CA3133881A1 - Device and method for sterilizing medical products by means of x-radiation - Google Patents

Abstract

The invention relates to a device comprising a radiation source and preferably a detector, between which a medical product is introduced, wherein the radiation source can be controlled by means of an open-loop and/or closed-loop control device and feedback from the detector or can be controlled by means of a result of dose mapping or a simulation. The method for sterilizing medical products comprises the following steps: introducing a medical product into a sterilization device; irradiating the medical product with a radiation source, preferably an X-radiation source, in the sterilization device; determining the radiation intensity at each position on the medical product; controlling and/or re-adjusting the radiation source according to the relationship, [determined in a reference measurement or simulation and] stored in the control device, between radiation intensity at the detector and minimum dose in the medical product at the corresponding point, such that the medical product is homogeneously irradiated and thus sterilized.

Description

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Device and method for sterilizing medical products by means of X-ray radiation Description [1] The invention relates to a device and a method for sterilizing three-dimensional medical products using low-energy X-ray radiation Background of the invention

[2] Sterility is a key requirement for many medical products A medical product is described as sterile if the probability that a viable microorganism is on or in the product is less than or equal to 10-6 (EN 556-1 2001)

[3] A medical product describes an object or a substance that is used for medically therapeutic or diagnostic purposes for people In contrast to medicines, the main intended effect of medical products is primarily not pharmacological, metabolic or immunological, but physical or physicochemical Medical products are therefore all instruments, apparatuses, devices, software, substances or other objects used individually or in combination that are intended by the manufacturer for people for the following purposes. identifying, preventing, monitoring, treating or alleviating disease, identifying, monitoring, treating, alleviating or compensating for an injury or disability, investigating, replacing or modifying the anatomical structure or a physiological process, conception control and its intended main effect Likewise, "products that are specifically intended for cleaning, disinfecting or sterilizing" medical products are considered to be medical products

[4] One possibility for sterilizing medical products is that of irradiation with ionizing radiation (radiation sterilization) Methods used on a large scale for the irradiation of medical products are sterilization using gamma radiation (gamma sterilization), sterilization using accelerated electrons (e-beam sterilization, electron beam sterilization, beta sterilization) and sterilization using high-energy X-ray radiation (X-ray sterilization) Gamma sterilization

[5] Gamma radiation is a particularly penetrating electromagnetic radiation that arises from spontaneous transformations ("decay") of the atomic nuclei of many naturally occurring or artificially produced radioactive nuclides Gamma radiation is the term used to describe short-wave photons that are created by nuclear reactions, while X-ray radiation results from the change In speed of charged particles. Gamma radiation is often used to sterilize single-use medical devices such as syringes, needles, cannulas and IV sets, as well as food, since its penetration depth is usually more than 50 cm Radioisotopes, mostly cobalt-60 (6000) or cesium-137 (137Cs), emitted with photon energies of up to 1 3 or 0 66 MeV, have a technical application

[6] Gamma rays are electromagnetic waves (as well as light, infrared, X-ray or UV rays) However, gamma rays have a shorter wavelength (less than 0 005 nm) and therefore have more energy During irradiation, this energy is transferred to the electrons of the molecules of the products and generates highly reactive radicals in the process This is therefore also referred to as ionizing radiation These free radicals now break the DNA of the existing microorganisms such that they can no longer multiply and die The irradiated product is therefore sterile Since gamma radiation only affects the electron shell of the molecules, it is physically impossible for the irradiated product itself to become radioactive

[7] The irradiation process takes place in a special facility The gamma rays required therefor result from the decay of the radioactive isotope cobalt-60. Said isotope is stored in stainless steel cylinders within the facility and constitutes the radiation source During the irradiation operation, the radiation source is surrounded by the products to be irradiated on a conveyor system In order to be able to enter the facility safely, the radiation source can be lowered into a water basin, the water column of which shields the rays A great advantage is the good penetration capacity of the gamma radiation, which makes it possible to sterilize the products in the final packaging. This simplifies the production process and ensures that the products are not contaminated again by subsequent packaging work

[8] The energy absorbed by the product or the irradiated object during irradiation is measured in kilogray (kGy) The energy absorbed by the product or the irradiated object depends on various factors (including exposure time, radiation intensity of the source, density of the material, packing density and packing size of the products, packaging material) and is checked using one or more dosimeters It can thus be determined that every product receives the specified radiation dose Electron beam sterilization

[9] Electrons emitted by an electron source (cathode) are accelerated in an electric field (direct voltage or alternating field) in a vacuum vessel to almost the speed of light, either on curved paths (e.g. Rhodotron, cyclotron, betatron) or linearly (cathode ray tube, linear accelerator, Cockcroft¨
Walton accelerator, Van de Graaff accelerator) The accelerated electrons are then optionally deflected (scanned) by an alternating magnetic field in order to be able to expose a defined area, optionally additionally deflected by a static magnetic field in order to achieve product exposure deviating from the direction of acceleration, and then directed through a suitable exit window from the vacuum to the ambient atmosphere and then to the product The actual sterilization process takes place under ambient conditions Electron energies of 70 keV to 10 MeV are used for electron beam sterilization

[10] In the e-beam irradiation process, the beam generation begins with electrons generated in a hot cathode, which electrons are introduced into the acceleration unit, which is referred to as the cavity With the Rhodotron principle, said electrons pass through the cavity several times with the aid of magnetic deflection systems until they have reached the intended energy In electron beam treatment of medical products, the electrons are channeled out of the cavity with a maximum energy of 10 MeV The generated electrons are caused to move in a horizontally oscHlating manner by a scanning magnet, as a result of which the electrons or the X-ray photons sweep over the entire article to be sterilized X-ray sterilization

[11] The spectrum of X-ray radiation begins below extreme UV radiation at a wavelength of around 10 nm (super-soft X-ray radiation) and extends down to less than 1 pm (super-hard or high-energy X-ray radiation) The energy ranges of the gamma radiation and X-ray radiation overlap over a wide range Both types of radiation are electromagnetic radiation and therefore have the same effects with the same energy The distinguishing criterion is the origin in contrast to gamma radiation, X-ray radiation does not arise from processes in the atomic nucleus, but rather from high-energy electron processes The radiation spectrum generated in X-ray tubes is a superposition of a continuous spectrum (bremsstrahlung) with a discrete (characteristic X-ray radiation) spectrum Photons from X-ray tubes have an energy of approximately 1 keV to 250 keV

[12] For electron beam sterilization and X-ray sterilization, high-energy electrons are generated by an electron accelerator For electron beam sterilization, the electrons are used directly for sterilization During product treatment using X-ray technology, the electrons do not leave the vacuum vessel, but are accelerated onto a metal plate, which is referred to as the target. When interacting with this target, part of its energy is converted and emitted in the form of X-rays, which are used for product sterilization. Facilities with electron energies of 5-7 MeV are used for X-ray sterilization.

[13] X-rays, like gamma radiation, are a very penetrating type of radiation that allows larger volumes and higher densities to be sterilized than when using e-beam technology Gamma and X-ray sterilization are suitable for sterilizing palletized articles due to the high penetration depth of the photons Disadvantages of radiation sterilization

[14] The three sterilization methods explained have specific disadvantages Facilities for gamma sterilization are dependent on a radioactive isotope Both the production of Co-60 by neutron activation of 00-59 in nuclear reactors and the transport and disposal of the decay products are associated with safety risks and high costs. In addition, long-term availability cannot be ensured

[15] Electron beam sterilization is only suitable for medical products of small dimensions and densities due to its low penetration capacity compared with gamma or X-ray radiation of the same energy

[16] For X-ray sterilization, there is the difficulty that a large part of the electrical energy used is not inherently converted into X-ray radiation, but instead releases as heat on the X-ray target, and this results in a low degree of efficiency A cost-intensive high-energy electron accelerator is also necessary for electron beam and X-ray sterilization facilities

[17] Complex shielding measures are necessary for all 3 methods in order to ensure sufficient radiation protection Gamma, electron beam and X-ray sterilization facilities are therefore operated in a radiation protection bunker With the explained conventional sterilization methods, the construction of compact sterilization units that can be integrated directly into the manufacturing process of medical products is difficult and very time-consuming Low-enerqy X-ray radiation

[18] One possibility for implementing a sterilization method that is based on the sterilizing effect of ionizing radiation and that can be integrated into the continuous production process of many medical products is to use lower-energy ionizing radiation This has two main advantages the measures for shielding the radiation are reduced, since the depth of penetration of the radiation decreases with decreasing energy, in addition, no high-energy electron accelerators are necessary to generate low-energy X-ray radiation, but compact electron guns or X-ray tubes can be used Using these devices, electron energies of up to approximately 800 keV can be generated In the following, the term "low-energy" or "soft" X-ray radiation denotes the energy range up to this limit

[19] Low-energy X-ray radiation can be generated without the use of a high-energy electron accelerator and requires less effort for radiation shielding, which allows a sterilization method to be implemented that can be integrated into the continuous production process of many medical products Penetration depth

[20] In order to sterilize a medical product using ionizing radiation, the radiation has to be able to penetrate sufficiently deeply Accelerated electrons (in electron beam sterilization) have a high probability of interaction with matter due to their particle properties Their depth of penetration is therefore low For example, electrons having an energy of 600 keV have a penetration depth of approx 2 mm in polyethylene and are therefore only suitable for sterilizing two-dimensional, i e , very thin, medical products or for sterilizing surfaces Low-energy electrons are therefore not suitable for sterilizing three-dimensional medical products, i e , medical products of which the height/thickness is on the same order of magnitude as the length and width thereof and is in the range of centimeters or greater ,

[21] In contrast to electrons, photons (gamma radiation/X-ray radiation) have neither a charge nor a mass The interaction probability of photons when penetrating matter is therefore much lower than for electrons Gamma radiation or X-ray radiation can therefore penetrate much more deeply into matter than electron radiation of the same energy Photon energies in the low two-digit keV range are sufficient to penetrate many three-dimensional medical products such as dialyzers with photon radiation An increase in the energy of the photon radiation leads to an increase in the dose homogeneity If the homogeneity of the input absorbed dose is too low, high doses that cause material damage can occur at points at which dose maxima form These can affect the performance characteristics of the medical product, for example reducing biocompatibility Prior art

[22] WO 2014/132049 A2 (Apparatus for the generation of low-energy X-rays) discloses a device that is used to generate X-ray radiation with low energy, as well as a method for sterilizing products using this device The field of application for sterilization using this device includes, inter elle, medical products and pharmaceutical products. The device differs in some respects from a classic X-ray tube (for example the X-ray radiation generated at the anode (X-ray target) is scattered back to the cathode and penetrates said cathode, whereas in an X-ray tube the anode has a defined angle and the X-ray radiation is emitted at an angle)

[23] GB 2 440 310 A (Surface sterilization) discloses a device which generates X-ray radiation with an energy of less than 50 keV. The apparatus can be used to sterilize surfaces and thin materials

[24] EP 2 668 963 Al (Device for sterilizing containers with sterilization checking) discloses a device for sterilizing containers, which are guided, by means of a transport device, past a sterilization means, where they are sterilized by means of radiation The containers are then moved past another means that checks the success of the sterilization. Electron radiation is mentioned as the preferred type of radiation for the sterilization and it is explained that X-ray radiation or UV radiation can also be used to sterilize the containers Other than containers, no further application examples are mentioned The purpose of the method is exclusively to sterilize surfaces

[25] WO 2008/129397 A2 (Sterilization system for PET containers and bottles) discloses a system for sterilizing containers made of PET Electron radiation is used for the sterilization The sterilization effect of the electron radiation is facilitated by X-ray targets being arranged within the system, which targets convert the incident electron radiation into X-ray radiation

[26] WO 93/17446 Al (A microwave X-ray source and methods of sterilization) discloses a device which generates X-ray radiation by means of a cyclotron resonance plasma Among other things, the sterilization of medical equipment and instruments is disclosed as an application Disadvantages in the prior art

[27] X-ray sources in the low-energy range are mainly used for analytical purposes They are therefore designed to achieve the highest possible image quality Sterilization, in contrast, requires the generation of a high radiation power in order to achieve the required sterility assurance level (SAL) in the shortest possible time The use of commercial X-ray tubes for sterilizing medical products is therefore not expedient

[28] Conventional sterilization methods for medical products that are based on the sterilizing effect of ionizing radiation (gamma, electron beam and high-energy X-ray sterilization) can be integrated into the production process of medical products only with great effort The main reason for this is the high radiation energy that occurs, which requires complex radiation protection measures Electron beam and high-energy X-ray sterilization also require the use of a high-energy electron accelerator of high radiation energy and power, which takes up a lot of space and is cost-intensive Object of the invention

[29] The object of the present invention is therefore that of providing a device and a method for sterilizing medical products, which device is compact, avoids the use of radioactive substances, is easy to control in an open-loop and closed-loop manner, has a high level of sterilization efficiency, allows a high penetration depth and achieves a homogeneous dose in the product to be sterilized

[30] As explained above, low X-ray energies lead to reduced homogeneity of the dose input into a three-dimensional medical product, and this can lead to material damage in these regions if a local overdose is then necessary Furthermore, many medical products are inhomogeneous in their geometric shape and material composition, i e , there are regions in which the medical product has a greater thickness and/or density than in other regions, and this can also cause high local overdoses and thus material damage

[31] Thus, it is preferably also an object of the invention to irradiate an inhomogeneous medical product/three-dimensional medical product as homogeneously as possible even with low X-ray energies or to reduce the overdose factor (max locally applied dose in the product/target dose).
Brief description of the invention

[32] The object or objects of the invention is/are achieved by a method for sterilizing medical products according to claim 1 and a device for sterilizing medical products according to claim 9

[33] The device for sterilizing at least one medical product has at least one radiation source, preferably at least one detector for detecting a radiation intensity, at least one holder for holding a , medical product in front of the radiation source, preferably between the radiation source and the detector, and at least one control unit for controlling the radiation source and preferably the holder in an open-loop or closed-loop manner The intensity of the radiation from the radiation source can be controlled by the control unit, preferably continuously or cyclically, in a closed-loop manner by means of feedback and/or in an open-loop manner by means of feedforward control such that the radiation intensity assumes a predetermined or predeterminable value that is minimally necessary for sterilization at every position of the medical product. In other words, the intensity of the radiation from the radiation source can be controlled by the control unit, preferably continuously or cyclically, in a closed-loop manner by means of feedback and/or in an open-loop manner by means of feedforward control such that predetermined optimal intensity distribution of the X-ray radiation is achieved which leads to achieving the required sterilization dose at every point of the medical product, more homogeneous dose distribution in the medical product (minimization of the overdose factor) and a reduced irradiation time (= time to achieve the required sterilization dose) Predetermined optimal intensity distribution of the X-ray radiation is preferably determined experimentally by means of dose mapping or using a simulation Every position of the medical product means at every position in/on the three-dimensional body of the medical product

[34] The device for sterilizing at least one medical product can also be referred to as a sterilization device or sterilization unit or can be provided and adapted, in the form of a sterilization device or sterilization unit, for the sterilization of medical products

[35] The radiation source is preferably a directional radiation source, preferably an electromagnetic radiation source, preferably an X-ray radiation source and particularly preferably a low-energy X-ray radiation source, which is provided and adapted to provide/generate primary electrons having an energy of 100 to 800 keV The radiation source is also provided and adapted to individually set the radiation intensity/the absorbed dose of the radiation locally/in a spatially resolved manner/in a locally determined manner/individually, that is to say cyclically or continuously within an exposed irradiated region The absorbed dose input into the medical product can thus be locally controlled in an open-loop or closed-loop manner, generally resulting in an inhomogeneous/controllable irradiation intensity within the medical product

[36] The detector is preferably provided and adapted to detect the radiation from the radiation source The detector is also preferably an area detector (detector having a large-area sensor), preferably an X-ray detector or an area X-ray detector The detector is further preferably a digital detector which generates data signals and forwards said signals to a control device The radiation source emits radiation and emits the radiation directionally, the detector is preferably introduced in the directional radiation/in the beam path This means that the detector is irradiated by the radiation source The detector preferably has at least the size required to be able to detect the smallest dimension of the shaded area, preferably at least the size required to detect the entire area shaded =

by the medical product, in order to be able to draw conclusions about the absorbed dose in the entire medical product If the detector is moved in the direction of the other dimension, or if the medical product moves in this direction, the same statement can be obtained

[37] A medical product is generally known and is defined in the introductory part The method and the device are provided and adapted to sterilize at least one medical product at a time

[38] The device has a holder/clamping device/holding device/medical product holder, which is preferably provided and adapted to hold at least one medical product, particularly preferably between the radiation source and the detector The holder further preferably has a transport device by means of which the medical product can be transported between the radiation source and the detector In other words, the transport device moves the medical product into the beam path for a certain period and then out again Furthermore, the holder preferably has a movement device/rotation device which rotates the medical product about at least one axis or causes said product to wobble In other words, the at least one medical product can be secured/stabilized/held in the holder and, preferably, can be rotated about the longitudinal axis The holder is introduced in the directional radiation/in the beam path of the radiation source, preferably an X-ray radiation beam path The holder and thus the medical product are arranged between the radiation source and the detector In one variant, the holder can only introduce part of the medical product into the beam path if the size thereof exceeds the irradiated region in the beam path, but it can also introduce a single medical product or a plurality of medical products into the beam path at the same time and thus sterilize said product(s) Furthermore, the holder holds the medical product in such a way that the irradiation of the product is not hindered or any hindrance is minimized The holder preferably holds the medical product or the medical product is clamped in the holder in such a way that the holder does not overlap the medical product in the direction of irradiation. In other words, the medical product and the holder are not arranged one behind the other in the direction of radiation, but rather in parallel therewith The medical product is preferably held or clamped by the holder on the outer surfaces of said product

[39] In a further aspect of the invention, the holder has a transport device by means of which the at least one medical product can be transported through a beam path between the X-ray radiation source and the X-ray detector In other words, the at least one medical product can be transported mechanically/electromechanically through the beam path, preferably by means of a conveyor belt or the like

[40] The device can thus consist of a radiation source and a detector, between which the medical product is introduced, but may also consist of a plurality of radiation-source¨detector pairs, the medical product being arranged therebetween The device preferably has at least two, preferably three, X-ray radiation sources and X-ray detectors

[41] The method for sterilizing medical products has the following steps a introducing a medical product into a sterilization device, locally irradiating the medical product with a radiation source of the sterilization device, locally determining the radiation intensity by means of (dose mapping) or using simulations, and controlling the radiation source in an open-loop or closed-loop manner by means of a control unit such that at least one radiation intensity that is minimally necessary for sterilization is achieved at every position of the medical product In other words, predetermined optimal intensity distribution of the X-ray radiation is achieved, which leads to achieving the required sterilization dose at every point of the medical product, more homogeneous dose distribution in the medical product, and a reduced irradiation time.

[42] The medical product can be introduced into the sterilization device/irradiation device/device for sterilizing medical products manually and/or mechanically, preferably between the radiation source and the detector or the sensor of a detector Further preferably, the medical product can be introduced/subsequently changed automatically, preferably in a computer-controlled manner In addition, the medical product is further preferably held/secured/supported by a holder/clamping device between the radiation source and the detector The holder has a movement device and/or rotation device and/or a transport device The rotation device of the holder rotates the medical product about at least one axis and the transport device changes the medical product or transports said product

[43] The local/individual irradiation, preferably stepwise and/or continuous, of the medical product (along the medical product) with a radiation source of the sterilization device is preferably carried out by means of a directional radiation source or electromagnetic radiation source or X-ray radiation source or low-energy X-ray radiation source or low-energy X-ray radiation source which is provided and adapted to use a primary electron having an energy of 100 to 800 keV Local irradiation is to be understood as irradiation having a local intensity resolution that can irradiate different surfaces/points/locations/positions of an object or medical product with a relatively/mutually different radiation/radiation intensity/radiation dose/dose/absorbed dose/photon energy This means that the medical product can be irradiated with a different intensity at every point/individual points/other points

[44] The determination of the radiation intensity at every position of the medical product shows how much of the radiation emitted by the radiation source is absorbed by the medical product

[45] The radiation source is controlled in an open-loop or closed-loop manner such that at every position of the medical product a radiation intensity that is minimally necessary for sterilization is achieved in the medical product In other words, previously determined optimal intensity distribution of the X-ray radiation is achieved, which leads to the required sterilization dose being achieved at every point of the medical product, more homogeneous dose distribution in the medical product, and a reduced radiation time In other words again, a(n) (intensity) model for irradiation for the medical product can be set up in advance and loaded onto a storage unit of the control unit/CPU such that the control unit controls the spatial resolution of the radiation source The (intensity) model can be determined by a simulation/calculation or reference measurement

[46] In a further aspect of the invention, the medical product is irradiated from a plurality of sides and/or rotates about at least one axis, preferably in/on/with the holder This means that the medical product is introduced into a sterilization device having a plurality of radiation sources and/or rotates on/in/with the holder, preferably about its own axis. In addition to the plurality of radiation sources, the device can also have a plurality of detectors

[47] In the variant with a plurality of radiation sources, the medical product is irradiated from two, three or more sides at the same time The means for generating the low-energy X-ray radiation is accordingly designed such that there is a plurality, and these means are arranged around the medical product so as to be uniformly offset. Irradiation from multiple sides has the advantage that the use of a plurality of X-ray sources with the same power as with irradiation from one side shortens the sterilization time Alternatively, by reducing the power of the individual X-ray sources, the thermal load on the targets can be reduced and their service life can thus be increased Since the medical product does not have to be rotated, the holder can be constructed in a structurally more simple way The dose homogeneity increases with an increasing number of X-ray sources that are arranged around the medical product The rotation of the medical product during the irradiation is comparable to the arrangement of an infinite number of X-ray sources around the medical product and therefore provides the best dose homogeneity.

[48] In a further alternative embodiment variant, the design of irradiation from two or more sides is selected and arranged two or more times one behind the other This results in a sterilization tunnel through which a plurality of medical products can be transported by means of a transport device and, in the process, can be irradiated and thus sterilized For a given target dose, the transport speed and thus the achievable throughput are dependent on the intensity of the radiation sources and on the number of radiation sources arranged one behind the other in the transport direction

[49] Further design variants can be obtained by combining the design variants explained above For example, the rotating irradiation can also take place from two or more sides in order to achieve a high level of dose homogeneity with a reduced irradiation time or reduced thermal load of the target 1 i

[50] In a further aspect of the invention, the medical product is irradiated in such a way that the radiation intensity of the X-ray radiation varies locally and is set such that the dose is distributed as homogeneously/evenly as possible in the medical product This means that at least the minimum dose occurs at every point/every position of the medical product In this case, specific intensity distribution of the transmitted X-ray radiation is preferably established, which can be measured by a detector located behind the product in the beam path in order to readjust the radiation source accordingly if necessary This distribution of the radiation intensity is referred to as the optimal intensity distribution

[51] As already explained above, the radiation source can be controlled in an open-loop or closed-loop manner by the control unit, such that the optimal intensity distribution is achieved at every position of the medical product The control is carried out by the position and the shape of the medical product in the sterilization device being stored on the control device and the medical product being irradiated with a previously determined intensity by the radiation source in a spatially resolved manner A(n) (intensity) model (a model for spatially resolved irradiation with a predetermined intensity) for the particular medical product is thus set up in advance The (intensity) model is determined by a reference measurement or by means of a simulation The reference measurement includes, inter alia, dose mapping

[52] With dose mapping, a test sample is equipped with dosimeters (e g , alanine dosimeters).
The dosimeters are placed wherever minima and maxima of the dose are expected The medical product is then irradiated and the dosimeter is evaluated

[53] To determine the optimal intensity distribution, the medical product is divided over its length into a plurality of regions that differ significantly in terms of their geometry and/or material composition For each region', a factor k_i is determined by which the intensity of the X-ray radiation in the corresponding region is multiplied in order to achieve the optimal intensity for this region is selected in each case such that the minimum dose in the region under consideration corresponds to the required sterilization dose To determine the factor the occurring minimum dose D_min,i has to be determined for each region, either by means of dose mapping or by means of simulations The harmonic mean D_min,HM is calculated from the dose minima D_rnin,i of each region Dmin,f/M (Dnun,t 0) 1 Dmin,1

[54] The factor for each region results from the harmonic mean of the minimum doses divided by the dose minimum of the particular region kt Dmin,f/M/Dmin,t The data obtained in this way for the intensity distribution are valid for all medical products of this type and can be used as long as the geometry and materials of the medical product as well as the parameters of the sterilization apparatus (radiation energy, distance between target and medical product, etc) remain unchanged

[55] The simulation can be a Monte Carlo simulation or a simulation based on the law of attenuation or the like.

[56] The detector can be used to check the dose introduced into the medical product, in order to release the medical product immediately after irradiation For this purpose, the determined intensity distribution is set in a pre-test and a medical product equipped with dosimeters is irradiated Since the medical product is located in the beam path, "shadowing" occurs on a detection surface of the detector The doses measured at the detector during the irradiation are recorded The dosimeters in the medical product are then evaluated and checked to determine whether the required sterilization dose has been achieved at every point. If this is the case, the data recorded by the detector can be used for all subsequent irradiations of medical products of the same type or the same size During each sterilization process, the doses determined at the detector are compared with the recorded doses If the deviations do not exceed a specified limit, the irradiated medical products can be designated as sterile and released

[57] The variation of the intensity of the radiation source or of an electron beam impinging on an X-ray target over the surface of the target allows an X-ray radiation field to be adapted to the medical product in a spatially resolved manner For at least one medical product, the holder allows the medical product to move in space, preferably to rotate axially along an axis The detector allows the X-ray radiation absorbed by the medical product to be measured Shielding the sterilization device protects the operator The method for using this sterilization unit for sterilizing medical products is carried out using the above device The X-ray radiation field is, so to speak, adapted to the medical product to be sterilized, and is also adapted continuously over time if the medical product is rotating in order to adapt the absorbed dose. The intensity distribution is preferably determined before the irradiation in series on test samples of the medical product to be irradiated.
For this purpose, either dose mapping or computer simulations (e g , Monte Carlo simulation) are carried out

[58] The shielding of the sterilization unit is designed in such a way that the production staff and the environment are protected from the effects of radiation, and the applicable laws, regulations and standards are complied with I
,

[59] The holder is designed in such a way that it can hold at least one or more medical products at the same time and does not hinder the desired radiation exposure of the product In one embodiment variant, the holder makes it possible to move the medical product during the irradiation, and in the preferred embodiment for the example product makes it possible to rotate said product With this system, the dose inhomogeneity due to the depth dose distribution that occurs at low energies because of the limited penetration depth of the X-ray radiation can be improved The dose homogeneity can be increased by increasing the number of X-ray sources that are arranged around the medical product The rotation of the medical product corresponds to an infinite number of X-ray sources and thus represents the best possible case in terms of achieving a high level of dose homogeneity The holder is preferably designed in such a way that fully automatic loading and unloading of the medical product(s) is made possible

[60] The invention makes it possible to achieve a high level of dose homogeneity despite the low energy of the X-ray radiation Furthermore, due to the low radiation energy and the associated lower required shielding measures, for example in comparison with Co-60 gamma irradiation facilities or MeV e-beam irradiation facilities, the invention allows integration into the continuous production process of medical products There is no longer any dependency on service providers who perform sterilization using gamma radiation, high-energy electron radiation or high-energy X-ray radiation The system is easily scalable depending on the throughput of the production system, the necessary number of sterilization units is purchased A high level of production reliability can be achieved by operating a number of sterilization units redundantly Sterilization using low-energy X-ray radiation also has the known advantages of methods that are based on the sterilizing effect of ionizing radiation This includes avoiding the use of toxic substances such as ethylene oxide, the possibility of sterilization in the final packaging and parametric product release based on the applied absorbed dose

[61] Process observation is preferably provided for monitoring the sterilization process This consists of at least one X-ray radiation detector which is arranged in such a way that it is possible to draw conclusions about the absorbed dose in the medical product For this purpose, electronically readable detector plates are preferably arranged in such a way that the medical product to be sterilized is located between the X-ray source and the detector plates The size of the detector plate is selected such that it fully detects the X-ray radiation shadowed by the medical product and also covers a region in which the X-ray radiation was not attenuated by the medical product From the difference in the intensity of the X-ray radiation attenuated by the medical product and the unattenuated X-ray radiation, conclusions can be drawn about the energy absorbed by the medical product A method for sterilizing three-dimensional medical products using low-energy X-ray radiation can be carried out in the following steps

[62] For the sake of simplicity, the specific sequence of the method is explained only for a single medical product = providing and introducing the medical product in a radiation-resistant sterile barrier system/packaging suitable for sterilization using ionizing radiation (optionally removing oxygen from the packaging for medical products for which irradiation in the presence of oxygen can cause material damage), = equipping the sterilization unit with the packaged medical product, preferably by means of an automatic handling system, = initiating all necessary measures to ensure the radiation safety of the arrangement, = irradiating the medical product with locally differing radiation intensities according to the above description over a defined irradiation time in order to achieve the required irradiation dose, which is required, for example. according to national standardswithdrawing the sterile medical product, preferably by means of an automatic handling system, = evaluating the data from the X-ray detectors and dosimetrically releasing the medical product

[63] The device has a radiation source and preferably a detector, between which a medical product is introduced, the radiation source being controllable by means of an open-loop and/or closed-loop control device in a closed-loop manner by means of feedback from the detector or in an open-loop manner by means of a result of dose mapping or a simulation Preferably, during closed-loop control of the radiation source using the spatially resolved intensity, the closed-loop control is carried out in such a way that the setpoints of the spatially resolved detector are reached The method for sterilizing medical products comprises the following steps introducing a medical product into a sterilization device, irradiating the medical product with a radiation source, preferably an X-ray radiation source, of the sterilization device, determining the radiation intensity at every position of the medical product, controlling and/or readjusting the radiation source according to the relationship, [determined in a reference measurement or simulation and] stored in the control device, between the radiation intensity at the detector and the minimum dose in the medical product at the corresponding point, such that the medical product is homogeneously irradiated and thus sterilized

[64] Description of the figures Fig 1 shows the structure of the device in an abstract form Fig 2 shows an X-ray radiation source with a solid target in a vacuum (classic X-ray tube) Fig 3 shows an X-ray radiation source with a transmission target Fig 4 shows a simplified model for operating adapted intensity distribution =

Fig 5 shows the targeted change in the intensity distribution of the X-ray radiation field in accordance with the geometry and material composition of a medical product (here by way of example for a dialyzer) Fig 6 shows the increase in dose homogeneity by increasing the number of X-ray sources Fig. 7 shows a second embodiment of the invention, irradiation from three sides (holder and shield not shown) Fig 8 shows a third embodiment of the invention, a two-sided arrangement of a plurality of X-ray modules to form a sterilization tunnel (X-ray detector, holder and shield not shown)

[65] Fig. 1 shows, in an abstract form, the structure of the device for sterilizing medical products according to a preferred embodiment of the invention An X-ray radiation source 2 (radiation source) is introduced into a sterilization device 1. The X-ray radiation source is controlled by a CPU/control unit 3. The representation in Fig. 1 is schematic and the CPU 3 is actually located outside the radiation space The radiation source 2 emits directional radiation 4 with a locally determined absorbed dose or intensity A detector 6 is located in the direction of the directional radiation 4 A
medical product 8, for example a dialyzer, is introduced in front of the detector 6 in the directional radiation 4, i e., between the radiation source 2 and the detector 6 The medical product 8 is held by a holder 10 and can also be rotated by said holder

[66] Fig 2 shows an X-ray radiation source with a solid target in a vacuum (classic X-ray tube) The radiation source consists of an electron source 12 which directionally accelerates electron radiation 14 The electron radiation 14 hits an X-ray target 16 and generates directional X-ray radiation 4 at said target The X-ray radiation emerges from the vacuum through the exit window 18

[67] Fig. 3 shows an X-ray radiation source with a transmission target The structure of the X-ray source in Fig. 3 is analogous to that in Fig 2, with the exception that the electron radiation does not hit a solid X-ray target, the X-ray radiation being generated at said target, but rather the electron radiation 14 hits a very thin X-ray target 22 that simultaneously serves as an exit window, in which target the directional X-ray radiation 4 is generated in the direction of the primary electron radiation

[68] In other words, the arrangement of the X-ray target 16 and 22 can be possible in two variants the X-ray target can be designed as a solid target (thick target) 16, which is located within the vacuum vessel of the electron accelerator (this structure corresponds to the classic X-ray tube) The X-ray target can, however, also be designed as a transmission-type target (thin target) 22 ,

[69] The electron source 12 subsequently has,ie , between the electron source 12 and the target 16, 22, a system for the spatially resolved increase or decrease in the intensity of the electron current impinging on the X-ray target 16, 22 in defined regions The X-ray target then converts the kinetic energy of the accelerated electrons into X-ray radiation with a spatially resolved increase or decrease in intensity

[70] The X-ray target 16, 22 preferably consists of a metal with a high atomic number One embodiment is tungsten because of its high X-ray yield and very good heat resistance. Another embodiment is silver, since its emission lines of the characteristic X-ray radiation are in a lower energy range than for tungsten In this lower energy range, the mass energy absorption coefficient pen/p of the materials of the medical product is greater than at higher energies, as a result of which the absorbed dose input into the medical product is greater, and this can lead to increased efficiency of the irradiation process The X-ray target 16, 22 preferably has a means for cooling said target

[71] Fig 4 shows the absorbed doses that occur, greatly simplified, by means of two individual, one-dimensional, monoenergetic X-rays 24 and 26 extending in parallel The two X-rays penetrate a medical product 8 consisting of a homogeneous material, the thickness of the material which is penetrated by the ray 24 being only half as great as the thickness of the material which is penetrated by the ray 26 A detector 6 is shown in the beam direction behind the medical product 8 In the high-density region, a longer irradiation time is required to reach the sterilization dose than in the low-density region However, since the medical product 8 is irradiated as a whole, every region experiences the same irradiation time The low-density region is thus irradiated for a longer time than would be necessary to achieve the sterilization dose

[72] Fig 5 shows the targeted change in the intensity distribution of the X-ray radiation field in accordance with the geometry and material composition of the medical product 8, here by way of example for a dialyzer (top picture schematic representation of the medical product, bottom picture location-dependent radiation intensity) In the region of the PUR potting compound (9), a dialyzer has a higher density at the two ends of the dialyzer than in the middle region In order to achieve more homogeneous dose input, the intensity of the radiation field is increased in the high-density region and reduced in the low-density region (total intensity or power remains constant) As an alternative or in addition to this, homogeneous dose input can also be achieved by estimating a longer irradiation time and/or rotating the dialyzer during irradiation This results in more homogeneous dose distribution overall The irradiation time across the entire medical product is reduced This reduced irradiation time in combination with the reduced radiation intensity in the low-density region leads to a lower maximum dose in the low-density region, and this reduces potentially harmful radiation-induced material changes. In the high-density region, in contrast, the maximum dose remains unchanged, since the reduced irradiation time and the increased radiation intensity balance each other out. The reduced irradiation time results in increased efficiency of the process I

In Fig 5, the dialyzer ports of the dialyzer are drawn leading upward (leading away from the image of the radiation intensity), while the radiation is radiated onto the drawing in the image plane

[73] Fig 6 shows the increase in dose homogeneity by increase in the number of X-ray sources, with a rotation of the medical product in front of an X-ray source being the best case (here simulated with 16 sources) Simulation parameters solid tungsten target, target angle 450, electron energy 400 keV, 1 mm Al filter, distance from the X-ray source(s) to the center of the dialyzer 12 cm, the dose absorbed in water is shown A shows the absorbed dose in the case of one source on the left, B shows the absorbed dose in the case of two sources, on the left and right, respectively, and C
shows the absorbed dose in the case of 16 sources evenly distributed around the medical product

[74] Fig 7 shows a second embodiment of the invention, more precisely irradiation of the medical product 8 from three sides (holder and shield not shown) The medical product 8 is irradlated with directional X-ray radiation 4 from three radiation sources 2 that distributed uniformly on one plane at an angular spacing (at a circular angle of approx 120 ) A detector is located in each case behind the medical product 8 in the radiation direction of the X-ray radiation

[75] Fig 8 shows a third embodiment of the invention, more precisely an embodiment in which a two-sided arrangement of a plurality of X-ray modules to form a sterilization tunnel is shown (X-ray detector, holder and shield not shown) The medical products 8 are irradiated from two opposite sides by radiation sources 2 and transported in a transport direction 28 (shown schematically) by means of a transport device (not shown) The medical products 8 are thus conveyed through an "irradiation tunnel" A different arrangement of the radiation sources 2, for example as shown in Fig 7, would also be possible here , , List of reference signs 1 sterilization device 2 radiation source 4 directional X-ray radiation 6 detector 8 medical product holder 12 electron source 14 electron radiation 16 X-ray target 18 exit window vacuum 22 exit window with integrated X-ray target 24 low-intensity X-ray 26 high-intensity X-ray 28 transport direction

Claims (14)

, Claims

1 Method for sterilizing medical products (8), comprising the following steps a introducing a medical product (8) into a sterilization device (1), b locally irradiating the medical product (8) with a radiation source (2) of the sterilization device (1) in a stepwise or continuous manner, c locally determining the radiation intensity in the medical product (8) by means of dose mapping and/or a simulation, d controlling, in an open-loop or closed-loop manner, the radiation source (2) by a control device (3) such that a radiation intensity that is minimally necessary for sterilization is achieved everywhere at every position of the medical product (8)

2 Method according to claim 1, characterized in that the medical product (8) is irradiated from a plurality of sides at the same time and/or rotates about an axis

3 Method according to either claim 1 or claim 2, characterized in that the radiation intensity is different and/or variable in terms of spatial resolution

4 Method according to claim 1, characterized in that the medical product (8) is introduced between the radiation source (2) and a detector (6)

Method according to any of claims 1 to 4, characterized in that the radiation source (2) is controlled in a closed-loop manner by means of feedback from the detector (6)

6 Method according to any of claims 1 to 5, characterized in that the detector (6) has an area which is larger than the medical product (8), and determines the radiation intensity

7 Method according to any of claims 1 to 5, characterized in that the radiation source (2) is controlled in an open-loop manner by means of the simulation or by means of the dose mapping

8 Device (1) for sterilizing at least one medical product (8), having - at least one radiation source (2), - preferably at least one detector (6) for detecting a radiation intensity, - at least one holder (10) for holding a medical product (8) in front of the radiation source (2), preferably between the radiation source (2) and the detector (6) and - at least one control unit (3) for controlling the radiation source (2) and preferably the holder (10) in an open-loop or closed-loop manner, characterized in that the intensity of the radiation from the radiation source (2) can be controlled by the control unit (3) continuously or cyclically in a closed-loop manner by means of feedback and/or in an open-loop manner by means of feedforward control such that at least one radiation intensity that is minimally necessary for sterilization is achieved at every position of the medical product (8)

9 Device (1) according to claim 8, characterized in that the radiation source (2) is provided and adapted to provide photon energy of 100 to 800 keV

10 Device (1) according to either claim 8 or claim 9, characterized in that the holder (10) has a transport device by means of which the medical product (8) can be transported between the radiation source (2) and the detector (6)

11 Device (1) according to any of claims 8 to 10, characterized in that the holder (10) is rotatable, preferably about at least one axis

12 Device (1) according to any of claims 8 to 10, characterized in that the device (1) has in each case at least two, preferably three, radiation sources (2) and detectors (6)

13 Device (1) according to any of claims 8 to 12, characterized in that the control unit (3) has a storage medium on which the method steps according to claim 1 are stored

14 Device (1) according to any of claims 8 to 13, characterized in that the radiation source (2) is provided and adapted to provide X-ray radiation from primary electron radiation having an energy of 100 to 800 keV