrees around is shown in FIGS. 3B and 4B.
• FIGS. 3C and 4C show the combined dose levels at each location x1 , x2, x3, and x4 after both passes, obtained by summing the dose levels at each location for each pass.
• the reduction in variance in dosage levels made possible by the invention is seen in the comparison of the final dose levels in FIG. 3C with the final dose levels in FIG. 4C.
• 3 and 4 is 40 KGy before radiation damage occurs and the minimum dose level for SAL 10 "6 is 25 KGy.
• the variance in dose levels when the same dose level (25 KGy) is applied is 10 KGy.
• the minimum dose level for SAL 10 "6 (25 KGy) is reached in one location, while a maximum dose of 35 KGy is reached elsewhere.
• FIG. 4C shows a more favorable dose variance of 4 KGy (compare x3 with x4) with the minimum dose level being 30 KGy and maximum dose being 34 KGy.
• the method of the invention there is a lower operating range of 5 KGy and an upper operating range of 6 KGy. As the operating range is wider, it is more easy to control the beam to ensure a SAL without exceeding the upper limit of 40 KGy.
• the wider operating range also allows the operator to provide more space between the beam dose level and upper limit than in the case of FIGS 3A-3C, so that he/she may account more for uncertainty in the actual dose levels received by the device.
• FIGS. 5A-5C and FIGS. 6A-6B depict the dose-depth distribution for the device taking the shape of the disc in FIG. 2.
• the disc is best viewed as a three-sided body when its denser components are arranged in this way, as will be more fully appreciated from the following discussion.
• FIGS. 5A-5C show dose levels after two passes at the same dose level. The device is flipped 180 degrees around after the first pass, which is typical in the art, regardless of the arrangement of the denser components in the device.
• the beam direction is shown, as is the dose level at depth-wise coordinates y1 , y2, y3 . . . y6. A 25 KGy dose is applied for each pass.
• FIGS. 6A-6B show the dose levels when the same device is, instead, exposed to radiation in three different orientations, each 120 degrees apart, with the same dose levels for each pass (17 KGy). Consistent with a three-sided density profile, there are three passes made. The beam direction is normal to the sides of the triangle in FIG. 6A, as indicated. In this example, the same dose level may be applied for each orientation. For medical devices having, or best approximated by a three-sided density profile, the dose levels can be different for each pass to minimize variances in dosage levels, as explained in greater detail below.
• the same dose level is applied for each orientation.
• the components are more dispersed, so that a density profile can only roughly approximate the distribution by a polygon.
• one may increase the number of passes, e.g., 4, 5, 6, or more to reduce variance.
• each pass may have its own, unique dose level selected to minimize the sum total variance after all passes before the radiation source are made, although as the above example shows, it is contemplated that for some devices proper selection of the orientations may obviate the need to adjust the dose level for each pass, which is desirable.
• the minimization may be based on a variance over all locations selected for the dose map, or the locations where the maximum and minimum occurred.
• the dose levels for each pass, and/or the number of passes may be selected in order to minimize the difference between a first dosimeter location (predicting the dosage level of the device near a first device location) and a second dosimeter location (predicting the dosage level of the device near a second device location).
• the dose levels for each pass, and/or the number of passes may be selected to minimize the dosage variance across or over all dosimeters making up the dose maps, i.e., minimize the variance over the entire device, as opposed to, for example, only two locations on the device.
• each of the m equations may, at least initially, be expressed, in terms of each of the n unknowns (dose levels) as the summation of the dose levels at each of the m dosimeter locations.
• the resulting equations (e.g., differences in total dosage between dosimeter locations) would in general define an over-determined set of equations to solve for the dose levels (since there can be more dosimeter locations than passes before the radiation source, there are more equations than unknowns to solve for). This assumes, of course, that each equation is linearly independent of the other equations.

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• 2010
  • 2010-04-02 US US12/753,830 patent/US8981316B2/en not_active Expired - Fee Related
• 2011
  • 2011-03-24 WO PCT/US2011/029815 patent/WO2011123327A1/en not_active Ceased
  • 2011-03-24 JP JP2013502660A patent/JP6202497B2/ja not_active Expired - Fee Related
  • 2011-03-24 EP EP11712428.9A patent/EP2552495B1/en not_active Not-in-force
• 2015
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