Method for sterilizing a set comprising at least one single-use device for biopharmaceutical fluids

Abstract

A method (40) for sterilizing an assembly (32) by X-rays, the assembly (32) comprising a disposable device (2) intended for receiving a biopharmaceutical fluid (C), the method comprising: - mounting a plurality of dosimeters (50); - repeatedly passing the assembly (32) in front of an X-ray radiation window (38) to repeatedly expose a first side (32a) and then a second side (32b) of the assembly (32) to a plurality of irradiation power-time pairs (PTi), subsequently mapping the irradiation dose; and - determining an optimal power-time pair (PTopt) for which the mapping reveals that all dosimeters (50) have recorded a radiation dose above a minimum sterile dose (Dmin), and for the optimal power-time pair, a dosimeter associated with a vulnerable element of the disposable device has recorded a radiation dose below a maximum dose (Dmax), the maximum dose being defined as the dose at which X-ray radiation degrades the vulnerable element.

Description

Technical Field

[0001] This disclosure relates to the field of sterilization of disposable devices intended for receiving biopharmaceutical fluids, and more specifically, to the field of sterilizing by X-ray a tray or pod containing one or more disposable containers intended for receiving biopharmaceutical fluids, which are products derived from biotechnology (culture media, cell cultures, buffer solutions, artificial nutrient solutions, blood products, and blood product derivatives) or pharmaceutical products, or more generally products intended for use in the medical field. Background Technology

[0002] A bioreactor bag (or container) for biopharmaceuticals is a device that supports a biologically active environment. It can be made of a membrane, polycarbonate, polyethylene, or polypropylene sheath and includes a can designed for receiving biopharmaceuticals or bioproducts.

[0003] Bioreactors can incorporate various sensors (such as temperature or pressure sensors) to monitor the evolution of the biologically active environment. The size of bioreactors is variable and typically ranges from 50 liters to 2000 liters.

[0004] Prior to commercialization, bioreactors were typically irradiated with gamma rays to destroy any microorganisms that might later disrupt their function. Gamma radiation is electromagnetic radiation emitted during the decay of a radioactive source (Cobalt-60). The emitted radiation energy allows for the destruction of microorganisms and, at certain doses, can allow for the sterilization of the product. To sterilize the product, it is automatically conveyed through an irradiation chamber. The product is typically packaged and stacked on pallets or pods to form a batch, allowing for bulk transport. The assembly is then received with a controlled dose of gamma rays and subsequently removed from the irradiation chamber. By rotating the assembly itself, it can be irradiated multiple times, for example, according to several faces, to ensure that all parts of the assembly have been irradiated. The energy absorbed during radiation is measured in kilogras (kGy). This absorbed energy, measured using a dosimeter, depends on several factors, including exposure duration, radiation intensity, material density, and packaging size.

[0005] At excessively high doses of gamma radiation, for example, it could damage or even destroy some components of a bioreactor, such as sensors. Therefore, strictly speaking, gamma ray treatment cannot currently sterilize bioreactors. In fact, the relative fragility of sensors within these containers does not allow for irradiation at doses sufficient for sterilization; instead, the dose is limited to lower levels. Thus, we simply speak of “irradiated containers.” This irradiation certainly allows for relative sterility (i.e., approximately 1 in 100,000 organisms surviving), but it does not allow for compliance with the ISO 11137 standard for sterility in a healthy environment (i.e., approximately 1 in 1 million organisms surviving). Summary of the Invention

[0006] This disclosure improves upon this situation.

[0007] A method for sterilizing an assembly by X-ray is provided. The assembly includes a support and a disposable device designed for receiving biopharmaceutical fluids. The assembly has a non-uniform density and a height that is 65% or greater of the size of the X-ray radiation window, taken in relation to a direction perpendicular to the support. The disposable device includes a sensor and a mixing device. The method includes: - placing a plurality of dosimeters distributed on and / or within the disposable device according to a predetermined arrangement, one dosimeter arranged on and / or at the port of the sensor, and another dosimeter arranged on the mixing system; - forming the assembly according to a predetermined configuration by arranging the disposable device equipped with the plurality of dosimeters in a package on the support; - repeatedly positioning the assembly in front of the X-ray radiation window according to a first face of the assembly under several irradiation power-time pairs. The process involves passing through the X-ray radiation window according to the second face of the component, while incrementing the power-time pair between a minimum power-time pair and a maximum power-time pair. Subsequently, for each of the incrementing power-time pairs, the radiation dose received by each of the plurality of dosimeters is mapped, the first and second faces containing the height of the component, the second face of the component being opposite to the first face; and determining an optimal X-ray radiation power-time pair for which the mapping reveals that, after passing through according to the first face and according to the second face, all dosimeters record a radiation dose higher than the minimum dose, and the dosimeter associated with the sensor records a radiation dose lower than the maximum dose, the minimum radiation dose being defined as the sterile effective dose, and the maximum radiation dose being defined as the dose at which X-ray radiation degrades the sensor.

[0008] For example, in the case of containers, the density of the container, and therefore the density of the components, is non-uniform due to the presence of components made of different materials (e.g., the shaft of the mixing device is made of polyethylene terephthalate, while the container walls are made of polypropylene, or ball bearings may contain ceramic and / or metal components). Therefore, for a given amount of radiation, the received radiation dose may vary from one point in the container to another. Materials with higher densities will receive a lower radiation dose than materials with lower densities. Therefore, if the dose received in high-density areas of the components is insufficient, sterility may not be guaranteed everywhere. When the density of the material is higher than 0.6 g / cm³... 3 At this time, the material is said to have high density. On the other hand, the container includes fragile elements (such as sensors) that may be damaged if an excessively high radiation dose is applied. Therefore, the method takes these parameters into account so that components comprising one (or more) packages (each package comprising one (or more) containers) can be sterilized with minimal throughput. This is especially important when the height of the component is 65% or greater of the X-ray radiation window size. According to one embodiment, the height of the component is 65% or greater of the X-ray radiation window size. According to one embodiment, the height of the component is 70% or greater of the X-ray radiation window size. According to one embodiment, the height of the component is 75% or greater of the X-ray radiation window size. In one embodiment, the height of the component is 80% or greater of the X-ray radiation window size. In one embodiment, the height of the component is 85% or greater of the X-ray radiation window size. In one embodiment, the height of the component is 90% or greater of the X-ray radiation window size. In this case, the radiation window may produce an edge effect, i.e., the area surrounding the radiation window does not receive the prescribed irradiation. The method disclosed herein also allows for at least partial overcoming of these edge effects.

[0009] Alternatively, the features disclosed in the following paragraphs can be implemented. These features can be implemented independently of each other, or they can be implemented in combination with each other:

[0010] The method also includes prior steps of determining the maximum dose and / or determining the minimum dose.

[0011] - The disposable device comprises a plurality of sensitive elements, which are defined as elements that degrade when a predetermined irradiation dose is exceeded. A sensor forms part of the plurality of sensitive elements. The step of placing the dosimeter includes placing a dosimeter on each of the plurality of sensitive elements. In the step of determining the optimal X-ray radiation power-time pair, the optimal power-time pair is a power-time pair for which the mapping reveals that all dosimeters record an irradiation dose higher than the minimum dose, and the dosimeter associated with the sensitive element records an irradiation dose lower than the maximum dose, and the maximum dose is defined as the lowest dose at which X-ray irradiation damages the function of one of the sensitive elements.

[0012] - Before each pass of the component in front of the radiation window under a given irradiation power-time pair, a plurality of new dosimeters that have not yet been irradiated are placed in the predetermined arrangement on a new disposable device that has not yet been irradiated to form a new component that has not yet been irradiated.

[0013] - Before each pass of the second face in front of the radiation window under a given irradiation power-time pair, a plurality of new dosimeters that have not yet been irradiated are placed in the predetermined arrangement on a new disposable device that has not yet been irradiated to form a new component that has not yet been irradiated.

[0014] - The minimum radiation dose is defined by standard ISO 11137.

[0015] - The minimum irradiation dose is at least 25 kGy, preferably at least 27.5 kGy, and more preferably at least 30 kGy.

[0016] - The maximum irradiation dose is included between 45 kGy and 50 kGy, preferably 47 kGy.

[0017] The power-time pair is selected from a combination of irradiation power and irradiation time, wherein the irradiation power is included between a minimum power of 75 kW and a maximum power of 1100 kW, and the irradiation time is included between a minimum irradiation time of 0.1 hours and a maximum irradiation time of 20 hours.

[0018] - Irradiation time increments are included in increments between 0.1 hours and 2 hours.

[0019] - The power increments of irradiation are carried out in increments between 50kW and 200kW.

[0020] The method further includes: repeating the passage of the component in front of the radiation window based on the other two opposing faces of the component.

[0021] - The packaging includes several disposable devices, and / or the component includes several packages arranged on a support.

[0022] The method further includes irradiating a new component, comprising a new package and a new disposable device, under optimal power-time pairing. The new package and the new disposable device are of the same shape and size as the package and disposable device in the previous step. The disposable device and the package are arranged in a predetermined configuration. The irradiation is performed according to a first side of the component and then according to a second side of the component.

[0023] According to another aspect, a component is provided, comprising: - a support, on which a package is placed, the package containing a disposable device intended for receiving a biopharmaceutical fluid, the component having a non-uniform density, the component having a height of 65% or greater of the size of an X-ray radiation window, the disposable device including a sensor and a mixing device, the component being sterilized according to the method described above. Attached Figure Description

[0024] Further features, details, and advantages will be revealed by reading the detailed description below and analyzing the accompanying drawings, which are shown in the drawings:

[0025] Figure 1

[0026] [ Figure 1 [Illustration of a disposable device according to one embodiment for receiving biopharmaceutical fluids.]

[0027] Figure 2

[0028] [ Figure 2 [Illustration of an assembly comprising several packages according to one embodiment, each package containing one or more disposable devices, the assembly being arranged in front of an X-ray radiation window.]

[0029] Figure 3

[0030] [ Figure 3 [This is a flowchart of a method for sterilizing a component according to one embodiment, the component including at least one disposable device intended for receiving biopharmaceutical fluids.] Detailed Implementation

[0031] Now for reference Figure 1 , Figure 1 A schematic diagram of an example of a disposable device 2 for receiving biopharmaceutical fluid C is shown. This disposable device can be a bag or container, or a filter. When the bag or container 2 is intended for use in a chemical reaction, the container 2 can be referred to as a "bioreactor".

[0032] The disposable device 2 may be designed to receive biopharmaceutical fluid C for transport operations, cell culture, mixing and / or chemical reactions and / or filtration. The biopharmaceutical fluid may be a biotechnology-derived product—culture medium, cell culture, buffer solution, artificial nutrient solution, blood product and derivatives of blood products—or a pharmaceutical product, or more generally a product used in the medical field.

[0033] According to one embodiment, the disposable device 2 is a container 2 formed by a wall 3, which is preferably made of a plastic material (e.g., polycarbonate, polyethylene, or polypropylene). The wall 3 is flexible and impermeable to the biopharmaceutical fluid C. The wall 3 of the container 2 may include a lower portion 3a, a lateral portion 3b, and an upper portion 3c, which are formed, for example, by one or more segments fixed or welded together. Thus, the container 2 defines an internal space 4 capable of receiving a given amount of biopharmaceutical fluid C. The wall 3 may be completely or partially transparent or translucent so that the biopharmaceutical fluid C in the internal space 4 can be observed from the outside.

[0034] Container 2 is intended for single use, and its capacity can range from 10 liters to 5000 liters depending on the need and application. According to another embodiment, the capacity of container 2 is 10 liters, 50 liters, 100 liters, 200 liters, 1000 liters, 2000 liters, or 5000 liters.

[0035] Container 2 has a main axis XX along which it extends. Container 2 can be manufactured such that the internal space 4 has a generally cylindrical, rectangular, or even somewhat flat shape, especially for bags with small volumes.

[0036] Depending on the size of container 2, container 2 can be more or less complex and contain more or fewer components. Container 2 includes at least a sensor 27 and a device 7 for mixing the biopharmaceutical fluid C. Container 2 may include several sensors 27 (e.g., contact sensors, optical sensors, temperature sensors, pressure sensors) and / or several mixing devices 7. The sensors 27 and mixing devices 7 will be described in more detail below.

[0037] Container 2 may include one or more through ports 5 for introducing biopharmaceutical fluid C or components of biopharmaceutical fluid C, the through ports 5 engaging with one or more inlet orifices formed in container 2. Container 2 may also include at least one through port 6 for evacuating fluid biopharmaceutical C, the through port 6 engaging with at least one outlet orifice formed in container 2. The outlet port 6 can be closed when needed, and conversely, can be opened for evacuation. "Port" should be understood as a physical connection or link. Such ports are through when it involves ensuring communication between the interior space 4 and the exterior of container 2, for example, for introducing or evacuating substances that should be placed or are placed in container 2. Such ports may also be non-through when it involves ensuring the function of components maintaining the mixing container. Conduits, bags, and reservoirs are flexible where appropriate and may be associated with inlet ports via fluid-communication, sealable, and removable connections where appropriate. Similarly, flexible conduits, bags, and reservoirs can be associated with outlet ports 6 via fluid-communication, sealable, and removable connections where appropriate. Figure 1 In the illustrated embodiment, the discharge port is shown at the lowest portion of container 2. However, this embodiment is not limiting, and one or more inlet ports may be located in the lower portion 3a or the lateral portion 3b of container 2. Container 2 may also include a venting device 13 capable of delivering a given amount of venting gas to the biopharmaceutical fluid C. Thus, the device 13 is capable of venting 10 the material in the internal space 4 of container 2, whether the material is biopharmaceutical fluid C or part of its components. The venting device 13 may include a venting gas supply device 14 having at least one tubular element 14a extending in fluid communication from the outside of container 2. The venting device 13 may be functionally associated with at least one venting gas discharge port 36 formed in the upper portion 3c of the container wall 3 of container 2. This venting gas discharge port 36 allows gas that has not yet been mixed with the biopharmaceutical fluid C in container 2 to be discharged from container 2 to the outside. In some embodiments, container 2 may also include other ports known per se, for example for mounting functional devices, to ensure maintenance of components, typically for collecting or measuring data or extracting samples for analysis.

[0038] The mixing device 7 is capable of mixing substances within the internal space 4 of the container 2, whether the substance is a biopharmaceutical fluid C or a component thereof. The mixing device 7 includes at least one shaft 8, which is rotatable by a motor 9 (particularly magnetically driven) and capable of driving at least one mixing member 10 mounted on the shaft 8 to rotate. The mixing member 10 is significantly spaced from the lower portion 3a and the lateral portion 3b of the container wall 3. The mixing member 10 may be in the form of a propeller with a hub supporting several blades. The shaft 8 may have a fixed length or an adjustable length. The shaft 8 may be driven by a motor 9 located outside the container 2 (in... Figure 2 (Partially shown in the middle) Rotation.

[0039] The container 2 also includes at least one first bearing 11 adjacent to the upper portion 3c of the container wall 3, with the upper portion 8b of the shaft 8 cooperating with the first bearing 11. The first bearing 11 includes a rigid collar. "Collar" should be understood herein as a rigid portion in the general shape of a solid container wall, which is at least substantially planar, laid flat, and intended for maintenance. The collar is rigidly and tightly fastened to the upper portion 3c of the container wall 3. More specifically, the collar is made of a substantially rigid material (preferably a hard plastic material) and is attached to the container wall or plate of the container 2 at the center of the upper portion 3c. The collar can be attached to the container wall 3 of the container 2 in any suitable manner to form a rigid and airtight joint between the respective rigid and flexible materials of the collar and the container wall 3.

[0040] According to one embodiment, the shaft 8 of the mixing device 7 is entirely located within the internal space 4. Therefore, the shaft 8 extends vertically between its lower end 8a and upper end 8b. When the container 2 is in a position suitable for its operation, the shaft 8 extends vertically along the main axis XX, with the lower end 8a positioned toward the lower portion 3a of the container 2, and the upper end 8b positioned toward the upper portion 3c of the container 2.

[0041] According to one embodiment, the drive motor 9 allows rotation of the drive shaft 8 via magnetic drive. For this purpose, the motor 9 includes a drive disc located outside the container 2. The shaft 8 then includes a driven disc 15 designed to functionally, and particularly magnetically, engage with the drive disc 30 of the motor 9. More specifically, the driven disc 15 includes a plurality of magnets 17 integrated together by any fastening or construction means to enable rotation of the shaft 8 during rotation of the drive disc of the motor 9. The driven disc 15 is fixed to the shaft 8, particularly in rotational direction.

[0042] According to one embodiment, container 2 includes an attachment or port 25 for securing sensor 27 to container wall 3. According to one embodiment, sensor 27 is a probe in contact with biopharmaceutical fluid C, and attachment 25 is an annular component surrounding the measurement port and protecting sensor 27. This measurement port may be separate from port 5 and discharge port 6. Sensor 27 may be a contact probe that allows measurement of parameters related to biopharmaceutical fluid C that would be detected without the internal space 4 of container 2, such as pressure, pH, temperature, color, biomass, or conductivity. Container 2 may accommodate other types of sensors, such as optical sensors, temperature sensors, and / or pressure sensors, instead of the sensor in measurement port 24. Some sensors may be associated with a securing area not surrounding a port or opening of container 2. They can then be simply placed on the container wall of container 2 (inside or outside the container) via attachment or sensor hatch 25.

[0043] Depending on the application type, container 2 may have additional components.

[0044] The disposable device 2 can be packaged for easy and safe transport from the manufacturing plant to its final destination, particularly during sterilization. For this purpose, and referring to... Figure 2 The disposable device 2 (optionally together with other disposable devices) can be placed in the package 30 on the support 33 to form a component 32 comprising one or more stacked packages. Figure 2 In the example, for illustration, package 30 contains four disposable devices 2. Package 30 may contain fewer or more than four disposable devices 2. For example, package 30 may contain only one disposable device 2. This would be, for example, the case of a large-sized container 2 (e.g., 500 liters or more). The disposable devices 2 may also be foldable, wherein the shaft 8 is optionally retracted to occupy a smaller footprint in package 30. Disposable devices 2 within the same package 30 (in the case where package 30 contains several disposable devices 2) may all have the same orientation or different orientations. According to one embodiment, the disposable devices 2 may, for example, be arranged end-to-end to make package 30 more compact.

[0045] If the packaging dimensions allow, several packages 30 can be stacked on top of each other and / or arranged adjacent to each other on the support 33. The distribution of the packages 30 in a stacked or adjacent arrangement can be selected according to the type and / or size of the disposable device 2. Figure 2 In the example, component 32 contains four stacked packages 30, and each stack contains eight packages 30.

[0046] The support member 33 can also have several shapes and sizes. According to... Figure 2For example, support 33 is a flat rectangular base of the pallet or cargo tray type. According to one embodiment, support 33 measures 80cm × 120cm. According to another embodiment, support 33 measures 100cm × 120cm. Support 33 may be made of wood and has lateral notches that allow for its transport. Therefore, a forklift can be used to move support 33. Support 33 may also be placed on a conveyor belt.

[0047] The support 33 shown in the attached diagram is pallet-shaped. However, support 33 can be part of a pod (sometimes also called a swing element). According to one embodiment, the pod includes two pallets arranged perpendicularly to each other, each pallet serving as a support for container packaging. Therefore, the pod can transport twice the product of a single pallet. The pod is typically suspended from the top, allowing it to move forward as needed (via a conveyor) and rotate on its own.

[0048] Because the disposable device 2 is intended for receiving biopharmaceutical fluids, it is preferable to ensure that the disposable device 2 is sterile. In fact, the presence of undesirable microorganisms in the internal space 4 could lead to a reaction or contamination of the biopharmaceutical fluid C. Therefore, sterility is typically achieved once the disposable device 2 has been packaged and placed on the support 33. Sterilization can be performed using X-rays. For this purpose, the component 32 located on the conveyor can be directed toward the radiation window to receive an irradiation dose that allows for the elimination of microorganisms.

[0049] Still refer to Figure 2 And supplementary reference Figure 3 Component 32 includes a support 33 and on the support 33 is placed at least one package 30 including at least one disposable device (such as container 2). Sterilization method 40 uses X-rays to sterilize the disposable device 2 in batches by sterilizing component 32. The disposable device may be a bag or a filter. For the purpose of illustrating method 40, reference will be made to the case where the disposable device is a container. Container 2 is intended for single use and is intended for receiving biopharmaceutical fluid C. Container 2 includes at least a sensor 27 and a mixing device 7. Component 32 may be presented in front of X-ray radiation window 38 to sterilize multiple containers 2 in batches.

[0050] Method 40 is particularly suitable for cases where the density of container 2 (and therefore component 32) is non-uniform. Method 40 allows for the determination of X-ray radiation capable of sterilization, and this sterilization is effective in high-density areas of container 2 (e.g., mixing device 7) without damaging sensitive elements of container 2 (e.g., sensor 27). This is especially relevant when the material density is higher than 0.6 g / cm³. 3 At that time, it was said that the material had high density.

[0051] Method 40 is also particularly suitable for situations where the height H of component 32 is close to the height of X-ray radiation window 38. In practice, component 32 is presented in front of radiation window 38 for irradiation. A side surface 32a of irradiation component 32 has been selected, which contains the height H of component 32, defined relative to the direction perpendicular to support 33. The height H of component 32 is considered close to the height of X-ray radiation window 38 when it is 65% or greater than the size T of X-ray radiation window 38. In practice, when the size of the product to be irradiated is substantially the size of radiation window 38, radiation produces edge effects, i.e., areas around the periphery of radiation window 38 do not receive the prescribed irradiation. The method disclosed herein allows for at least partial overcoming of these edge effects. According to one embodiment, the height of the component is 65% or more of the size of X-ray radiation window. According to one embodiment, the height of the component is 70% or more of the size of X-ray radiation window. In one embodiment, the height of the component is 75% or more of the size of X-ray radiation window. According to one embodiment, the height of the component is 80% or more of the size of the X-ray radiation window. According to one embodiment, the height of the component is 85% or more of the size of the X-ray radiation window. According to one embodiment, the height of the component is 90% or more of the size of the X-ray radiation window.

[0052] Method 40 begins at step 42, in which multiple (at least two) dosimeters 50 are placed on and / or within container 2. Some dosimeters may also be placed on packaging 30 and / or support 33. The dosimeters 50 allow for the determination of the effective irradiation dose received. This data allows for ensuring, on the one hand, that the received dose is higher than that required for sterilizing container 2, and on the other hand, that the dose does not exceed a value that could damage components of container 2.

[0053] For a given irradiation, the received dose depends on the non-uniformity of container 2. In fact, for a given irradiation, the density of the material affects the received irradiation dose: the higher the material density, the lower the received dose. Therefore, at least one dosimeter 50 is arranged on the mixing system 7. The mixing device 7 forms part of the container with the highest density region (compared to other parts of container 2). Preferably, several dosimeters are distributed in the highest density region other than the mixing device 7 to control the actual irradiation dose received at different locations on container 2. According to one embodiment, a high-density region is a region with a density locally higher than the average density of container 2. According to one embodiment, a high-density region is a region with a density locally twice the average density of container 2. High-density regions can be determined based on the material and / or material thickness considered. For example, compared to the rest of container 2, and particularly the rest of the flexible container wall 3, the following elements can be considered high-density regions: the mixing shaft supporting the propeller, including the upper and lower bearings of the ball bearings.

[0054] When determining the high-density area, the density of the packaging 30 and the support 33 can be equivalent to the density of the container 2. In fact, according to one embodiment, the packaging 30 is made of cardboard, and the support 33 is made of wood or steel, both having a substantially homogeneous construction. Therefore, they do not represent a significant additional density compared to the unpackaged container 2. Therefore, the determination of the high-density area at the horizontal level of the container 2 (for the placement of the dosimeter 50 in step 42) will generally be considered as the determination of the high-density area at the horizontal level of the component 32.

[0055] On the other hand, dosimeter 50 is arranged on sensor 27 to ensure that sensor 27 does not receive radiation doses that could damage it. Dosimeter 50 may be arranged on or adjacent to sensor 27, such as, for example, on the port of sensor 25. More than one dosimeter 50 may be arranged at the horizontal height of sensor 27.

[0056] According to one embodiment, dosimeters 50 are distributed in vulnerable areas of container 2, excluding sensor 27, which are identified as potentially altered if exposed to excessive doses of X-rays. In fact, sensor 27 may not be the only type of element in container 2 that could be altered by excessive irradiation. Following excessive X-ray exposure, the material forming the container wall 3 of container 2 undergoes chemical modification, characteristic oxidation of the polymer, and the generation of oxidants within and on the polymer's surface. This generation of oxidants can lead to the formation of free radicals, and thus to polymer modification. These free radicals can induce the aggregation and oxidation of product proteins in disposable biological containers. Therefore, according to one embodiment, dosimeters 50 are also arranged on the container wall 3.

[0057] According to one embodiment, several dosimeters 50 are arranged on sensor 27, and several dosimeters are arranged on mixing device 7. According to one embodiment, the dosimeters 50 are uniformly distributed on and / or within container 2. According to another embodiment, the dosimeters 50 are non-uniformly distributed on container 2 to benefit high-density areas and vulnerable elements of container 2.

[0058] Within the volume of container 2, as many dosimeters as possible can be selected based on the required accuracy of the measured readings. The number and distribution of dosimeters in and / or on container 2 affect the mapping of the received irradiance.

[0059] Type I or Type II dosimeters exist. Type I dosimeters can use Frick solutions, dichromate solutions with spectrophotometric evaluation, high-cerium-cerium solutions with spectrophotometric or potentiometric measurements, or ethanol-chlorobenzene solutions with titration analysis to determine the absorbed radiation dose during radiation. Type II dosimeters include process colorimeters, cellulose triacetate, polymer matrices containing lithium fluoride (fluorescent), plexiglass systems, and radiochromic films and liquids.

[0060] In order to place the dosimeter on and / or in container 2, container 2 is sacrificed because container 2 is cut open to allow the dosimeter 50 to be installed and can no longer be used for its usual purpose.

[0061] From step 42, we move to step 43, in which assembly 32 is formed according to a predetermined configuration by arranging containers 2 equipped with the plurality of dosimeters 50 in packaging 30 and then on support 33. According to one embodiment, if assembly 32 comprises several packaging 30s, each packaging 30 containing one or more containers 2, then each container 2 is equipped with a dosimeter 50 and placed in the packaging 30 and on assembly 32 in the same manner as during batch sterilization (step 47) (i.e., according to the predetermined configuration) to replicate the passage of a tray 32 of packaging equipped with containers 2 in front of radiation window 38. Note also the orientation of assembly 32 relative to radiation window 38, which is part of the predetermined configuration and is replicated during step 47 of batch sterilization.

[0062] From step 43, we switch to step 44, which includes: repeating the passage of component 32 in front of X-ray radiation window 38 according to a first face 32a and then according to a second face 32b at different X-ray irradiation power-time pairs. Component 32 includes a container 2 equipped with a plurality of dosimeters 50. This passage is repeated while increasing the power-time pair between a minimum power-time pair (PTmin) and a maximum power-time pair (PTmax). At each irradiation, for a given power-time pair, and for each given face 32a, 32b, the dose received by each dosimeter is recorded. According to one embodiment, component 32 passes in front of X-ray radiation window 38 successively according to the first face 32a and then according to the second face 32b at a given power-time pair, then successively according to the first face 32a and then according to the second face 32b at another given power-time pair, and so on. The first surface 32a and the second surface 32b are opposing lateral surfaces of the assembly 32. The first surface 32a and the second surface 32b comprise the height H of the assembly 32. Therefore, the X-ray radiation window 38 is arranged laterally relative to the assembly 32 to irradiate the lateral surfaces of the assembly 32. If the top surface of the assembly 32 is preferably already used for irradiation, the radiation window 38 will be arranged above the assembly 32.

[0063] In order to irradiate according to the first lateral surface 32a and then according to the opposing second lateral surface 32b, the assembly 32 is flipped before passing again in front of the X-ray radiation window 38. The flipping corresponds to a 180-degree rotation depending on the direction perpendicular to the support 33. This rotation can be performed in several ways. The support 33 with the packaging 30 and container 2 can be lifted and rotated 180 degrees. If the assembly is a pod, the pod can be flipped by rotating itself about the vertical pivot of the suspended pod. If the pod comprises two supports arranged perpendicularly to each other, each support containing the packaging of the container, such that the height of the pallet-pod is greater than the height of the radiation window 38, the position of the pod can also be vertically adjusted relative to the dimension T of the radiation window 38 so that each of the supports of the pod is irradiated.

[0064] According to one embodiment, the power-time pair is selected from combinations of irradiation power and irradiation time, wherein the irradiation power is between a minimum power of 75 kW and a maximum power of 1100 kW, and the irradiation time is between a minimum irradiation time of 0.1 hours and a maximum irradiation time of 20 hours. According to one embodiment, the irradiation time is increased in increments between 0.1 hours and 2 hours. According to one embodiment, the irradiation power is increased in increments between 50 kW and 200 kW. The increments between each power-time pair can be constant or variable.

[0065] Because the irradiation dose is cumulative, the same component 32 can be irradiated consecutively, and subtraction can be performed between measurements to determine the dose received for a given power-time pair.

[0066] Alternatively, component 32 can be modified for each measurement so that dosimeter 50 receives only one radiation dose. To this end, in step 42, a plurality of components 32 containing dosimeter 50 are prepared, wherein dosimeter 50 is identically positioned in each component 32, and container 2 and packaging 30 are in a predetermined configuration of component 32. Using the plurality of components 32 containing dosimeter 50 for a single pass in front of a radiation window may be preferred, as dosimeters are typically calibrated between 0 and approximately 80 / 100 kGy, thus limiting prolonged exposure (>100 kGy).

[0067] The increase in the power-time pair between the minimum power-time pair (PTmin) and the maximum power-time pair (PTmax) can be achieved by first changing the power and then changing the time, or alternatively by first changing the time and then changing the power, or by changing both the time and the power. The minimum power-time pair and the maximum power-time pair were found experimentally.

[0068] For each incrementing power-time pair, the irradiation dose received by each dosimeter under the power-time pair is recorded to create a mapping of the irradiation dose received by each of the plurality of dosimeters based on their position on and / or within the container (and possibly on the packaging 30 and / or support 33). If the same component 32 containing dosimeter 50 is subjected to an irradiation power-time pair more than once, subtraction is performed to determine the actual dose received under each power-time pair.

[0069] The mapping of each irradiation power-time pair can be recorded in memory for processing in the next step.

[0070] From step 44, we move to step 46, which involves determining the optimal X-ray radiation power-time pair PTopt. This optimal pair is selected from the power-time pairs whose mappings have already been established in step 44. The optimal power-time pair PTopt is defined as a power-time pair for which the mapping reveals that, after passing according to the first face 32a and according to the second face 32b, all dosimeters 50 record an irradiation dose higher than the minimum dose Dmin, and the dosimeter associated with sensor 27 (and generally with the sensitive element of container 2) records an irradiation dose lower than the maximum dose Dmax. The sensitive element is a component in disposable device 2 that deteriorates when the predetermined irradiation dose is exceeded. For example, in the case of container 2, the sensitive element contains a sensor, electronic components, and some mechanical components. For example, if sensor 27 involves optical readings through a diaphragm, the color of the diaphragm may deteriorate due to excessive irradiation, which will distort the sensor's readings. The same problem may also occur for electrodes of biosensors or dry pH probes. The minimum irradiation dose Dmin is defined as the dose that is sterile and effective. According to one embodiment, the minimum irradiation dose is defined by standard ISO 11137. According to one embodiment, the minimum irradiation dose is at least 25 kGy, preferably at least 27.5 kGy, and more preferably at least 30 kGy. The maximum irradiation dose Dmax is defined as a dose above which X-ray irradiation damages the function of sensor 27 (and more generally, the sensing element). According to one embodiment, the maximum irradiation dose Dmax is between 45 kGy and 50 kGy. According to one embodiment, the maximum irradiation dose Dmax is 47 kGy. If container 2 comprises several sensing elements, each with an associated level dose that causes it to begin to deteriorate, preferably, the maximum irradiation dose Dmax common to all sensing elements will be selected as the lowest of the level doses of the sensing elements.

[0071] Once the optimal power-time pair is established, we proceed to step 47, which involves batch sterilizing several components 32, preferably automatically conveyed by a conveyor to the front of the radiation window 38. The new components 32 are irradiated with the optimal power-time pair PTopt determined in step 46. These new components 32 include a new package 30 and a new container 2 (except for the presence of a dosimeter not present in step 47) of the same shape and size as those in the previous steps. Container 2 and package 30 are arranged in a predetermined configuration. Irradiation is performed according to the first side 32a of component 32 and then according to the second side 32b of component 32 at the optimal power-time pair PTopt, after which the assembly moves to another component to be irradiated. According to another embodiment, for each component 32 to be irradiated, irradiation is performed according to the first side 32a at the optimal power-time pair PTopt, and then the component again passes in front of the radiation window 38, but this time, irradiation is performed according to the second side 32b to be irradiated at the optimal power-time pair PTopt.

Claims

1. A method (40) for sterilizing a component (32) by X-ray, the component (32) comprising a support (33) and a disposable device (2) intended for receiving a biopharmaceutical fluid (C), the component (32) having a non-uniform density, the height (H) of the component (32) being 65% or greater of the size (T) of an X-ray radiation window (38), the height (H) being considered in relation to a direction perpendicular to the support (33), the disposable device (2) comprising a sensor (27) and a mixing device (7), the method (40) comprising: Multiple dosimeters (50) are placed on and / or in the disposable device (2) according to a predetermined arrangement. One dosimeter (50) is arranged on or adjacent to the sensor (27), and another dosimeter (50) is arranged on the mixing device (7). The assembly (32) is formed according to a predetermined configuration by arranging the disposable device (2) equipped with the plurality of dosimeters in a package (30) on the support (33). At several power-time pairs (PTi), the component (32) is repeatedly passed in front of the X-ray radiation window (38) according to the first face (32a) and then the second face (32b) of the component (32), while the power-time pair is incremented between the minimum power-time pair (PTmin) and the maximum power-time pair (PTmax), and then for each of the incrementing power-time pairs, the radiation dose received by each of the plurality of dosimeters is mapped, the first face (32a) and the second face (32b) containing the height (H) of the component (32), the second face (32b) being opposite to the first face (32a); as well as The optimal X-ray power-time pair (PTopt) is determined, for which the mapping reveals that after passage according to the first surface (32a) and according to the second surface (32b), all dosimeters (50) record a radiation dose higher than the minimum radiation dose (Dmin), and the dosimeter associated with the sensor (27) records a radiation dose lower than the maximum radiation dose (Dmax), the minimum radiation dose (Dmin) being defined as the sterile effective dose, and the maximum radiation dose (Dmax) being defined as the dose at which X-ray irradiation degrades the sensor (27).

2. The method (40) of claim 1 further includes the prior steps of: determining the maximum irradiation dose (Dmax) and / or determining the minimum irradiation dose (Dmin).

3. The method (40) of claim 1 or 2, wherein The disposable device (2) comprises a plurality of sensitive elements, the sensitive elements being defined as elements that deteriorate when a predetermined irradiation dose is exceeded, the sensor (27) forming part of the plurality of sensitive elements, and wherein the step of placing the dosimeter (50) comprises placing the dosimeter on each of the plurality of sensitive elements, and in the step of determining the optimal X-ray power-time pair (PTopt), the optimal X-ray power-time pair is an optimal X-ray power-time pair for which the mapping reveals that: all dosimeters (50) record an irradiation dose higher than the minimum irradiation dose (Dmin), and the dosimeter associated with the sensitive element records an irradiation dose lower than the maximum irradiation dose (Dmax), and the maximum irradiation dose (Dmax) is defined as the lowest dose at which X-ray irradiation damages the function of one of the sensitive elements.

4. The method (40) of any one of claims 1-2, wherein, Before the component (32) passes in front of the radiation window (38) at a given irradiation power-time pair (PTi) each time, a plurality of new dosimeters (50) that have not yet been irradiated are placed in the predetermined arrangement on a new disposable device (2) that has not yet been irradiated to form a new component that has not yet been irradiated.

5. The method (40) according to any one of claims 1-2, wherein, Before the component (32) passes in front of the radiation window (38) each time under the irradiation power-time pair (PTi), a plurality of new dosimeters (50) that have not yet been irradiated are placed in the predetermined arrangement on a new disposable device (2) that has not yet been irradiated to form a new component that has not yet been irradiated.

6. The method (40) according to any one of claims 1-2, wherein, The minimum irradiation dose (Dmin) is defined by standard ISO 11137.

7. The method (40) of any of claims 1-2, wherein The minimum irradiation dose (Dmin) is at least 25 kGy.

8. The method (40) according to any one of claims 1-2, wherein, The maximum radiation dose (Dmax) is included between 45 kGy and 50 kGy.

9. The method (40) according to any one of claims 1-2, wherein, The power-time pair is selected from combinations of irradiation power and irradiation time, wherein the irradiation power is included between a minimum power of 75 kW and a maximum power of 1100 kW, and the irradiation time is included between a minimum irradiation time of 0.1 hours and a maximum irradiation time of 20 hours.

10. The method (40) of any of claims 1-2, wherein The irradiation time increments are included in increments between 0.1 hours and 2 hours.

11. The method (40) of any of claims 1-2, wherein The power increments of the irradiation are carried out in increments ranging from 50 kW to 200 kW.

12. The method (40) of any of claims 1-2, further comprising: Repeat the process of passing the component (32) in front of the radiation window (38) along the other two opposite faces of the component (32).

13. The method (40) of any of claims 1-2, wherein The package (30) includes several disposable devices (2), and / or the component (32) includes several packages (30) arranged on the support (33).

14. The method (40) according to any one of claims 1-2, further comprising: The new component (32) is irradiated at the optimal X-ray power-time pair (PTopt), the new component (32) comprising a new package (30) and a new disposable device (2), the new package (30) and the new disposable device (2) having the same shape and size as the package and the disposable device in the previous step, the disposable device and the package being arranged in the predetermined configuration, the irradiation being performed according to the first side (32a) of the component (32) and then according to the second side (32b) of the component (32).

15. The method (40) according to claim 7, wherein, The minimum irradiation dose (Dmin) is at least 27.5 kGy.

16. The method (40) of claim 7, wherein The minimum irradiation dose (Dmin) is at least 30 kGy.

17. The method (40) of claim 8, wherein The maximum irradiation dose (Dmax) is 47 kGy.

18. A component (32), comprising: A support (33) and a package (30) are placed on the support (33), the package (30) containing a disposable device (2) for single use, the disposable device (2) being designed for receiving a biopharmaceutical fluid (C), the component (32) having a non-uniform density, the height (H) of the component (32) being 65% or greater of the size (T) of the X-ray radiation window (38), the disposable device (2) including a sensor (27) and a mixing device (7), the component (32) being sterilized according to the method of claim 14.

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