EP3982754A1

EP3982754A1 - Method for determining the effectiveness of a sterilization method for a medical product in a sterilizer, data processing system, computer program product, and medical product

Info

Publication number: EP3982754A1
Application number: EP20711612.0A
Authority: EP
Inventors: Manuel FEUERHUBER; Ralf NEUSCHWANDER; Thomas TAUPITZ; Christoph Hochenauer
Original assignee: Fresenius Medical Care Deutschland GmbH
Current assignee: Fresenius Medical Care Deutschland GmbH
Priority date: 2019-06-12
Filing date: 2020-03-20
Publication date: 2022-04-20
Also published as: US20220205014A1; WO2020249276A1; CN113950251A; EP3982753A1; US20220257820A1; WO2020249243A1; CN113950252A; DE102019116013A1

Abstract

The invention relates to a method for determining the effectiveness of sterilisation methods for medical products, comprising the following steps: providing a data structure, said data structure representing a grid formed from a plurality of three-dimensional cells; reproducing in said data structure the medical product placed in the sterilization device in such a way that a first plurality of cells of said grid represent a body of said medical product and that a second plurality of cells represent an interior space of the sterilization device which is not occupied by the body of the medical product; reproducing an initial state in said data structure in such a way that each cell of said second plurality of cells has data relating to the temperature prevailing in the cell, which is assigned to the amount of a first medium located in the area of the cell and to the amount of a second medium located in the area of the cell; reproducing step by step changes in temperature, in the amount of the first medium and the amount of the second medium occurring during the sterilization process in each cell of the second plurality of cells, and calculating a reduction in bacterial load in each cell of the second plurality of cells during the sterilization process, taking into account the temperature, the amount of first medium and the amount of second medium prevailing in each step in the respective cell. The invention also relates to a data processing system and to a computer program product.

Description

Method for determining the effectiveness of a sterilization process for a medical product in a sterilization device, data processing system,

Computer program product, and medical product

The invention relates to a method for determining the effectiveness of a sterilization method for a medical product or a packaged medicament in a sterilization device. In the following, in order to avoid lengths, medical devices are mainly used, always including packaged drugs.

Sterilization processes are used to sterilize medical devices or packaged pharmaceuticals before they are used, i.e. to free them from potentially harmful germs. Known sterilization methods include steam sterilization, hot air sterilization, autoclaving, gamma sterilization, electron steel sterilization, ethylene oxide sterilization and plasma sterilization. In the context of this application, drugs, in particular packaged drugs, further in particular bag-packed drugs, further in particular bag-packed solutions and devices for peritoneal dialysis, are referred to as medical products.

The sterilization usually takes place in a closed sterilization chamber of a sterilization device into which the medical product is placed.

In order to avoid endangering patients on whom the medical product is to be used, it must be ensured that the medical product is actually sterile, i.e. essentially free from germs, after the sterilization process has been carried out.

While the basic effectiveness of known sterilization processes has been sufficiently scientifically proven, the actual effectiveness of a sterilization process when applied to a specific medical product depends on many parameters, including the shape and material properties of the medical product and the selected process parameters of the sterilization process, e.g. the temperature profile, media quantities used and the duration of the process.

Since the individual control of the sterility of a medical product is practically impossible without at least limiting the usability of the medical product, the sterility is verified by validating the sterilization process used. It is scientifically proven that a with sterilization process carried out with certain parameters always achieves the desired result. The desired result is defined by the factor by which the germ load in the medical product is reduced by the sterilization process. An effective sterilization can, for example, be considered to have taken place if the germ load has been reduced by a factor of 10 ¹² .

A common method for determining the effectiveness of a sterilization process consists in placing a test specimen at a critical point on a medical product which is provided with a known bacterial load. A critical point here is a point on the medical product at which a particularly low effect of the sterilization process is expected, for example because the point heats up particularly slowly or because it is particularly difficult to reach for media used for sterilization.

The medical device is then subjected to the sterilization process. The test specimen is then removed and the remaining germ load is determined.

Paper strips that are inoculated with particularly temperature-stable germs, for example with Geobacillus stearothermophilus, are often used as test specimens.

If the evaluation of the test specimen shows that the required reduction in bacterial load has been achieved, the sterilization process is considered safe and has been validated.

While the method described is generally recognized, it does have considerable disadvantages in some cases. On the one hand, the evaluation of the test specimens requires a considerable amount of equipment and time, since an incubation period of several days in a nutrient medium is required before the remaining germs can be evaluated in order to return to a germ density that can be meaningfully evaluated. On the other hand, it is often difficult to introduce the test specimens into the medical product to be sterilized. If, for example, the medical product has a closed volume, this may have to be opened in order to introduce the test body. This can also falsify the results of the validation. In addition, it can happen that a critical point on the medical product is difficult or impossible to reach with the test specimen, for example if the medical product is thin Includes channels or tubing. Another disruptive effect is that a test specimen influences the concentration of a medium used in the sterilization process, for example by a strip of paper absorbing water and thus reducing the humidity in its surroundings. From the patent applications WO 00/27228 A1 and WO 00/27229 A1 methods are known for calculating the reduction in bacterial load achieved at a critical point of a food product during thermal sterilization. For this purpose, however, only the temperature profile is simulated at a so-called "cold spot" of the product, the dependence on other media is not taken into account.

In particular in the case of sterilization processes in which more than one medium is used, these processes are inadequate.

It is therefore an object of the invention to provide a method for determining the effectiveness of a sterilization method for a medical product in a sterilization device, which method is improved with regard to the problems described.

Another object of the invention is to provide an improved method for validating a sterilization method for medical products.

One or more of the stated objects are achieved according to a first aspect of the invention by a method for determining the effectiveness of a sterilization method for a medical product in a sterilization device, comprising the steps of: providing a data structure, the data structure being a grid formed from a plurality of three-dimensional cells represents, replication of the medical product arranged in the sterilization device in the data structure in such a way that a first plurality of cells of the grid represent a body of the medical device and that a second plurality of cells represent an interior of the sterilization device that is not occupied by the body of the medical device , Simulating an initial state in the data structure in such a way that each cell of the second plurality of cells contains data relating to the temperature prevailing at the location of the cell, the amount of a first Me diums, and the amount of a second medium in the area of the cell replicating, stepwise, changes in temperature, amount of first medium, and amount of second medium occurring in each cell of the second plurality of cells during the sterilization process, calculating a reduction achieved in each cell of the second plurality of cells during the sterilization process a germ load taking into account the temperature prevailing in each step in the respective cell, the amount of the first medium, and the amount of the second medium.

It has surprisingly been found that with methods known from numerical fluid mechanics, in which a continuous space is divided into discrete cells, in which constant conditions are assumed, not only media flows can be well simulated, but also that for each location of the Medical product, even when a complex geometry is present, an instantaneous and a cumulative reduction in the germ load can be calculated with high accuracy.

When emulating sterilization processes with more than one medium, the amount of individual media in each cell of the data structure is important for several reasons.

On the one hand, the individual media can have a significant influence on the heat transfer between the individual cells, e.g. on the heat transfer between the interior of the sterilization device and the body of the medical device. The entire free interior space that is not filled by solid components of the medical product is referred to as the interior of the sterilization device. This also includes internal cavities in the medical device.

On the other hand, the amount of the individual media can also have a direct influence on the reduction of the germ load.

In general, the time course of the germ load N at one point on the medical device can be described with the following differential equation: Here, k is the so-called inactivation rate, which indicates what proportion of the germ population is deactivated or killed in an infinitesimally short time interval dt. On the one hand, the inactivation rate is heavily dependent on the temperature, the inactivation rate increasing roughly exponentially with the temperature. The temperature dependence of the inactivation rate can be determined using the Arrhenius equation:

On the other hand, the inactivation rate is also dependent on the heat transfer from the medium surrounding a germ to the germ itself. Thus, for example, at the same temperature and with a high proportion of water vapor in the atmosphere, a significantly higher inactivation rate can result than with dry air. Of course, the amount or concentration of directly active media such as ethylene oxide also has a direct influence on the inactivation rate k.

Furthermore, the inactivation rate k depends on whether the germ load is in a free space or whether it adheres to a surface. A distinction is therefore made below between a volume inactivation rate kv and a surface activation rate ko. The surface deactivation rate k _{0 is} additionally dependent on a material composition of the surface.

For the computational simulation, the above-mentioned differential equation is replaced by a difference equation which calculates with discrete time intervals Ät:

DN

- k *

At

In the difference equation given above, changes in the germ load due to flow and diffusion are disregarded; these do not play a significant role in conventional sterilization processes.

In the method according to the invention, it is now calculated in many individual steps how the temperature and the amount of the individual media changes in the cell of the grid. Causes for the change in the amount of media are, for example, flow and diffusion processes, but also heat transfer processes such as Condensation and evaporation. In each step, the resulting change in the germ load is determined for each cell of the grid and for the interfaces, so that after the simulation of the complete sterilization process, the finally achieved reduction in the germ load is known for each cell of the grid and for each interface. The replication also affects the edges of the cells and thus possibly the surface of the medical device. Thus, the entire sterilization process is computationally reproduced or simulated.

The method according to the invention offers the advantage that the effectiveness of a sterilization method for a specific medical product can be determined without this method actually having to be carried out and without subsequently having to evaluate test specimens in a complex manner. This makes it possible to determine the impact of changes on the effectiveness of the procedure. Both design changes of the medical product and parameter changes of the sterilization process can be simulated. In this way, both the medical product and the sterilization process can be optimized with regard to the use of material and energy.

Furthermore, the method according to the invention offers the advantage that when determining the effectiveness of a sterilization method, it is also possible to take into account locations of a medical product which are not accessible to test bodies.

In a further development of a method according to the invention, the amount of a third medium in each cell can also be taken into account.

Ethylene oxide or hydrogen peroxide, for example, which are used in gas or plasma sterilization, can be taken into account as a third medium. The amount of this media in each cell has a direct influence on the respective rate of inactivation.

The calculation of the reduction in the germ load can take place taking into account a volume inactivation rate kv, which is dependent on the composition of an atmospheric composition prevailing in the respective cell. For example, a proportion of water vapor in the atmosphere and / or a proportion of ethylene oxide and / or hydrogen peroxide can be taken into account here. In a development of a method according to the invention, the reduction of a germ load on the corresponding interface can be calculated for each interface between a cell of the first plurality of cells and a cell of the second plurality of cells, a surface inactivation rate ko being taken into account for the calculation which is dependent on the composition of the atmosphere prevailing in the adjacent cell of the second type and on the material of which the interface is made. In this way, germ loads on surfaces and their reduction are also taken into account in the simulation.

When simulating the sterilization process, a phase transition of the first, second and / or third medium can be taken into account according to a special development.

For example, before sterilization in the autoclave, a medical product can be loaded with water in order to provide sufficient steam for the actual sterilization process. For this purpose, a medical product or a gas-filled component of the medical product can first be exposed to a vacuum in a pretreatment so that air is sucked out of the medical product, and then “ventilation” with water vapor takes place. The water vapor then penetrates into the medical device and largely condenses on the surface of the medical device to form water droplets.

These water droplets must first be evaporated in the actual sterilization process, which has a major influence on the temperature and media distribution during the sterilization process. By taking this phase transition into account, the simulation of the method becomes even more accurate.

According to a further embodiment of a method according to the invention, a change in shape of the medical product can also be taken into account when simulating the sterilization method. For this purpose, values for the elastic and / or plastic behavior of the respective material can be assigned to the cells of the grid that represent the medical product.

If, for example, in an interior of a flexible medical product, such as a blood, serum or dialysis bag, a water supply evaporates during the sterilization process, the medical product can inflate, whereby the flow and Diffusion processes are significantly influenced. Taking this deformation into account results in an even more precise simulation of the sterilization process.

In an additional development of a method according to the invention, a diffusion of the first, second and / or third medium through the material of the medical product can be taken into account when simulating the sterilization method.

Diffusion of media can be intended or even necessary. For example, during the ethylene oxide sterilization of packaged medical products, the ethylene oxide has to diffuse through the packaging in order to reach the actual medical product. In the context of the invention, the packaging is to be understood as a component of the medical product. However, unintentional diffusion can also have a significant impact on the effectiveness of the sterilization process. Overall, the significance of the simulation can be increased even further by taking diffusion into account.

In a further embodiment of a method according to the invention, a convection of the first, second and / or third medium between the cells of the second plurality of cells can be taken into account for the simulation of the sterilization method.

Convection processes are critical to the distribution of media and / or energy during the sterilization process. Taking the convection into account therefore enables an even more precise simulation of the actual processes taking place.

The first medium to be considered is usually air. The second medium to be considered is usually water, which can be both liquid and water vapor. Ethylene oxide or hydrogen peroxide can be used as the third medium or, in the absence of water, as the second medium.

One or more of the above-mentioned objects are achieved according to a second aspect of the invention by a method for validating a sterilization method for medical products with the following steps: determining a germ load reduction to be achieved by the sterilization method; Performing a method according to the first aspect of the invention; Comparing the reduction in the germ load determined in each cell of the second plurality of cells; and ruling the sterilization process effective when the required reduction is achieved for each of the cells the germ load has been reached, or classification of the sterilization process as ineffective if the required reduction in the germ load has not been achieved for at least one of the cells.

The method described significantly simplifies the validation of a sterilization process, since the introduction of test specimens and the subsequent evaluation of the test specimens can be dispensed with. Since the validation of a sterilization process for a specific medical product is a prerequisite for the approval of both the sterilization process and the medical product itself in many legal systems, the approval of new medical products can be simplified and accelerated so that new and innovative medical products can be marketed more quickly and thus benefit patients can.

In a further development of the method according to the invention for validating a sterilization method, a control method can also be carried out with the following steps: introducing a test specimen provided with a known germ load at a predetermined location of a medical product to be sterilized, performing the sterilization process to be validated with the medical product, determining the Sterilization processes achieve a reduction in the germ load of the test specimen, and the sterilization process is classified as effective only if the actually achieved reduction in the germ load of the test specimen corresponds sufficiently precisely to the reduction in the germ load calculated for the corresponding location.

Even if the placement and subsequent evaluation of a test body is required for the validation according to the further development described, the method is advantageous compared to the validation according to the prior art. For example, the simulation can prove that the location at which the test specimen was introduced is actually a critical location for the medical product, i.e. a location at which the sterilization process brings about the slightest reduction in the germ load. However, even if the critical location of the medical device cannot be reached by a test specimen, the method described can be used to prove that the result of the simulation at the location where the test specimen was introduced corresponds to the actual result of the sterilization process. It can then be assumed that the simulation result is also correct for the actually critical location. One or more of the stated objects are achieved according to a third aspect of the invention by a data processing system comprising at least one processor, a memory, input means, and output means, which is further developed in that program code information is stored in the memory that is suitable for execution to cause the processor to carry out a method according to the above descriptions.

The data processing system can comprise a commercially available computer which is expediently equipped with one or more powerful processors and sufficient main memory for the computationally expensive method.

In addition to the usual input means such as a keyboard, mouse, touchscreen, etc., the input means can also include an interface to a network via which the data processing system is connected to a database in which information about geometric and material-specific properties of one or more medical products is stored.

In addition to the usual output means such as a monitor and / or printer, the output means can also comprise a storage medium on which the results of the described methods are stored as data. This data can include tables in which the results are presented numerically. The data can also include images and / or videos by means of which the course or the result of the described method are visualized.

The program code information can be stored in the form of an executable computer program on a storage medium of the computer, for example on a hard disk.

According to a fourth aspect of the invention, one or more of the objects mentioned are achieved by a computer program product, comprising a data carrier and program code information stored on the data carrier which, when executed by a processor, is suitable to cause the processor to execute a method as described above.

One or more of the stated objects are achieved according to a fifth aspect of the invention by a sterilized medical product which has been subjected to a sterilization process, the effectiveness of which is achieved by a process has been determined in accordance with the description above, or which has been validated by a method in accordance with the above statements.

One or more of the objects mentioned are achieved according to a sixth aspect of the invention by a medical product which was manufactured in a sterilization device, the effectiveness of the sterilization method on which this system is based having been determined by a method according to the description above, or which is determined by a method according to the above has been validated.

The sterilization device includes all means that are necessary to carry out the sterilization process. For example, the sterilization device also includes the means that are necessary to ensure ventilation with water vapor, but also, for example, an autoclave chamber.

The invention is explained in more detail below with the aid of some exemplary representations. The exemplary embodiments shown are only intended to provide a better understanding of the invention without restricting it.

Show it:

Fig. 1: a medical product,

Fig. 2: a sterilization device for a medical product,

3a: a sectional view of the medical product. Fig. 1, Fig. 3b: a section of Fig. 3a with a lattice structure,

4a-4e: possible visualizations of a simulation result. FIG. 5: a data processing system.

FIG. 1 shows a medical product; the example shown is a bag set 1 for peritoneal dialysis. In peritoneal dialysis, dialysis fluid is introduced into the patient's abdominal cavity via a catheter in the abdominal wall. Through the extensive contact of the dialysis fluid with the peritoneum, which surrounds all organs in the abdominal cavity, pollutants from the patient's blood are washed into the dialysis fluid and thus removed from the blood. After a certain dwell time, which is usually about four hours, the dialysis fluid enriched with harmful substances, the so-called dialysate, is drained from the patient's abdomen and replaced with fresh dialysis fluid.

The bag set 1 comprises a solution bag 2 which has two chambers 3, 4 filled with dialysis fluid and an empty chamber 5 for technical reasons. The empty chamber 5 is also referred to as a lambda chamber due to its shape. Each of the chambers 3, 4, 5 is provided with a connecting piece. Two components of a dialysis solution are stored in the chambers 3, 4, a glucose solution and a buffer solution for regulating the pH of the finished dialysis solution. The glucose solution and the buffer solution are only mixed during use, i.e. immediately before being introduced into the patient's abdominal cavity.

Furthermore, the bag set 1 comprises an empty drainage bag 10 which is provided with two connecting pieces. The drainage bag 10 has a single receiving chamber 11, not visible in FIG. 1, for dialysate. In order to facilitate the entry of the dialysate into the drainage bag 10, the latter can be equipped with stiffening rods (not shown).

A central connector 15 of the bag set 1 is used to connect the bag set to the patient's catheter. The central connector 15 is connected to the solution bag 2 and to the drainage bag 10 via hoses 16, 17. Either the solution bag 2 or the drainage bag 10 can be connected to the catheter via a valve (not shown).

The tube 16 connects the central connector 15 to the solution bag 2. In the packaged state, the tube 16 is rolled up in a spiral shape, which is why it is also referred to as a solution ring. At this stage, the hose 16 is connected to the connection piece of the solution bag 2, which opens into the empty chamber 5. Only immediately before the bag set 1 is used is the hose 16 with it the chambers 3 and 4, which were previously separated from one another, are connected in order to conduct the now mixed solutions to the central connector 15.

The hose 17 connects the central connector 15 to one of the connecting pieces of the drainage bag 10. A second connecting piece can be provided, for example, in order to gain access to the drainage bag with the aid of a syringe. Then, for example, a sample can be made for analyzing the dialysate. The hose 17 is also rolled up in the packed state and is referred to as a drainage ring.

The individual components of the bag set 1 are subjected to a pretreatment before they are put together in order to deposit water in all the air-filled rooms for the later sterilization process. To do this, the components are placed in a vacuum chamber. This chamber is then evacuated to a pressure of, for example, between 150hpa and 300hpa residual pressure and then suddenly flooded with water vapor, for example to a pressure of about 1450hpa, for example with the aid of a steaming nose. The steam penetrates the cavities of the components of the medical device and condenses into water droplets. This pretreatment is known as vapor deposition.

The bag set 1 is then put together and welded into a plastic bag (not shown) for storage and transport.

The packaged bag set 1 must be sterilized before use in order to avoid infection of the patient. For this purpose, as a rule, several sets of bags are placed in a sterilization device, which is shown in FIG.

FIG. 2 shows a sterilization device for medical products, which is an autoclave 20. The autoclave has a sterilization chamber 21, in which in the example shown 24 packaged bag sets 1 are arranged on suitable lattice supports. The sterilization chamber 21 can be closed pressure-tight by a door, not shown.

During the sterilization process, the sterilization chamber 21 is exposed to hot steam under high pressure. For example, a pressure of 2600hpa and a temperature of about 130 ° C can be achieved. The combination of high pressure and high temperature kills germs present in the bag system 1 so that they can no longer cause infection of the patient.

The effectiveness of the sterilization process depends on various parameters. In addition to the pressure and the temperature in the sterilization chamber 21 and the duration of treatment, this also includes the temperatures actually reached in the medical product and the amounts of water available in the cavities, their evaporation rate and the resulting water vapor concentrations.

According to a conventional method for determining the effectiveness of a sterilization method for medical products, one or more samples of the medical product to be sterilized are provided with test bodies which have a known load of test germs. As a rule, particularly temperature-stable germs are used as test germs, for example of the genus Geobacillus stearothermophilus.

The samples equipped in this way are then subjected to the sterilization process in question, and the effect of the sterilization process on the test specimens is then determined. For this purpose, these are incubated in a nutrient solution for several days and the population of the test germs is evaluated.

In order to reduce the effort associated with the conventional method, a method is proposed here to determine the effectiveness of the sterilization process by means of a simulation. For this purpose, the medical product and the interior of the sterilization device are reproduced in a three-dimensional grid. This is shown schematically in FIGS. 3a and 3b.

FIG. 3 a shows a section through the bag set 1 along a plane which runs through the line AA ′ (FIG. 1) and runs perpendicular to the bag 2, 10 plane of extension. It can be seen that the solution bag 2 is formed from a lower film layer 30 and an upper film layer 31, which are connected along connecting lines 32, 33, 34, 35 such that the chambers 3, 4 for the dialysis solutions and the lambda chamber 5 form. The drainage bag 10 also consists of a lower film layer 40 and an upper film layer 41, which are connected along connecting lines 42, 43 such that the receiving chamber 11 is formed.

At the connecting lines 32, 33, 34, 35, 42, 43, the respective film layers 30, 31, 40, 41 can be glued, welded or otherwise connected to one another in such a way that an essentially gas and liquid-tight connection results.

FIG. 3 b shows an enlargement of a detail X from FIG. 3 a, which shows the lower film layer 30 and the upper film layer 31 of the solution bag 2 in the area of the lambda chamber 5. In addition, a three-dimensional grid 100 is shown here, which is used to simulate the bag set 1 in a data structure.

Although the grid 100 is shown two-dimensionally in FIG. 3b for the sake of clarity, it is actually a three-dimensional grid made up of a plurality of grid cells Z. In the example shown, all cells Z of the grid are of the same size and shape, for example as a tetrahedron. Depending on the complexity of the shape of the medical product, individual cells can also have a different shape and / or size.

For each of the cells Z it is determined whether there is a physical component of the medical product at the corresponding location, such as the film layers 30, 31 of the solution bag 2 at the locations of the cells Zi, Z ₂ , or whether it is a cell in a flea room or in the vicinity of the medical device, such as cells Z ₃ , Z ₄ .

A data record is provided in the data structure for each cell Z of the grid 100.

For the cells that are filled with physical components of the medical device, the data record contains the prevailing temperature and material data of the medical device, such as the elastic properties of the material, the heat capacity, the thermal conductivity and the permeability for various media (air, water, steam, Etc.). For the other cells, the data set contains the quantities of media (air, water, water vapor, etc.) present in the respective cell as well as data on their thermodynamic state (temperature, pressure, flow speed and direction, etc.). In addition, for each cell representing a flea space, information is provided regarding a germ load or an achieved reduction in germ load. Boundary surfaces G, which can be seen as lines in FIG. 3b, are formed between adjacent cells Z. The data structure can also include data records for interfaces. These data records mainly include information about whether the interface is a physical surface, for example an inner or outer surface of a medical product, and possibly a germ load on the surface or a reduction in this germ load that has already been achieved.

The data structure is then filled with data in such a way that it represents an initial state at the beginning of the sterilization process. For example, all cells will be around room temperature, and the pressure will be around 1000hpa in each cell that represents a cavity.

At the same time, a mixture of air and water vapor is present in all cells that are located outside the medical device, for example steam or a steam-air mixture with approx. 2.6 to 3.6 bar absolute pressure and a temperature of 130 ° C., for example.

In the case of cells that are located in closed cavities of the medical device, the previous vapor deposition may result in different conditions. Some cells here are possibly filled with water, while in other cells there is a mixture of air and water vapor and also condensed water, which corresponds to complete saturation.

For cells in liquid-filled cavities of the medical device, all cells are correspondingly filled with the respective liquid.

As a result, it is calculated step by step how the conditions in the individual cells Z of the grid change while the sterilization process is being carried out. A time interval simulated by a computation step can be, for example, one second, but longer or shorter time intervals can also be implemented.

During a heating phase of the sterilization process, the sterilization chamber 21 is supplied with superheated steam, so that in some cells, which represent this space, the pressure, the amount of water vapor and the temperature rise. As soon as there are differences between two neighboring cells, there is a transfer of energy and / or media through the respective interface between the cells. Which thereby The resulting changes in the state of the individual cells are calculated. The calculation methods to be used for this are well known from numerical fluid mechanics and therefore do not need to be explained in more detail here. Essentially, the following effects will have to be taken into account:

Temperature compensation: If there is one between two neighboring cells

Temperature difference, heat energy is transferred through the interface from the warmer to the colder cell, whereby the temperatures equalize.

Pressure equalization: If there is a pressure difference between two neighboring cells, some of the media from the cell with higher pressure will flow through the interface into the cell with lower pressure, so that the pressures will equalize.

Concentration equalization: If there is a difference in concentration of a medium or a difference in the partial pressures of the media between two neighboring cells, then part of the medium will diffuse through the interface into the cell with a lower concentration or partial pressure, so that the concentrations or partial pressures are equal .

Gravitation: If there is a height difference between two cells, some of the media will flow from the higher cell through the interface into the lower cell.

Natural convection: If there is a difference in density between two neighboring cells, this results in natural convection.

The interaction of pressure equalization, gravity, convection and concentration equalization (diffusion) leads to a height-dependent change in the mixing ratio of gaseous media such as air, water vapor and ethylene oxide. This can affect the effectiveness of the sterilization process and must therefore be simulated as precisely as possible.

In particular in liquid-filled parts of medical devices, convection processes have a considerable influence on the temperature distribution. This is another reason why such convection processes must be reproduced as precisely as possible. In addition, convection processes play a decisive role in the distribution of media, such as water vapor, in parts of the medical device that occur at the beginning of the Sterilization process does not contain the medium concerned or does not contain sufficient quantities. This applies, for example, to the penetration of water vapor into the hoses 16, 17 and into the central connector 15.

After the completion of the heating phase, the state of the atmosphere in the sterilization chamber 21 is kept constant, so that essentially only compensation processes take place within the medical product. The course of these equalization processes is, however, of considerable importance for the success of the sterilization process, so the entire duration of the sterilization process is further modeled or simulated using the method described above.

A cooling process downstream of the sterilization process, in which the dialysis solutions present in the solution bag in particular are to be cooled in order to avoid premature degradation, can, however, be excluded if necessary.

Other media can be taken into account in the simulation. For example, a biocidal gas such as ethylene oxide can be introduced into the sterilization chamber and diffused into the medical product. The corresponding diffusion processes can be simulated using the simulation method. For example, the injection of ethanol, for example in plug connections, can also be adjusted in this way.

The diffusion of media through the material of the medical device can be modeled in the simulation by adding data on the absorption capacity (for example as permeability or diffusion data) of the material for individual media to the data structure. If, for example, the material can absorb a certain amount of water vapor, then water vapor will diffuse into the respective cell via an interface if the concentration of the water vapor in the neighboring cell is sufficiently high. In this way, water vapor can slowly spread through the material cell by cell and also escape again at the interfaces with cavities where there is a lower concentration. For example, water vapor can diffuse from the sterilization chamber through the film layers 30, 31 into the lambda chamber 5. The diffusion of other media such as ethylene oxide or ethanol can also be simulated in the same way.

Other effects can occur during the sterilization process that must be taken into account in the simulation. For example, there will be an increase in internal pressure in closed volumes of a medical product. This An increase in pressure is particularly relevant if liquid water is present in the corresponding volumes at the beginning of the sterilization process, which water evaporates as a result of the temperature increase. The evaporation process must be taken into account in the simulation, as it has a considerable influence on the heat distribution in the medical device. Condensation can also occur at some points on the medical device, which also affects the temperature distribution.

As a result of the evaporation of water, the lambda chamber 5 or the receiving chamber 11 can continue to expand, as a result of which the geometry of the corresponding volumes changes.

This effect can be taken into account in different ways. On the one hand, the elastic and / or plastic deformability of the material of the medical product can be stored in the data structure. In each calculation step, it can then be determined whether a force is acting on a cell that represents a physical component of the medical product so that it moves. If a movement of the material in the cell is detected, the grid can either remain unchanged and the movement can be mapped by assigning the corresponding status data to an adjacent cell into which the material has moved. It may also be necessary to add or remove individual cells. In this case, however, it can happen that after the shift there are cells to which no status data are assigned, which leads to problems.

A better solution is that the entire grid is constructed dynamically in such a way that the size and position of the individual grid cells can change in order to take account of such expansion effects. Care must be taken that in areas where a significant change in volume is to be expected, a sufficiently fine grid structure is selected so that the result does not end up being inaccurate due to grid cells that are too large.

As a crucial part of the simulation, the effect of the prevailing state on a possible germ population is calculated in each calculation step for each cell of the grid that does not correspond to a physical component of the medical device and for each interface that represents a physical surface. When defining the initial state of each cell or interface, a specific germ load can be assigned, for example an occupancy with 10 ⁶ germs of the genus Geobacillus stearothermophilus.

The relationship between the time course of a germ load, the temperature and an atmosphere composition is shown in FIGS. 6a to 6c.

FIG. 6a shows the course of the germ load in a cell or interface of the grid at constant temperature and with different atmospheric compositions. The germ load log (N) is plotted on the floch axis 601 in random logarithmic units, while the time is plotted on the longitudinal axis 602. The intersection of the axes represents on the one hand a harmless germ load (e.g. log (N) = - 6) and on the other hand the start of the sterilization process (e.g. t = 0).

The diagonal lines 603, 604, 605, 606, 607, 608, 609 represent the time course of the germ load with different atmospheric compositions. Thus the line 603 shows a very slow decrease in a pure air atmosphere, the lines 604, 605, 606 the faster decrease in an air-water vapor mixture (604: 80% air, 605: 50% air, 606: 20% air), the line 607 the decrease in a pure water vapor atmosphere. Lines 608, 609 represent the decrease in the bacterial load in pure water (line 608) and in dialysis solution (line 609).

The slopes of the lines 603 to 609 each represent the inactivation rate k, which results in the atmosphere in question.

FIG. 6b shows an exemplary temperature profile which occurs in a cell of the grid during a sterilization process. The temperature is shown in arbitrary units on the floch axis 610, while the time is shown again on the longitudinal axis 61 1. It can be seen that the temperature initially rises to a maximum during the sterilization process and then falls again.

Finally, in FIG. 6c, courses of germ loadings are shown which, taking into account the atmospheric composition and the temperature course, tend to be different. Fig. 6b result. For a better overview, only three courses 621, 622, 623 are shown which correspond to the atmospheric compositions of lines 601, 606, 609.

With the aid of the difference equation DN, = -k ^* N ^* At, the change in the germ load and the remaining germ load are now determined. In this case, the inactivation rate k is determined as a function of the environmental parameters present in each case, that is to say for example the temperature, the water vapor concentration, and / or the concentration of active media such as ethylene oxide. This applies equally to volume inactivation rates kv and to surface inactivation rates ko.

Instead of calculating a fictitious germ load, a logarithmic germ reduction F can also be determined in each calculation step and for each calculation cell and then added up in order to determine the germ reduction achieved during the entire sterilization process:

The results of the simulation can be displayed or visualized in different ways. One possibility is to output the smallest germ reduction achieved in the medical product as a number.

The course of a parameter of interest over the duration of the sterilization process can be output as a diagram for a selected cell.

Further options are to display selected parameters in a color-coded or gray-scale-coded manner in sectional views of the medical product. The state can be displayed at a certain point in time during the sterilization process, for example the temperature or the germ reduction achieved after 1000 seconds, after 2000 seconds and at the end of the sterilization process.

In FIGS. 4a to 4c, for example, visualizations of the temperature of the dialysis solutions after a sterilization process are shown. Fig. 4a shows the Temperature on the outer surfaces of the solution chambers 3, 4, FIG. 4b shows the temperature in a section parallel to the extension surface of the solution bag 2, and FIG. 4c shows the temperature in a section perpendicular thereto. It can be seen that in the example shown a very homogeneous end temperature of the solutions has been reached.

The flow velocities prevailing at a specific point in time can also be visualized in the medical product. For example, FIGS. 4d and 4e show the flow conditions in a solution bag after about 1000 seconds, FIG. 4d showing a contour plot with velocities coded in gray, while FIG. 4e shows a vector illustration of the flow directions. Convection vortices 51 can clearly be seen here in a liquid-filled part of the bag, while there is hardly any flow in a small air bubble 52 in the upper region of the figures.

The course of the respective parameters over the duration of the sterilization process can also be provided as a video. Pressure, water vapor concentration and / or the achieved germ reduction can also be shown in similar displays.

The simulation method described can be used to determine the effectiveness of a sterilization method for a specific medical product, as in the example shown for the bag set 1. In this way e.g. After a design change or a new development of a medical device, a check is made to determine whether a known sterilization process is sufficient to safely sterilize the medical device. In this way, the effects of adjustments on sterilizability can be tested without having to make and sterilize samples for each adjustment.

This means that new or modified medical products can be brought onto the market quickly, as the effectiveness of a suitable sterilization process can be quickly demonstrated.

Likewise, parameter changes to sterilization processes can be examined with the described simulation process for their effects on the result without having to accept the described effort for the implementation and sampling. In order to examine individual components of a medical device with regard to their sterilizability, it can make sense to initially limit the simulation to these components and their immediate surroundings. The computational effort required can thereby be considerably reduced. However, a complete simulation should always be carried out for a final assessment.

Ultimately, it is even conceivable to use the results of the simulation process described to validate a sterilization process for the approval of a new or modified medical product or a sterilization process under medical product law.

For this purpose, a germ reduction to be achieved by the sterilization process is specified, which is, for example, 12 log levels, i.e. a germ reduction by a factor of 10 ¹² . The simulation is then used to check that the required germ reduction is achieved at every point on the medical device. If the required reduction is achieved, the successful sterilization is validated and the medical device can be approved.

The reliability of the detection can be further increased if, in addition to the simulation, a sample is taken with a test specimen and the result of the simulation is compared with the result of the sampling. Approval can then be made dependent on the results agreeing.

In contrast to the conventional validation method, the sampling can be carried out at a point on the medical device that is not a critical point, since only the conformity with the simulation result has to be proven. This can reduce the cost of sampling. Influences of the test specimen on the media distribution in the medical device can be taken into account in the simulation or compensated for by a corresponding media surcharge or discount.

In contrast to the conventional validation process, proof of correspondence between simulation and sampling can be provided if the sterilization process is aborted, if, for example, the actually necessary germ reduction has not yet been achieved. This has the advantage that there is still a larger population of test germs on the test specimen after the sterilization process, which is easier to evaluate. With the described validation procedure, a new or modified medical device can be brought onto the market even faster.

In the simulation process described, it must be taken into account that the initial state may not be identical for each individual medical product. In particular, the position and / or size of water droplets which get into the medical product as a result of the vaporization can be random and differ from medical product to medical product. Particularly in the case of medical products with unfavorable geometries, for example long tube sections, the position of water droplets in the tube section can have relevant effects on the result of the sterilization process.

It may therefore be necessary to model some possible distributions of the water droplets and to simulate the effects separately. For a validation, the distribution that gives the worst sterilization result would have to be used as a basis.

In order to determine the effect of the steaming of the medical product and the resulting distribution of water droplets in the medical product, a simulation method for the steaming process can also be carried out analogously to the simulation method of the sterilization process described above. However, it must be taken into account here that the actual position and size of water droplets formed by condensation are, on the one hand, highly random, so that at best estimates are possible. On the other hand, the water droplets can move and unite in the medical device when the medical device is moved between the steaming and the sterilization.

The described simulation method can be carried out on a data processing system as shown in FIG.

The data processing system 100 comprises a central unit 101 with at least one processor 102 and a memory element 103. The at least one processor 102 can be a powerful multi-core processor which is optimized for the execution of complex mathematical tasks. The memory element 103 can have writable components (RAM) and non-writable components Components (ROM) include. The storage element 103 preferably has a high storage capacity and a high writing or reading speed.

The central processing unit 101 can be operated by a commercially available computer, e.g. a pc.

The central unit is connected to input means and output means via which information about the sterilization process to be simulated can be input and output. The input means can e.g. a keyboard 104 and a mouse 105. The output means can comprise a monitor 106. If the monitor 106 is a touchscreen, it can also function as an input means at the same time.

The central unit can be connected directly or via a network 110 to a database 111 in which design data of one or more medical products, one or more sterilization devices and / or data of one or more sterilization processes are stored. The processor 102 can access the data stored in the database 11 to simulate a medical product and / or a sterilization device in a data structure and / or to simulate a sterilization method using the simulation method described above.

The central unit 101 is also connected to a write / read device 112 for data carriers 113. In the example shown, the data carrier 113 is a CD or DVD; alternatively, other known exchangeable or non-exchangeable data carriers can be used.

Program code information that can be transferred by the processor 102 into the memory element 103 can be stored on the data carrier 113. The processor 102 can then read out this program code information step by step from the memory element 103 and execute it, which causes the processor to execute the simulation method described above.

The central unit can also use the write / read device to store the results of the simulation method on a data carrier 113. Alternatively, the results can be visualized on the monitor 106 and / or stored in the database 1 1 1. The representation of the data processing system 100 in FIG. 5 is greatly simplified for a better overview. In particular, the at least one processor 102 in a real data processing system is not connected directly to the peripheral devices 104, 105, 106, 112, but rather via suitable interface elements.

Claims

1. A method for determining the effectiveness of a sterilization method for a medical product (1) in a sterilization device (20), comprising the steps

Providing a data structure, the data structure representing a grid (100) formed from a plurality of three-dimensional cells (Z),

Reproduction of the medical product (1) arranged in the sterilization device (20) in the data structure such that a first plurality of cells (Z) of the grid (100) represent a body of the medical product (1), and that a second plurality of cells (Z ) represent an interior of the sterilization device (20) which is not occupied by the body of the medical device (1),

Reproduction of an initial state in the data structure in such a way that each cell (Z) of the second plurality of cells contains data regarding the temperature prevailing at the location of the cell, the amount of a first medium in the area of the cell and the amount of a second medium in the area of the cell Medium is assigned,

Step-by-step simulation of changes in the temperature, the amount of the first medium and the amount of the second medium occurring during the sterilization process in each cell of the second plurality of cells (Z),

Calculating a reduction in a germ load achieved in each cell of the second plurality of cells during the sterilization process, taking into account the temperature, the amount of the first medium and the amount of the second medium prevailing in the respective cell in each step.

2. The method according to claim 1, characterized in that an amount of a third medium present in each cell (Z) of the second plurality of cells is also taken into account.

3. The method according to claim 1 or 2, characterized in that the

The reduction in the germ load is calculated taking into account a volume inactivation rate k, which depends on the

Composition of an atmospheric composition prevailing in the respective cell.

4. The method according to any one of the preceding claims, characterized in that for each interface between a cell of the first plurality of cells and a cell of the second plurality of cells, the reduction of a germ load on the corresponding interface is calculated, wherein for the calculation a surface Inactivation rate k ₀ takes place, which is dependent on the composition of the atmosphere prevailing in the adjacent cell of the second type and on the material from which the interface is made.

5. The method according to any one of claims 1 to 4, characterized in that a phase transition of the first, second and / or third medium is taken into account for the simulation of the sterilization process.

6. The method according to any one of claims 1 to 5, characterized in that a change in shape of the medical product (1) is taken into account for the simulation of the sterilization process.

7. The method according to any one of claims 1 to 6, characterized in that a diffusion of the first, second and / or third medium through the material of the medical product is taken into account for the simulation of the sterilization process.

8. The method according to any one of claims 1 to 7, characterized in that a convection of the first, second and / or third medium between the cells of the second plurality of cells is taken into account for the simulation of the sterilization process.

9. The method according to any one of the preceding claims, characterized in that the first medium is air.

10. The method according to any one of the preceding claims, characterized in that the second medium is water.

1 1. The method according to any one of the preceding claims, characterized in that the second or the third medium is ethylene oxide.

12. Procedure for the validation of a sterilization procedure for a medical device (1) with the following steps:

Establishing a reduction in a germ load to be achieved by the sterilization method;

Carrying out a method according to one of claims 1 to 1 1,

Comparing the reduction in the germ load determined in each cell (Z) of the second plurality of cells; and

Classifying the sterilization process as effective if the required reduction in the germ load has been achieved for each of the cells (Z), or

Classification of the sterilization process as ineffective if the required reduction in the germ load has not been achieved for at least one of the cells (Z).

13. The method according to claim 12, characterized in that a control method is also carried out, with the steps:

Introducing a test specimen provided with a known germ load at a predetermined point on a medical product (1) to be sterilized,

Carrying out the sterilization process to be validated with the medical device (1),

Determination of the reduction in the germ load of the test specimen achieved by the sterilization process, and The sterilization process is only classified as effective if the actually achieved reduction in the germ load of the test specimen corresponds with sufficient accuracy to the reduction in the germ load calculated for the corresponding location.

14. Data processing system (100), comprising at least one processor (102), a memory (103),

Input means (104, 105), and output means (106), characterized in that program code information is stored in the memory (103) which is suitable, when executed by the processor (102), to cause the processor (102) to perform a method according to one of claims 1 to 13.

15. Computer program product, comprise a data carrier (1 13) and program code information stored on the data carrier (1 13) which, when executed by a processor (102), causes the processor to carry out a method according to one of claims 1 to 12.

16. Sterilized medical product, characterized in that the medical product has been subjected to a sterilization process, the effectiveness of which has been determined using a process according to one of claims 1 to 11.

17. Sterilized medical product, characterized in that the medical product has been subjected to a sterilization process which has been validated by a process according to claim 12 or 13.

18. Sterilized medical product, characterized in that the medical product was manufactured in a sterilization device, the effectiveness of the sterilization method on which this system is based by a method according to one of claims 1 to 1 1 has been determined, or which has been validated according to a method according to claim 12 or 13.