U.S. patent application number 17/617952 was filed with the patent office on 2022-06-30 for 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.
The applicant listed for this patent is FRESENIUS MEDICAL CARE DEUTSCHLAND GMBH. Invention is credited to Manuel FEURHUBER, Carsten FRANK, Christoph HOCHENAUER, Frank MUELLER, Valentin SCHWARZ.
Application Number | 20220205014 17/617952 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-30 |
United States Patent
Application |
20220205014 |
Kind Code |
A1 |
FRANK; Carsten ; et
al. |
June 30, 2022 |
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
Abstract
A process is presented for determining the effectiveness of
sterilization processes for medical devices, with the steps of:
providing a data structure, wherein the data structure represents a
grid formed of a plurality of three-dimensional cells, recreating
the medical device arranged in the sterilizer 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 sterilizer which is not occupied by
the body of the medical device, recreating an initial state in the
data structure in such a way that each cell of the second plurality
of cells is assigned data with respect to the temperature
prevailing at the location of the cell, the quantity of a first
medium located in the area of the cell and the quantity of a second
medium located in the area of the cell, recreating, step by step,
changes in the temperature, the quantity of the first medium and
the quantity of the second medium occurring in each cell of the
second plurality of cells during the sterilization process, and
calculating a reduction of a germ load achieved in each cell of the
second plurality of cells during the sterilization process taking
into account the prevailing temperature, quantity of the first
medium and quantity of the second medium in the respective cell in
each step. Furthermore, a data processing system as well as a
computer program product for carrying out the process are
presented.
Inventors: |
FRANK; Carsten; (Marpingen,
DE) ; MUELLER; Frank; (Beckingen, DE) ;
SCHWARZ; Valentin; (Saarbruecken, DE) ; FEURHUBER;
Manuel; (Mondsee, AT) ; HOCHENAUER; Christoph;
(Brodersdorf, AT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FRESENIUS MEDICAL CARE DEUTSCHLAND GMBH |
Bad Homburg |
|
DE |
|
|
Appl. No.: |
17/617952 |
Filed: |
August 22, 2019 |
PCT Filed: |
August 22, 2019 |
PCT NO: |
PCT/EP2019/072505 |
371 Date: |
December 10, 2021 |
International
Class: |
C12Q 1/22 20060101
C12Q001/22; A61L 2/28 20060101 A61L002/28; A61L 2/20 20060101
A61L002/20 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 12, 2019 |
DE |
10 2019 116 013.8 |
Claims
1. A process for determining the effectiveness of a sterilization
process for a medical device in a sterilizer, with the steps of
providing a data structure, wherein the data structure represents a
grid formed of a plurality of three-dimensional cells, recreating
the medical device arranged in the sterilizer 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 sterilizer which is not occupied by
the body of the medical device, recreating an initial state in the
data structure in such a way that each cell of the second plurality
of cells is assigned data with respect to the temperature
prevailing at the location of the cell, the quantity of a first
medium located in the area of the cell and the quantity of a second
medium located in the area of the cell, recreating, step by step,
changes in the temperature, the quantity of the first medium and
the quantity of the second medium occurring in each cell of the
second plurality of cells during the sterilization process,
calculating a reduction of a germ load achieved in each cell of the
second plurality of cells during the sterilization process taking
into account the prevailing temperature, quantity of the first
medium and quantity of the second medium in the respective cell in
each step.
2. The process according to claim 1, wherein a quantity of a third
medium present in each cell (Z) of the second plurality of cells is
additionally taken into account.
3. The process according to claim 1, wherein a phase transition of
the first, second and/or third medium is taken into account for the
recreation of the sterilization process.
4. The process according to claim 1, wherein a shape change of the
medical device is taken into account for the recreation of the
sterilization process.
5. The process according to claim 1, wherein a diffusion of the
first, second and/or third medium through the material of the
medical device is taken into account for the recreation of the
sterilization process.
6. The process according to claim 1, wherein the first medium is
air.
7. The process according to claim 1, wherein the second medium is
water.
8. The process according to claim 1, wherein the second or the
third medium is ethylene oxide.
9. A process for validating a sterilization process for a medical
device, with the steps of: defining a reduction of a germ load to
be achieved by the sterilization process; carrying out the process
according to claim 1, comparing the reduction of the germ load
determined in each cell of the second plurality of cells; and
grading the sterilization process as effective if the necessary
reduction of the germ load has been achieved for each of the cells,
or grading the sterilization process as not effective if the
necessary reduction of the germ load has not been achieved for at
least one of the cells.
10. The process according to claim 9, wherein a checking process is
additionally carried out, with the steps of: introducing a sample
provided with a known germ load at a predefined point of a medical
device to be sterilized, carrying out the sterilization process to
be validated on the medical device, determining the reduction of
the germ load of the sample achieved by the sterilization process,
and grading the sterilization process as effective only when the
reduction of the germ load of the sample actually achieved
corresponds sufficiently precisely to the reduction of the germ
load calculated for the corresponding point.
11. A data processing system, comprising at least one processor, a
memory, input means and output means, wherein program code
information which, when executed by the processor, is able to
prompt the latter to execute the process according to claim 1 is
stored in the memory.
12. A computer program product, comprising a data carrier and
program code information stored on the data carrier which, when
executed by a processor, is able to prompt the latter to execute
the process according to claim 1.
13. A sterilized medical device, wherein the medical device has
been subjected to a sterilization process, the effectivity of which
has been determined by the process of claim 1.
14. A sterilized medical device, wherein the medical device has
been subjected to a sterilization process, which has been validated
by the process of claim 9.
15. A sterilized medical device, wherein the medical device has
been produced in a sterilizer, wherein the effectivity of a
sterilization method used in the sterilizer has been determined in
the process of claim 1.
16. A sterilized medical device, wherein the medical device has
been produced in a sterilizer, wherein the effectivity of a
sterilization method used in the sterilizer has been validated by
the process of claim 9.
Description
[0001] The invention relates to a process for determining an
effectiveness of a sterilization process for a medical device or a
packaged medicinal product in a sterilizer. For sake of brevity the
following disclosure mainly refers to medical devices, while each
reference to medical devices shall also include packaged
pharmaceutical products.
[0002] Sterilization processes are used to sterilize medical
devices or packaged medicinal products prior to their use, thus to
rid them of potentially harmful germs. Known sterilization
processes comprise steam sterilization, dry heat sterilization,
autoclaving, gamma sterilization, electron beam sterilization,
ethylene oxide sterilization and plasma sterilization. Within the
framework of this application, medical device also denotes
medicinal products, in particular packaged medicinal products,
further in particular medicinal products packaged in bags, further
in particular solutions and devices for peritoneal dialysis
packaged in bags.
[0003] The sterilization is usually effected in a sealed
sterilization chamber of a sterilizer, into which the medical
device is introduced.
[0004] In order to avoid endangering patients on whom the medical
device is to be used, it must be ensured that the medical device is
actually sterile, i.e. substantially free of germs, after the
sterilization process has been carried out.
[0005] While the fundamental effectiveness of known sterilization
processes has been sufficiently proven scientifically, the actual
effectiveness of a sterilization process when applied to a
particular medical device is dependent on many parameters,
including shape and material properties of the medical device, and
on the selected process parameters of the sterilization process,
e.g. the temperature profile, quantities of media used and the
process duration.
[0006] As individually checking the sterility of a medical device
is impossible in practice, without in the process at least limiting
the availability for use of the medical device, proving the
sterility is effected by a validation of the sterilization process
used. Here, it is scientifically proven that a sterilization
process carried out with particular parameters always achieves the
desired result. Here, the desired result is defined via the factor
by which a germ load in the medical device is reduced by the
sterilization process. An effective sterilization can be regarded
as having been effected e.g. when the germ load has been reduced by
a factor of 10.sup.12.
[0007] A current process for determining the effectiveness of a
sterilization process consists of introducing a sample which is
provided with a known germ load at a critical point of a medical
device. A critical point here denotes a point of the medical device
at which a particularly small effect of the sterilization process
is expected, for example because the point heats up particularly
slowly, or because it is particularly difficult for media used for
the sterilization to reach.
[0008] The medical device is then subjected to the sterilization
process. The sample is then removed and the remaining germ load is
determined.
[0009] Paper strips, which are inoculated with particularly
temperature-stable germs, for example with Geobacillus
stearothermophilus, are often used as samples.
[0010] If the evaluation of the sample reveals that the necessary
reduction of the germ load has been achieved, the sterilization
process is regarded as reliable and is validated.
[0011] While the described method is widely recognized, it does to
some extent have substantial disadvantages. Firstly, the evaluation
of the samples requires a substantial outlay on equipment and time,
as an incubation in a culture medium lasting several days is
required first before an evaluation of the remaining germs, in
order to arrive again at a germ density to be evaluated
meaningfully. Secondly, the introduction of the samples into the
medical device to be sterilized is often difficult. If, for
example, the medical device has a sealed volume, this may have to
be opened in order to introduce the sample. The results of the
validation can also be distorted thereby. In addition, it can
happen that a critical point of the medical device is difficult for
the sample to reach or cannot be reached by it at all, for example
if the medical device comprises thin channels or tubes. A further
disruptive effect consists of a sample influencing the
concentration of a medium used in the sterilization process, for
example in that a paper strip absorbs water and thus reduces the
humidity in its surroundings.
[0012] From the patent applications WO 00/27228 A1 and WO 00/27229
A1 processes are known for computationally determining the
reduction of a germ load achieved at a critical point of a food
product during a thermal sterilization. For this, however, only the
temperature profile at a so-called "Cold Spot" of the product is
simulated, the dependence on other media is not taken into
account.
[0013] In particular in the case of sterilization processes in
which more than one medium is used, these processes are
inadequate.
[0014] An object of the invention is thus to provide a process for
determining the effectiveness of a sterilization process for a
medical device in a sterilizer which is improved with respect to
the described problems.
[0015] A further object of the invention is to provide an improved
process for validating a sterilization process for medical
devices.
[0016] One or more of the named objects are achieved according to a
first aspect of the invention by a process for determining the
effectiveness of a sterilization process for a medical device in a
sterilizer, with the steps of: providing a data structure, wherein
the data structure represents a grid formed of a plurality of
three-dimensional cells, recreating the medical device arranged in
the sterilizer 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 sterilizer which is not occupied by the body of the medical
device, recreating an initial state in the data structure in such a
way that each cell of the second plurality of cells is assigned
data with respect to the temperature prevailing at the location of
the cell, the quantity of a first medium located in the area of the
cell and the quantity of a second medium located in the area of the
cell, recreating, step by step, changes in the temperature, the
quantity of the first medium and the quantity of the second medium
occurring in each cell of the second plurality of cells during the
sterilization process, calculating a reduction of a germ load
achieved in each cell of the second plurality of cells during the
sterilization process taking into account the prevailing
temperature, quantity of the first medium and quantity of the
second medium in the respective cell in each step.
[0017] It has surprisingly been found that with processes known
from computational fluid dynamics, in which a continuous space is
divided into discrete cells in which constant relationships are
assumed in each case, not only can flows of media be recreated
well, but with it a current and an accumulated reduction of the
germ load can also be calculated with a high degree of precision
for each location of the medical device, even if there is a complex
geometry.
[0018] In the case of the recreation of sterilization processes
with more than one medium, the quantity of the individual media in
each cell of the data structure is important for several
reasons.
[0019] Firstly, the individual media can have a substantial
influence on the heat transfer between the individual cells, e.g.
on the heat transfer between the interior of the sterilizer and the
body of the medical device. Interior of the sterilizer here denotes
the total free interior which is not filled by solid constituents
of the medical device. Therefore, this also includes internal
cavities of the medical device.
[0020] Secondly, the quantity of the individual media can also have
a direct influence on the reduction of the germ load.
[0021] In general, the temporal progression of the germ load N at
one point of the medical device can be described with the following
differential equation:
dN dt = - k * N ##EQU00001##
[0022] Here, k is the so-called deactivation rate, which indicates
what proportion of the germ population is deactivated or killed in
an infinitesimally short time interval dt. Firstly, the
deactivation rate is strongly dependent on the temperature, wherein
the deactivation rate rises approximately exponentially with the
temperature. Secondly, the deactivation rate is also dependent on
the heat transfer from the medium surrounding a germ to the germ
itself. For example, at the same temperature a much higher
deactivation rate can thus result if there is a high proportion of
water vapour in the atmosphere than if the air is dry. Of course,
the quantity or concentration of directly active media such as
ethylene oxide also has a direct influence on the deactivation rate
k.
[0023] For the computational recreation, the above-named
differential equation is replaced by a finite difference equation
which, with discrete time intervals .DELTA.t, calculates:
.DELTA. .times. .times. N .DELTA. .times. .times. t = - k * N
##EQU00002##
[0024] In the case of the above-specified finite difference
equation, changes in the germ load due to flow and diffusion are
disregarded; these do not play an appreciable role in usual
sterilization processes.
[0025] Now, in the process according to the invention, it is
calculated in many individual steps how the temperature and the
quantity of the individual media change in the cell of the grid.
Causes for the change in the quantities of media are, for example,
flow and diffusion processes, but also heat transfer processes such
as for example condensation and evaporation. In each step the
resultant change in the germ load is then determined for each cell
of the grid, with the result that after the recreation of the
complete sterilization process the ultimately achieved reduction of
the germ load is known for each cell of the grid. The recreation
also relates to the edges of the cells and thus optionally the
surface of the medical device. The total sterilization process is
thus computationally recreated or simulated.
[0026] The process according to the invention offers the advantage
that the effectiveness of a sterilization process for a particular
medical device can be determined without this process having to be
actually carried out, and without samples then having to be
evaluated in a laborious manner. It thereby becomes possible to
determine the effects of changes on the effectiveness of the
process. Here, both design changes of the medical device and
parameter changes of the sterilization process can be simulated. In
this way both the medical device and the sterilization process can
be optimized with respect to the use of material and energy.
[0027] Furthermore the process according to the invention offers
the advantage that points of a medical device which are not
accessible to samples can also be taken into account in the
determination of the effectiveness of a sterilization process.
[0028] In a development of a process according to the invention the
quantity of a third medium can additionally be taken into account
in each cell.
[0029] For example, ethylene oxide or hydrogen peroxide, which are
used in gas or plasma sterilization, can be taken into account as
the third medium. The quantity of these media in each cell has a
direct influence on the respective deactivation rate.
[0030] According to a particular development, a phase transition of
the first, second and/or third medium can be taken into account in
the recreation of the sterilization process.
[0031] Thus, for example, a medical device can be provided with a
water load before the sterilization in the autoclave, in order to
provide sufficient water vapour for the actual sterilization
procedure. For this, a medical device or a gas-filled component of
the medical device can be exposed to a vacuum first in a
pre-treatment, with the result that air is sucked out of the
medical device, and then an "aeration" with water vapour can be
effected. The water vapour then penetrates into the medical device
and in a large part condenses to water droplets on the surface of
the medical device.
[0032] These water droplets have to be evaporated first in the
actual sterilization process, which has a great influence on the
temperature and media distribution during the sterilization
process. By taking this phase transition into account, the
recreation of the process becomes even more precise.
[0033] According to a further design of a process according to the
invention a shape change of the medical device can additionally be
taken into account in the recreation of the sterilization process.
For this, the cells of the grid which represent the medical device
can be assigned values for the elastic and/or plastic behaviour of
the respective material.
[0034] If now, for example, a water reserve evaporates during the
sterilization process in an interior of a flexible medical device,
such as a blood, serum or dialysis bag, then the medical device can
swell, whereby the flow and diffusion processes are substantially
influenced. Taking this deformation into account results in an even
more precise recreation of the sterilization process.
[0035] In an additional development of a process according to the
invention a diffusion of the first, second and/or third medium
through the material of the medical device can be taken into
account in the recreation of the sterilization process.
[0036] A diffusion of media can be intentional or even necessary.
Thus, for example, in the case of ethylene oxide sterilization of
packaged medical devices the ethylene oxide must diffuse through
the packaging in order to reach the actual medical device. Within
the meaning of the invention the packaging here is to be understood
as a constituent of the medical device. However, an unintentional
diffusion can also have an appreciable influence on the
effectiveness of the sterilization process. On the whole, the
validity of the recreation can be increased even further by taking
the diffusion into account.
[0037] As a rule air is to be taken into account as the first
medium. Water, which can be present both as a liquid and as water
vapour, is usually to be taken into account as the second medium.
Ethylene oxide or hydrogen peroxide comes into consideration as the
third medium or, in the absence of water, as the second medium.
[0038] One or more of the above-named objects are achieved
according to a second aspect of the invention by a process for
validating a sterilization process for medical devices, with the
steps of: defining a reduction of a germ load to be achieved by the
sterilization process; carrying out a process according to the
first aspect of the invention; comparing the reduction of the germ
load determined in each cell of the second plurality of cells; and
grading the sterilization process as effective if the necessary
reduction of the germ load has been achieved for each of the cells,
or grading the sterilization process as not effective if the
necessary reduction of the germ load has not been achieved for at
least one of the cells.
[0039] The described process greatly simplifies the validation of a
sterilization process as the introduction of samples and the
subsequent evaluation of the samples can be dispensed with. As the
validation of a sterilization process for a particular medical
device is a prerequisite in many legal systems for the approval
both of the sterilization process and of the medical device itself,
the approval of new medical devices can be simplified and
accelerated, with the result that new and innovative medical
devices can be put on the market, and thus benefit patients, more
quickly.
[0040] In a further development of the process according to the
invention for validating a sterilization process, a checking
process can additionally be carried out, with the steps of:
introducing a sample provided with a known germ load at a
predefined point of a medical device to be sterilized, carrying out
the sterilization process to be validated on the medical device,
determining the reduction of the germ load of the sample achieved
by the sterilization process, and grading the sterilization process
as effective only when the reduction of the germ load of the sample
actually achieved corresponds sufficiently precisely to the
reduction of the germ load calculated for the corresponding
point.
[0041] Even though the positioning and subsequent evaluation of a
sample is necessary for the validation according to the described
further development, the process is advantageous compared with the
validation according to the state of the art. Thus, for example, it
can be proved by the simulation that the location at which the
sample was introduced is actually a critical location of the
medical device, thus a location at which the sterilization process
brings about the smallest reduction of the germ load. Even if the
critical location of the medical device cannot be reached by a
sample, it can be proved with the described process that the result
of the simulation at the location at which the sample was
introduced matches the actual result of the sterilization process.
It can then be assumed that the simulation result is also correct
for the actually critical location.
[0042] One or more of the named 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, and which is developed in that program code information
which, when executed by the processor, is able to prompt the latter
to execute a process according to the above descriptions is stored
in the memory.
[0043] The data processing system can comprise a computer customary
in the trade, which is expediently equipped for the CPU-intensive
process with one or more powerful processors and enough RAM.
[0044] The input means can, in addition to usual input means such
as keyboard, mouse, touchscreen etc., also comprise an interface
with a network, via which the data processing system is connected
to a database in which information about geometric and
material-typical properties of one or more medical devices is
stored.
[0045] The output means can, in addition to usual output means such
as monitor and/or printer, also comprise a storage medium, on which
the results of the described processes are stored as data. These
data can comprise tables, in which the results are represented
numerically. The data can also comprise images and/or videos, by
which the progression or the result of the described processes is
visualized.
[0046] 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 drive.
[0047] One or more of the named objects are achieved according to a
fourth aspect of the invention 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 able to
prompt the latter to execute a process such as described
previously.
[0048] One or more of the named objects are achieved according to a
fifth aspect of the invention by a sterilized medical device, which
has been subjected to a sterilization process, the effectivity of
which has been determined by a method as described above, or which
has been validated by a method as described above.
[0049] One or more of the named objects are achieved according to a
sixth aspect of the invention by a medical device, which has been
produced in a sterilizer, wherein the effectivity of a sterilizing
method used in the sterilizer has been determined by a method as
described above, or which has been validated by a method as
described above.
[0050] The sterilizer encompasses all means required for executing
the respective sterilizing method. By example, the sterilizer shall
encompass means required for aeration with water vapour, and also
an autoclave chamber.
[0051] The invention is explained in more detail below with the aid
of some exemplary representations. The embodiment examples
represented are to serve merely for the better understanding of the
invention, without limiting it.
[0052] There are shown in:
[0053] FIG. 1: a medical device,
[0054] FIG. 2: a sterilizer for a medical device,
[0055] FIG. 3a: a sectional representation of the medical device
according to FIG. 1,
[0056] FIG. 3b: a section of FIG. 3a with a grid structure,
[0057] FIGS. 4a-4c: possible visualizations of a simulation
result,
[0058] FIG. 5: a data processing system.
[0059] FIG. 1 shows a medical device, in the example represented it
is a bag set 1 for peritoneal dialysis.
[0060] In peritoneal dialysis a dialysis fluid is introduced into
the patient's abdominal cavity via a catheter in the abdominal
wall. Via the extensive contact of the dialysis fluid with the
peritoneum, which surrounds all the organs located in the abdominal
cavity, harmful substances are flushed out of the patient's blood
into the dialysis fluid, and thus removed from the blood. After a
certain residence time, which is as a rule approximately four
hours, the dialysis fluid loaded with harmful substances, the
so-called dialysate, is drained off from the patient's abdomen and
replaced by fresh dialysis fluid.
[0061] The bag set 1 comprises a solution bag 2, which has two
chambers 3, 4 filled with dialysis fluid, as well as a technically
required empty chamber 5. The empty chamber 5 is also called the
lambda chamber because of its shape. Each of the chambers 3, 4, 5
is provided with a connecting piece. Two components of a dialysis
solution, a glucose solution and a buffer solution for regulating
the pH of the final dialysis solution are stored in the chambers 3,
4. The glucose solution and the buffer solution are not mixed until
they are used, thus not until immediately before introduction into
the patient's abdominal cavity.
[0062] 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 make it easier to run the dialysate into the
drainage bag 10, the latter can be equipped with stiffening rods,
not represented.
[0063] A central connector 15 of the bag set 1 serves 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
tubes 16, 17. Either the solution bag 2 or the drainage bag 10 can
be connected to the catheter via a valve, not represented.
[0064] The tube 16 connects the central connector 15 to the
solution bag 2. In the packaged state, the tube 16 is rolled up
spirally, it is therefore also called a solution coil. At this
stage the tube 16 is connected to the connecting piece of the
solution bag 2, which opens into the empty chamber 5.
[0065] Not until immediately before the use of the bag set 1 is the
tube 16 connected to the chambers 3 and 4 previously separated from
each other, in order to guide the now mixed solutions to the
central connector 15.
[0066] The tube 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 test for
analysis of the dialysate can be performed. The tube 17 is likewise
rolled up in the packaged state and is called a drainage coil.
[0067] The individual components of the bag set 1 are subjected to
a pre-treatment before being assembled, in order to deposit water
in all air-filled spaces for the later sterilization procedure.
[0068] For this, the components are positioned in a vacuum chamber.
This chamber is then evacuated to a pressure of for example between
150 hpa and 300 hpa residual pressure and then, for example with
the aid of a steam nozzle, flooded abruptly with water vapour, for
example to a pressure of approximately 1450 hpa. In the process the
vapour penetrates into the cavities of the components of the
medical device and condenses to water droplets. This pre-treatment
is called steaming.
[0069] The bag set 1 is then assembled and shrink-wrapped in a
plastic bag, not represented, for storage and for transport.
[0070] The finally packaged bag set 1 must be sterilized before
use, in order to avoid an infection of the patient. For this, as a
rule several bag sets are introduced into a sterilizer, which is
represented in FIG. 2.
[0071] FIG. 2 shows a sterilizer for medical devices which is an
autoclave 20. The autoclave has a sterilization chamber 21, in
which in the example represented 24 packaged bag sets 1 are
arranged on suitable mesh racks. The sterilization chamber 21 can
be closed in a pressure-resistant manner by a door, not
represented.
[0072] During the sterilization process the sterilization chamber
21 is exposed to superheated steam at high pressure. For example a
pressure of 2600 hpa and a temperature of approximately 130.degree.
C. can be achieved here.
[0073] Due to the combination of high pressure and high temperature
germs present in the bag system 1 are killed, with the result that
they can no longer cause an infection of the patient.
[0074] The effectiveness of the sterilization process depends on
various parameters. In addition to the pressure and temperature in
the sterilization chamber 21 and the treatment duration, these also
include the temperatures actually achieved in the medical device as
well as the quantities of water available in the cavities, their
evaporation rate and the resultant water vapour concentrations.
[0075] According to a conventional method for determining the
effectiveness of a sterilization process for medical devices one or
more models of the medical device to be sterilized are provided
with samples which have a known loading with test germs. As a rule
particularly temperature-stable germs are used as test germs, for
example of the species Geobacillus stearothermophilus.
[0076] The models equipped in this way are then subjected to the
sterilization process in question, and then the effect of the
sterilization process on the samples is determined. For this, they
are incubated in a culture medium over several days and the
population of the test germs is evaluated.
[0077] In order to reduce the outlay associated with the
conventional method, a method is proposed here for determining the
effectiveness of the sterilization process by means of a
simulation. For this, the medical device and the interior of the
sterilizer are recreated in a three-dimensional grid. This is
represented schematically in FIGS. 3a and 3b.
[0078] FIG. 3a shows a section through the bag set 1 along a plane
which runs through the line A-A' (FIG. 1) and runs perpendicular to
the plane of extension of the bags 2, 10. It is recognizable that
the solution bag 2 is formed of a lower film ply 30 and an upper
film ply 31, which are connected along connection lines 32, 33, 34,
35 such that the chambers 3, 4 for the dialysis solutions and the
lambda chamber 5 form.
[0079] The drainage bag 10 likewise consists of a lower film ply 40
and an upper film ply 41, which are connected along connection
lines 42, 43 such that the receiving chamber 11 forms.
[0080] At the connection lines 32, 33, 34, 35, 42, 43 the
respective film plies 30, 31, 40, 41 can be glued, heat-sealed, or
otherwise connected to each other such that a substantially gas-
and liquid-tight connection results.
[0081] In FIG. 3b an enlargement of a section X from FIG. 3a is
represented, which represents the lower film ply 30 and the upper
film ply 31 of the solution bag 2 in the area of the lambda chamber
5. In addition, a three-dimensional grid 100 is represented here,
which serves to recreate the bag set 1 in a data structure.
[0082] Although the grid 100 in FIG. 3b is represented
two-dimensionally for the sake of clarity, it is actually a
three-dimensional grid consisting of a plurality of grid cells Z.
In the example represented all the cells Z of the grid are the same
size and shape, for example tetrahedrons. Depending on the
complexity of the shape of the medical device, individual ones of
the cells can also have a different shape and/or size.
[0083] For each of the cells Z it is defined whether there is a
physical constituent of the medical device, such as the film plies
30, 31 of the solution bag 2 at the locations of the cells Z.sub.1,
Z.sub.2, at the corresponding point, or whether it is a cell in a
cavity or in the surroundings of the medical device, such as the
cells Z.sub.3, Z.sub.4.
[0084] For each cell Z of the grid 100 a dataset is provided in the
data structure.
[0085] For the cells which are filled by physical constituents of
the medical device, the dataset contains the prevailing temperature
as well as material data of the medical device, such as the elastic
properties of the material, the heat capacity, the thermal
conductivity, as well as the permeability for different media (air,
water, steam, etc.). For the other cells, the dataset contains the
quantities of the media present in the respective cell (air, water,
water vapour, etc.) as well as data about their thermodynamic state
(temperature, pressure, flow rate and direction, etc.).
Additionally, for each cell representing a cavity an item of
information with respect to a germ load or an achieved reduction of
the germ load is provided.
[0086] Boundary surfaces G, which are recognizable as lines in FIG.
3b, are formed between neighbouring cells Z.
[0087] The data structure is then filled with data, so that it
represents an initial state at the start of the sterilization
process. For example, approximately room temperature will be
present in all the cells, and the pressure is approximately 1000
hpa in each cell which represents a cavity.
[0088] At the same time, a mixture of air and water vapour, for
example steam or steam-air mixture with approx. 2.6 to 3.6 bar
absolute pressure and a temperature of for example 130.degree. C.,
will be present in all the cells which are located outside the
medical device.
[0089] In the case of cells which are located in sealed cavities of
the medical device, other relationships can result due to the
previous steaming. Thus, some cells here are optionally filled with
water, while in other cells there is a mixture of air and water
vapour and also condensed water, which corresponds to a complete
saturation.
[0090] For cells in cavities of the medical device filled with
fluid, all the cells are correspondingly filled with the respective
fluid.
[0091] Subsequently it is computationally determined step by step
how the relationships in the individual cells Z of the grid change
while the sterilization process is being carried out. A time
interval recreated by a computation step can be, for example, one
second, but longer or shorter time intervals can also be
realized.
[0092] During a heating phase of the sterilization process the
sterilization chamber 21 is supplied with superheated steam, with
the result that in some cells, which represent this space,
pressure, water vapour quantity and temperature rise. As soon as
there are differences between two neighbouring cells, a transfer of
energy and/or media through the respective boundary surface between
the cells results. The hereby resultant changes of state of the
individual cells are determined computationally. The computation
methods to be used for this are sufficiently known from
computational fluid dynamics and therefore need not be explained in
more detail here. The following effects are substantially to be
taken into account here:
[0093] Temperature equalization: if there is a temperature
difference between two neighbouring cells, heat energy is
transferred through the boundary surface from the warmer to the
colder cell, whereby the temperatures equalize.
[0094] Pressure equalization: if there is a pressure difference
between two neighbouring cells, some of the media will flow out of
the cell with higher pressure through the boundary surface into the
cell with lower pressure, with the result that the pressures
equalize.
[0095] Concentration equalization: if there is a difference in the
concentration of a medium between two neighbouring cells, or a
difference in the partial pressures of the media, some of the
medium will diffuse through the boundary surface into the cell with
lower concentration or partial pressure, with the result that the
concentrations or partial pressures equalize.
[0096] Gravity: if there is a height difference between two cells,
some of the media will flow out of the higher cell through the
boundary surface into the lower cell.
[0097] Natural convection: if there is a difference in density
between two neighbouring cells, this results in a natural
convection.
[0098] 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 vapour and ethylene oxide. This can have effects on
the effectiveness of the sterilization process and therefore has to
be recreated computationally as precisely as possible.
[0099] After completion of the heating phase the state of the
atmosphere in the sterilization chamber 21 is kept constant, with
the result that essentially only equalization procedures take place
within the medical device. The progression of these equalization
procedures is, however, of great importance to the success of the
sterilization process, therefore the total duration of the
sterilization process is further recreated or simulated according
to the above-described method.
[0100] A cooling process, in which above all the dialysis solutions
present in the solution bag are to be cooled in order to prevent
premature degradation, downstream of the sterilization process can
on the other hand optionally be excluded.
[0101] Further media can be taken into account in the simulation.
Thus, for example, a biocidal gas such as ethylene oxide can be
introduced into the sterilization chamber and diffuse into the
medical device. The corresponding diffusion procedures can be
recreated by the simulation process. For example, the injection of
ethanol for example into plug-in connections can thus also be
readjusted.
[0102] The diffusion of media through the material of the medical
device can be modelled in the simulation by adding to the data
structure data on the absorbency (for example as permeability or
diffusion data) of the material for individual media. If, for
example, the material can absorb a certain quantity of water
vapour, water vapour will diffuse via a boundary surface into the
respective cell if the concentration of the water vapour in the
neighbouring cell is high enough. Thus, water vapour can disperse
in the material slowly cell by cell and even escape again at
boundary surfaces to cavities where there is a lower concentration.
Thus, for example, water vapour can diffuse from the sterilization
chamber through the film plies 30, 31 into the lambda chamber 5. In
the same way, the diffusion of other media such as ethylene oxide
or ethanol can also be simulated.
[0103] During the sterilization process further effects can emerge,
which have to be taken into account in the simulation. Thus, for
example, in sealed volumes of a medical device an increase in the
internal pressure will result. This rise in pressure is
particularly relevant when liquid water, which evaporates due to
the temperature increase, is present in the corresponding volumes
at the start of the sterilization process. The evaporation
procedure must be taken into account in the simulation as it has a
substantial influence on the heat distribution in the medical
device. Likewise, at some points of the medical device condensation
can occur, which likewise influences the temperature
distribution.
[0104] Due to the evaporation of water the lambda chamber 5 or the
receiving chamber 11 can furthermore swell, whereby the geometry of
the corresponding volumes changes.
[0105] Allowances can be made for this effect in different ways.
Firstly, the elastic and/or plastic deformability of the material
of the medical device can be stored in the data structure. In each
computation step it can then be determined whether a force is
acting on a cell which represents a physical constituent of the
medical device, with the result that it moves. If a movement of the
material in the cell is established, either the grid can remain
unchanged and the movement can be imaged in that the corresponding
state data are assigned to a neighbouring cell into which the
material has moved. It can also become necessary for individual
cells to have to be added or removed. However, this can have the
result that after the shift cells exist which are no longer
assigned any state data, which leads to problems.
[0106] A better solution is to construct the entire grid
dynamically such that the size and position of the individual grid
cells can change, in order to allow for such expansion effects.
Here, it is to be borne in mind that in areas in which a clear
volume change is to be expected a sufficiently fine grid structure
is chosen in order that the result does not become imprecise due to
grid cells ultimately being too large.
[0107] As a decisive part of the simulation, in each computation
step for each cell of the grid which does not correspond to a
physical constituent of the medical device the effect of the
respectively prevailing state on a possible germ population is
calculated. During the definition of the initial state each cell
can be assigned a particular germ load, for example an occupancy
with 10.sup.6 germs of the species Geobacillus
stearothermophilus.
[0108] With the aid of the finite difference equation
.DELTA.N.sub.i=-k.sub.i*N.sub.i*.DELTA.t the alteration of the germ
load and the remaining germ load are then determined. In the
process the deactivation rate k is determined depending on the
respectively present ambient parameters, thus for example the
temperature, the water vapour concentration and/or the
concentration of active media such as ethylene oxide.
[0109] Instead of calculating a notional germ load, in each
computation step and for each computation cell a logarithmic germ
reduction F can also be determined and then added up in order to
determine the germ reduction achieved during the total
sterilization process:
F i = log .times. N i + 1 N 1 = log .function. ( 1 - k i * .DELTA.
.times. .times. t ) ##EQU00003## F tot = log .times. N end N start
= .SIGMA. .times. .times. F i ##EQU00003.2##
[0110] The results of the simulation can be represented or
visualized in different ways. One possibility is to output the
smallest germ reduction achieved in the medical device as a
number.
[0111] The progression of a parameter of interest over the duration
of the sterilization process can be output as a graph for a
selected cell.
[0112] Further possibilities are to represent selected parameters
colour-coded or greyscale-coded in sectional representations of the
medical device. Here the state at a particular point in time during
the sterilization process can be represented, for example the
temperature or the achieved germ reduction after 1000 seconds,
after 2000 seconds and at the end of the sterilization process.
[0113] In FIGS. 4a to 4c, for example, visualizations of the
temperature of the dialysis solutions after a sterilization process
are represented. FIG. 4a shows the temperature at the outer
surfaces of the solution chambers 3, 4; FIG. 4b shows the
temperature in a section parallel to the surface of extension of
the solution bag 2; and FIG. 4c shows the temperature in a section
perpendicular thereto. It is recognizable that in the example
represented a very homogeneous final temperature of the solutions
has been achieved.
[0114] The progression of the respective parameters over the
duration of the sterilization process can also be provided as a
video. In similar representations, pressure, water vapour
concentration and/or achieved germ reduction can also be
represented.
[0115] The described simulation process can be used to determine
the effectiveness of a sterilization process for a particular
medical device, such as for the bag set 1 in the example
represented. In this way, e.g. after a design change or
redevelopment of a medical device, it can be checked whether a
known sterilization process is sufficient to sterilize the medical
device reliably. In this way the effects of adjustments on the
sterilizability can be tested without the need to manufacture and
sterilize sample copies for every adjustment.
[0116] Thereby, new or modified medical devices can be made
available to the market fast, as the effectivity of a suitable
sterilization method can quickly be shown.
[0117] Parameter changes in sterilization processes can likewise be
tested with the described simulation process for their effects on
the result, without having to accept the described outlay for
performance and sampling.
[0118] In order to test individual components of a medical device
with respect to their sterilizability, it can make sense to limit
the simulation initially to these components and their immediate
surroundings. The necessary computational outlay can thereby be
reduced substantially. However, a complete simulation should always
be effected for a conclusive assessment.
[0119] Finally, it is even conceivable to use the results of the
described simulation process to validate a sterilization process
for the legal approval of a new or altered medical device or a
sterilization process.
[0120] For this, a germ reduction to be achieved by the
sterilization process is predefined, which is for example a 12-log
reduction, thus a germ reduction by a factor of 10.sup.12. It is
then checked, with the aid of the simulation, that the required
germ reduction is achieved at every point of the medical device. If
the required reduction is achieved, the successful sterilization is
validated and the medical device can be approved.
[0121] The reliability of the proof can be further increased if a
sampling with a sample is effected in addition to the simulation
and the result of the simulation is compared with the result of the
sampling. The approval can then be made dependent on the results
matching.
[0122] Here, in contrast to the conventional validation process,
the sampling can be effected at a point of the medical device which
is not a critical point, as only the match with the simulation
result needs to be proved. The outlay on the sampling can hereby be
reduced. Influences of the sample on the media distribution in the
medical device can be taken into account in the simulation or
compensated for by a corresponding addition or deduction of
media.
[0123] In contrast to the conventional validation process, proving
the match between simulation and sampling can optionally be
effected in an interrupted sterilization process, for example when
the actually necessary germ reduction has not yet been achieved.
This has the advantage that a larger population of test germs,
which can be evaluated more easily, is still present on the sample
after the sterilization process.
[0124] By the validation process described above, a new or modified
medical device can be made available to the market even faster.
[0125] In the described simulation process it must be taken into
account that the initial state is possibly not identical for every
individual medical device. Thus, in particular, the position and/or
size of water droplets which enter the medical device due to the
steaming can be random and can differ from medical device to
medical device. Precisely in the case of medical devices with
awkward 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.
[0126] It can therefore be necessary to model some possible
distributions of the water droplets and to simulate the effects
separately. For a validation, the distribution would then have to
be based on which one brings the poorest sterilization result.
[0127] In order to determine the effect of the steaming of the
medical device and a resultant distribution of water droplets in
the medical device, a simulation process designed analogously to
the above-described simulation process of the sterilization process
can likewise be carried out for the steaming process. However, it
must be taken into account here on the one hand that the actual
position and size are randomly affected strongly by water droplets
forming due to condensation, with the result that at best estimates
are possible. On the other hand the water droplets can move and
merge in the medical device, if the medical device is moved between
the steaming and the sterilization.
[0128] The described simulation process can be carried out on a
data processing system, such as is represented in FIG. 5.
[0129] The data processing system 100 comprises a central
processing unit 101 with at least one processor 102 and a storage
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 storage element 103 can comprise
writable components (RAM) and non-writable components (ROM). The
storage element 103 preferably has a large storage capacity and a
high write and read speed.
[0130] The central processing unit 101 can be formed by a computer
customary in the trade, e.g. a PC.
[0131] The central processing 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
comprise 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
at the same time also function as input means.
[0132] The central processing unit can be connected to a database
111, in which design data for one or more medical devices, one or
more sterilizers and/or data for one or more sterilization
processes are stored, directly or via a network 110. The processor
102 can access the data stored in the database 111 in order to
recreate a medical device and/or a sterilizer in a data structure,
and/or in order to recreate a sterilization process by means of the
above-described simulation process.
[0133] The central processing unit 101 is furthermore connected to
a write/read device 112 for the data carrier 113. In the example
represented the data carrier 113 is a CD or DVD, alternatively
other known removable or non-removable data carriers can be
used.
[0134] Program code information, which can be transferred into the
storage element 103 by the processor 102, can be stored on the data
carrier 113. From the storage element 103 the processor 102 can
then read and execute this program code information in steps,
whereby the processor is prompted to execute the above-described
simulation process.
[0135] The central processing unit can likewise use the write/read
device to store results of the simulation process on a data carrier
113. Alternatively, the results can be visualized on the monitor
106 and/or stored in the database 111.
[0136] 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 to the peripheral devices 104, 105, 106, 112 directly,
but via suitable interface elements.
* * * * *