Method for ensuring microbiological cleanliness of single-use equipment and cap for fluid connection of a separation unit used in such a method

Abstract

In a method for ensuring microbiological cleanliness of a single-use plant (10) for performing a bioprocess technology process, the single-use plant (10) comprises at least one gamma sterilizable component formed of a material suitable for sterilization by gamma radiation and at least one non-gamma sterilizable subunit containing a material not suitable for sterilization by gamma radiation. The component and the subunit have, respectively, areas that are in contact with process media when performing the bioprocess technology process. The method comprises the steps of: a) sterilizing the gamma sterilizable component by gamma radiation; b) protecting the media contact areas of the gamma sterilizable component by a sterile barrier; c) sterilizing the non-gamma sterilizable subunit with hot steam; d) protecting the media contact areas of the non-gamma sterilizable subunit by a sterile barrier; e) removing the sterile barrier; and f) mounting the gamma sterilized component and the hot steam sterilized subunit in the single-use plant (10) immediately after removing the sterile barrier.

Description

TECHNICAL FIELD

[0001] The present invention relates to a method for ensuring the microbiological cleanliness of a single-use apparatus for carrying out a bioprocess technology, in particular a single-use filtration apparatus. The present invention also relates to a cover for a fluid connection of a separation unit. Furthermore, the present invention relates to the use of a cover for a fluid connection of a separation unit in a method for ensuring the microbiological cleanliness of a single-use apparatus. BACKGROUND

[0002] The present invention is directed to large-scale, complex apparatuses for commercial production (production scale). Such apparatuses are distinguished in particular from smaller, more easily handled apparatuses for experimental purposes or for developing new processes (laboratory scale).

[0003] A single-use apparatus in the sense of the present invention is an apparatus which is set up for one-off use, which is then not cleaned and sterilized for reuse, but is generally disposed of completely. Correspondingly, a single-use apparatus differs from a reusable apparatus (which for example has components made of stainless steel) in the materials used for its individual components (mainly plastics).

[0004] In connection with the present invention, a separation unit is understood, for example, to be a filter capsule, a chromatography column or a membrane adsorber. In principle, however, the present invention is also applicable in single-use apparatuses having other functional units, in particular when these other functional units are not suitable for sterilization by gamma radiation (compared to the other components of the single-use apparatus). This will also be discussed later.

[0005] In principle, the user of a single-use apparatus for carrying out a bioprocess technology, in particular a single-use filtration apparatus, wishes that the single-use apparatus is ready for use as soon as it is delivered. The prerequisite for this is generally that the single-use apparatus meets specific requirements for microbiological cleanliness. This is necessary in many application cases, because otherwise there is a risk that the functional capability or performance of the separation unit and / or the target product is contaminated. The latter is particularly critical when the contaminant is similar to the target product and thus cannot be filtered out effectively afterwards either.

[0006] However, for the user, it means an additional load if it itself has to be responsible for the desired microbiological cleanliness of the single-use apparatus. Therefore, there is the wish that the single-use apparatus is already sterilized on the manufacturer's side. In order to enable the single-use apparatus to be delivered to the user in a sterile state, it must be provided with a sterile barrier which can at the same time serve as packaging for transport.

[0007] However, sterilization of the entire disposable device can be problematic for different reasons. If the disposable device contains a separation unit or other functional unit which is not sterilized in the same way as the other components of the disposable device which come into contact with the medium, then separate sterilization processes are required for the respective components. This means that the disposable device cannot be sterilized as a whole after assembly.

[0008] In principle, sterilization by gamma radiation is advantageous because it does not impair the dimensions (dimensional accuracy) of the components. However, some materials used in the separation unit, for example as filter material or membrane material, such as polytetrafluoroethylene (PTFE), polypropylene (PP) or polyvinyl chloride (PVC), are not suitable for sterilization by gamma radiation because they lose important material properties, in particular their mechanical stability, as a result of irradiation. This is important, for example, in the case of components which are subjected to strong or sudden mechanical loads, such as connectors at the end of a hose which can fall to the ground. Nor is severe contamination by "extractables" (chemical compounds extracted from the material of the component under extreme conditions) allowed in components which guide the fluid as a result of gamma irradiation. Also unsuitable for gamma sterilization are optical components, such as ports or sight glasses consisting of transparent or translucent plastic for optical sensors or for visual inspection, which discolor on irradiation.

[0009] Separation units (and other components) which cannot be used for gamma sterilization because of their material or other above-mentioned reasons must therefore be sterilized in another way, preferably by heat steam sterilization in an autoclave. However, heat steam sterilization has the disadvantage that the overpressure in the autoclave can lead to undesirable plastic deformation of the separation unit. As a result, plastic clamps and plastic clips which are produced by crimping are generally not suitable for autoclaving. At high temperatures, the plastic strongly creeps, so that the tightness of the crimped connection can no longer be guaranteed. The screwing of the clamps or clips is generally only conditionally possible or not possible at all.

[0010] Non-heat-resistant materials, such as polyethylene (PE), for example connectors or containers, which cannot be autoclaved but can be gamma sterilized. Screwed or glued components are also not autoclavable if the thermal expansion differs greatly. For example, hoses consisting of thermoplastic elastomers can only be autoclaved conditionally because they remain "frozen" in the curved form in which they were in the autoclave after autoclaving.

[0011] In any case, the person skilled in the art is able to assess, depending on the material from which the components provided for a bioprocess technology process are formed and depending on the intended use of the components, whether these components are suitable for gamma sterilization or for autoclaving.

[0012] If the disposable device is to be delivered as a whole, there is also the problem that contaminants can enter the interior of the separate units and the remaining components before, during and after assembly of the sterilized separate units and the remaining components in separate processes. SUMMARY

[0013] Against this background, it is an object of the present application to improve and simplify the assurance of microbiological cleanliness of disposable devices, in particular disposable filtration devices, for performing biotechnological processes before they are put into use.

[0014] This object is achieved by a method having the features of the embodiments and by a method having the features of the embodiments. Advantageous and expedient design options of the method according to the application are given in the embodiments.

[0015] The method for assuring microbiological cleanliness according to the application is provided for a disposable device for performing a biotechnological process, wherein the disposable device comprises at least one gamma sterilizable component formed from a material suitable for sterilization by gamma radiation and at least one non-gamma sterilizable subunit containing a material unsuitable for sterilization by gamma radiation. The components and subunits each have a region which, in performing the biotechnological process, is in contact with the process medium.

[0016] According to a first aspect, the method according to the application comprises the following steps: a) sterilization of the gamma sterilizable component by gamma radiation; b) protection of the medium contact region of the gamma sterilizable component by a sterile barrier; c) sterilization of the non-gamma sterilizable subunit using hot steam; d) protection of the medium contact region of the non-gamma sterilizable subunit by a sterile barrier; e) removal of the sterile barriers; and f) mounting of the gamma sterilized component and the hot steam sterilized subunit in the disposable device directly after removal of the sterile barriers.

[0017] The present application is based on the recognition that in disposable devices which cannot be sterilized as a whole after assembly, in particular disposable devices having one or more separate units, the risk of contamination is greatest in the phases before and during assembly of the disposable device. Therefore, the present application proposes special protective measures:

[0018] The gamma sterilizable components and the non-gamma sterilizable subunits are sterilized in separate processes, while the medium contact regions of the gamma sterilizable components and the non-gamma sterilizable subunits are each protected by a sterile barrier. Such a sterile barrier can in particular be a casing or packaging for the entire component or subunit, or a closure, such as a blind cover, a sterile connector or a cover, which protects the respective medium contact region, as will be explained more precisely still in the following.

[0019] The sterile barrier is removed only shortly before the installation of the gamma-sterilized component and the steam-sterilized subunit.

[0020] If no further protective measures, such as additional closures (for which further on), are provided after the removal of the sterile barrier, the time period between the removal of the sterile barrier and the installation of the respective gamma-sterilized component or the respective steam-sterilized subunit should be less than 4 minutes, preferably less than 2 minutes, more preferably less than 1 minute, and still more preferably less than half a minute, depending on the particle concentration in the environment. Practical tests have shown that the risk of contamination of the media contact area of the disposable device is very effectively reduced when these time periods are adhered to.

[0021] In principle, the at least one gamma-sterilizable subunit and the at least one gamma-sterilizable component can be sterilized at different times without having to take the sequence into account.

[0022] According to a second aspect of the present application, in addition to the sterile barrier (which can also be able to be provided not only for the at least one gamma-sterilizable component but also for the at least one gamma-sterilizable subunit), at least one closure is used, which covers the media contact area of the gamma-sterilizable component or the gamma-sterilizable subunit. This closure independent of the sterile barrier does not necessarily have to form a sterile barrier, as long as it at least contributes to significantly reducing the probability of undesired particles entering. After the removal of the sterile barrier, then, a broadened time window is left for the installation of the relevant component or subunit due to the additional closure.

[0023] According to this second aspect, the method according to the present application comprises the following steps: a) sterilization of the gamma-sterilizable component by gamma radiation; b) protection of the media contact area of the gamma-sterilizable component by a sterile barrier; c) sterilization of the gamma-sterilizable subunit with steam; d) protection of the media contact area of the gamma-sterilizable subunit by a sterile barrier; e) additional covering of the media contact area of the gamma-sterilized component with at least one first closure and / or additional covering of the media contact area of the non-gamma-sterilized subunit with at least one second closure; f) removal of the sterile barrier and subsequently removal of the first and / or second closure; and g) installation of the gamma-sterilized component or the steam-sterilized subunit in the disposable device directly after the removal of the first or second closure.

[0024] The terms "first" and "second" closure are used here only to distinguish the closure provided for the gamma-sterilized component from the closure provided for the non-gamma-sterilized subunit. That is, the "first" closure is not necessarily a prerequisite for the "second" closure, and vice versa.

[0025] In particular, the time span between removal of the respective sterile barrier and installation of the associated gamma-sterilized component with the first closure or of the associated heat-steam- sterilized subunit with the second closure can be less than 3 hours, preferably less than 2 hours, more preferably less than 1 hour and further preferably less than half an hour, respectively.

[0026] However, the time span between removal of the first or second closure and installation of the associated gamma-sterilized component or heat-steam-sterilized subunit should again be less than two minutes, preferably less than one minute and more preferably less than half a minute, respectively.

[0027] If, in addition to the sterile barrier, at least one closure is provided to cover the medium contact area of the gamma-sterilized component or the non-gamma-sterilized component, such a closure should form a barrier that reduces the ingress of particles with a gap size of at most 100 μm, preferably at most 50 μm and more preferably at most 10 μm, in order to be effective protection. In principle, it is also possible to use a closure that is a sterile barrier in itself.

[0028] In the method according to the application, it can also be proposed that step b) is carried out before step a) and / or step d) is carried out before step c), i.e. the medium contact area of the gamma- sterilizable component or the non-gamma-sterilizable subunit is already protected with a sterile barrier before sterilization. In the case of a gamma-sterilizable component, a material resistant to gamma radiation is correspondingly selected for the sterile barrier. In the case of a heat-steam-sterilized subunit, it must be ensured that the heat steam can sufficiently penetrate the sterile barrier. In both cases, it is then ensured that the medium contact area remains sterile after the sterilized component or subunit is placed in a non-sterile environment.

[0029] Basically suitable as a sterile barrier for a heat-steam-sterilized subunit is a closed envelope completely surrounding the subunit, which is composed of a nonwoven fabric, preferably ) composed of a nonwoven fabric, preferably

[0030] According to a particular aspect of the application, the media contact area of the subunit is covered by a second closure, in particular a lid, before sterilization with hot steam and until the hot steam sterilized subunit is installed. The closure has at least one selectively releasable and closable through-hole. As already mentioned at the outset, this closure can form the sterile barrier according to the application for the media contact portion of the subunit. However, this is not absolutely necessary if the sterile barrier is formed in another way, in particular by the above-mentioned envelope.

[0031] With regard to a preferred application of the application, the non-gamma sterilizable subunit has at least one functional unit, in particular a separation unit (for example a filter capsule, a chromatographic column or a membrane adsorber), which has at least one fluid connection. In the execution of the method according to the application, the fluid connection is preferably covered by the second closure. If an additional sterile barrier, such as the envelope described above, is provided, the exposure of the fluid connection can be shortened after its removal in such a way that the closure is removed only immediately before the installation of the functional unit. This means that the period of time available for a possible "clean" (contamination-free) installation is extended, since after the removal of the sterile barrier all fluid connections do not have to be installed within two minutes. This is advantageous in particular in complex configurations with many connections, since during the installation the closures can be removed one after the other.

[0032] In a particularly preferred embodiment, the method according to the application comprises the following further steps or measures: placing the second closure on the fluid connection of the functional unit; releasing the through-hole if the through-hole is closed; packaging the non-gamma sterilizable subunit into an envelope; sterilizing the packaged subunit with hot steam in the case where the through-hole is released; closing the through-hole in the closed envelope after sterilization with hot steam; unpacking the hot steam sterilized subunit from the closed envelope; and removing the second closure immediately before the installation of the subunit.

[0033] This means that the subunit with the functional unit, in particular the separation unit, is first packaged in the envelope and then sterilized in the closed envelope, so that after sterilization no further contaminants can enter the envelope. This is possible because the envelope (as already mentioned) can be made of a material which is permeable to hot steam, but normally functions as a sterile barrier.

[0034] A further prerequisite is that the functional unit is not plastically deformed by the hot steam sterilization. This is achieved by the fact that the through-hole of the second closure placed before sterilization is released during the hot steam sterilization, so that a pressure equalization is achieved through the open fluid connection of the separation unit.

[0035] Furthermore, it is ensured that after unpacking the subunit from the package, a barrier to reduce particle ingress continues to exist, which protects the media contact area from contamination. This barrier is provided by a second closure, the through-hole of which has been closed after sterilization in the closed package. Thus, after unpacking the subunit sterilized by heat steam, protection exists until the second closure is removed during assembly of the disposable device.

[0036] As already set out, according to the application at least one gamma-sterilizable component of the disposable device is sterilized separately, i.e. not together with the non-gamma-sterilizable subunit, since sterilization with heat steam entails the risk that thereafter the dimensional accuracy of the component is no longer provided. However, in precisely those components which are crucial in this respect, such as rigid connection tubes, to which a plurality of separate units fixed on rigid carriers and other connection tubes should be connected at their fluid connection, dimensional accuracy is of the utmost importance. This is not impaired in the sterilization by gamma radiation provided for the components according to the application.

[0037] In order to minimize the risk of contamination of the media contact area of the gamma-sterilizable component of the disposable device even after removal of the sterile barrier provided according to the application, it is proposed according to a second aspect of the application that the media contact area of the component remains covered by a first closure, preferably by a blind cover, a sterile connector or a housing. Since gamma radiation neither short-term nor long-term impairs the dimensional accuracy of the component and the closure (no elastic or plastic deformation, no brittleness, etc.), as long as the component and the closure are composed of suitable materials, the closure can already be placed before sterilization and remain there until the component is installed. Thus, the media contact area of the gamma-sterilized component is protected until the first closure is removed during installation of the component. However, according to the first aspect of the application, the first closure for covering the media contact area of the gamma-sterilized component can also form the only sterile barrier for the component.

[0038] With regard to a preferred application of the application, the at least one gamma-sterilizable component usually comprises a connection tube and / or a plurality of distributor assemblies connectable to one another for connecting a plurality of separation units and / or at least one connection hose line, wherein the gamma-sterilizable component has at least one fluid connection which is covered by a first closure as described above.

[0039] If no first closure is provided for the gamma-sterilizable component or such a closure does not form a sterile barrier, the sterile barrier provided according to the application for the media contact portion of the component is preferably formed by the closed main packaging completely surrounding the component.

[0040] To further minimize the risk of contamination from the environment, the steam-sterilized subunit and the gamma-sterilized components should be installed in a safety cabinet (laminar flow cabinet, clean bench) or a clean room, preferably in a separate area of the clean room separated by a wall.

[0041] The application also achieves a cover for a fluid connection of a non-gamma-sterilizable subunit for use in a method according to the application, wherein a second closure is provided for the separation unit of the subunit. The cover according to the application comprises a base body for precisely fitting the cover onto the fluid connection. The cover has at least one through-hole which, after the cover is placed on the fluid connection, provides a flow connection between the medium contact area of the separation unit and the immediate surroundings of the separation unit. The cover also comprises a mechanism for selectively releasing and closing the at least one through-hole.

[0042] This cover can be placed on the fluid connection of the separation unit before steam sterilization and remain there until the disposable device is assembled. The special closure mechanism allows the fluid connection to be optionally in flow connection with the environment or to be able to be separated from the environment (at least to counter the entry of undesirable particles) without having to remove the cover from the fluid connection to release and close. As already set out above, it is proposed in the method according to the application that, during the steam sterilization, the through-hole is released in order to achieve pressure equalization. Thereafter, the through-hole is closed in order to form the desired particle barrier with respect to the environment.

[0043] According to a preferred design of the cover according to the application, the mechanism has a closure body which can be transferred between a closed position, in which the closure body covers the at least one through-hole, and an open position, in which the closure body does not cover the at least one through-hole. That is to say, the covering and the release are not carried out by placing and removing the cover, but by moving the closure body when the cover is placed, respectively.

[0044] The mechanism for closing and releasing the through-hole should also be manually operable when the separation unit is in a closed enclosure. To this end, the cover has an operating element which can be easily touched and gripped.

[0045] In contrast to the separation unit itself, the cover can be a reusable component, which is preferably formed at least predominantly from stainless steel. If the cover is no longer required after the disposable device has been constructed, it can be used for the same purpose in another disposable device after corresponding cleaning. BRIEF DESCRIPTION OF DRAWINGS

[0046] Further features and advantages of the application result from the following description and the referenced drawings. In the drawings:

[0047] - Figure 1a perspective view of a single-use apparatus for performing a bioprocess technology process is shown;

[0048] - Figure 2 a top view of a single-use apparatus is shown Figure 1

[0049] - Figure 3 a separation unit with connected hose lines and connectors is shown;

[0050] - Figure 4 a cover for a fluid connection of a separation unit is shown;

[0051] - Figure 5 a lateral exploded view of a connection tube with multiple fluid connections is shown; and

[0052] - Figure 6 a top view of a connection tube is shown Figure 5 DETAILED DESCRIPTION

[0053] A single-use apparatus 10 for performing a bioprocess technology process in an assembled state is shown in Figure 1 and Figure 2

[0054] The single-use apparatus 10 comprises a plurality of separation units 12 which are arranged in a predetermined grid in a rigid holder 14. The separation units 12 can in principle be filter capsules, chromatography columns or membrane adsorbers.

[0055] The fluid connections (inlet and outlet) 16 of the separation units 12 are connected to one another via rigid connection tubes 18 or hose lines. Connection hose lines 20 are connected to the connection tubes 18 for the transport and discharge of media.

[0056] In addition, a sterile air filter 22 is connected to the upper connection tubes 18 in order to jointly vent all of the separation units 12.

[0057] The single-use apparatus 10 can also have further components. However, the exact construction and mode of operation of the single-use apparatus 10 is not important for the application described herein.

[0058] The single-use apparatus 10 is a "large" apparatus for use in commercial production with a large media throughput (production scale). In such apparatuses, a plurality of separation units are connected to one another, in particular more than three 30-inch filter capsules (length approximately 850 mm). This is to be distinguished from smaller apparatuses (laboratory scale) which are used in laboratories for experimental purposes or for process development.

[0059] ​​​The disposable device 10 should be delivered to the user as a whole and as far as possible in a sterile condition or at least with as little bioburden and other contamination by particles as possible. In principle, at this point it is preferred to sterilize by gamma radiation, since in this method the dimensional accuracy of the components can generally be ensured.

[0060] However, in the present case the disposable device 10 contains at least one separation unit 12 which is not suitable for sterilization by gamma radiation. This can be the case in particular if the filter material or membrane material is damaged so severely by the energy dose (e.g. 25 kGy) which is usually applied in gamma sterilization that a compliant function can no longer be guaranteed. Examples of such unsuitable materials are polytetrafluoroethylene (PTFE), polypropylene (PP) and polyvinyl chloride (PVC).

[0061] The separation unit 12 which cannot be sterilized by gamma radiation is sterilized as a subunit separately or in the form of a composite piece (possibly with other components) in an autoclave with hot steam. Such a subunit is only allowed to be so large that it can be accommodated in an autoclave.

[0062] When dividing the disposable device 10 into subunits, in addition to the outer dimensions another criterion must be taken into account: it must be ensured that the inner faces of the separation unit 12, in particular, are sufficiently and for a sufficiently long time in contact with the hot steam when being treated in an autoclave. This is important in particular if a plurality of separation units 12 are connected to one another, for example by connecting tubes 18, or are connected on a hose line 20, so that the hot steam cannot enter the separation unit 12 directly through the fluid connection 16. There is then basically the risk that the hot steam does not reach all the relevant faces or does not reach them quickly enough to ensure sufficient sterilization.

[0063] In practice it has proved to be that the total length of the subunit to be flowed through by the hot steam should not exceed 1800 mm. This is shown by way of example in Figure 3 in which the total length to be flowed through by the filter capsule 12 together with the two connected hose lines 20 at the free ends and the connectors 24 is approximately 1800 mm.

[0064] In the following it is described according to one preferred embodiment how the predefined cleanliness, in particular the predefined microbiological cleanliness, of the disposable device 10 is ensured until the entire disposable device 10 is put into use by the user.

[0065] Firstly, the hot steam sterilization of a subunit with a separation unit 12 is described. Alternatively, the description can be transferred to other separation units 12 of the same subunit or to separation units 12 of other subunits.

[0066] The end side of the separating unit 12, at which one or more of the fluid connections 16 are open, i.e. the fluid connections 16 are not connected with the connecting tubes 18 and the hose lines 20, etc. before sterilization, is provided with a closure. In the embodiment described here, a lid 26 is used as closure, as shown in Figure 4 Fig. 3. The lid 26, which is mainly formed from stainless steel, is a reusable component, i.e. it can be used for other sterilization processes.

[0067] The lid 26 essentially consists of a base body 28 with one or more continuous through-holes 30, a stop bolt 32 and a closure mechanism for selectively releasing and closing the through-holes 30.

[0068] The base body 28 precisely matches the outer contour of the associated end side of the separating unit 12 and can be fixed on the separating unit 12 by means of the stop bolt 32.

[0069] The closure mechanism has a closure body 34, which can assume two defined stable positions: a closed position, in which the closure body 34 firmly rests on the base body 28 and covers the through-holes 30, and an open position, in which the closure body 34 is lifted so that it does not cover the through-holes 30.

[0070] The closure mechanism can be operated manually by means of an operating element 36, i.e. by pressing or pulling at the operating element 36, the closure body 34 can be transferred into the respective other position.

[0071] In the fixed position of the lid 26, when the closure body 34 is in the open position, the one or more fluid connections 16 of the separating unit 12 are in flow connection with the immediate environment of the separating unit 12 via the through-holes 30. Conversely, if the closure body 34 is in the closed position, there is no or hardly any flow connection between the interior of the separating unit 12 and the environment, i.e. possible particles are prevented from entering as far as possible. The base body 28 and the closure body 34 are designed such that the gap size of the lid 26 in the closed position is at most 100 pm, preferably at most 50 pm and more preferably at most 10 pm, so that correspondingly larger particles are blocked.

[0072] After the lid 26 is placed on the end side of the separating unit 12 (and optionally another lid 26 is placed on the other end side), the subunit is packaged in a wrapper, wherein it is previously ensured that the through-holes 30 are released. The wrapper consists of or a similar material, which is waterproof and can be used as a sterile barrier under normal environmental conditions on the one hand, but is permeable to water vapor on the other hand. The wrapper is closed by welding.

[0073] The subunit in the wrapper is then loaded into an autoclave and sterilized with hot steam under preset conditions (for example 121°C for 40 minutes or 131°C for 30 minutes). The hot steam penetrates the wrapper to the outside of the subunit and enters the interior of the separation unit 12 through the release openings 30. The openings 30 are dimensioned large enough for this. The openings 30 also ensure sufficient pressure equalization during the steam sterilization so that the separation unit 12 does not plastically deform.

[0074] The wrapper remains closed after sterilization and serves as a sterile barrier for the subunit until assembly of the disposable device 10.

[0075] The remaining components of the disposable device 10 are sterilized by gamma radiation before their assembly. Before irradiation, the open fluid connections 16 of the connecting tubes 18 and the connecting hose lines 20 are likewise covered with closures, which here are in the form of seals 38 and blind caps 40, which are seated by means of connectors 24, for example three-jaw connectors. This is shown in Figure 5 and Figure 6 . The closures and possible auxiliary mechanisms for their fastening are composed of gamma radiation-resistant material and are designed in such a way that they effectively prevent the ingress of particles through the fluid connections 16, with the gap size being comparable to the preferred gap size in the case of the fluid connections 16 of the separation unit 12, which are covered by the cover 26. In principle, the closures can also be designed as sterile barriers.

[0076] Thereafter, the connecting tubes 18 and the connecting hose lines 20 are packaged into a main package, which serves as a sterile barrier. The sterilization of these components is then carried out in the packaged state, so that for the main package likewise a material is selected, the properties of which are not significantly impaired by the doses of gamma radiation that are customary for sterilization.

[0077] The assembly of the disposable device 10 either takes place at the manufacturer or, after shipping of the sterile packaged subunit and other components, at the user and preferably on a safety workbench that enables sterile connections or in a wall-separated area of a clean room.

[0078] Before unpackaging the subunit from the wrapper, the openings 30 of the cover 26 are closed. This is carried out in the closed wrapper by grasping the handling elements 36 and operating the closure mechanism. The handling elements 36 are easily found by touch, despite the wrapper in between.

[0079] By closing the openings 30, the cover 26 forms a protection against the ingress of particles even after unpackaging of the subunit and possibly even a sterile barrier, so that the intrusion of contaminants into the interior of the separation unit 12 is avoided as far as possible.

[0080] Likewise, after unpacking, the blind cover 40 serves as protection against ingress of particles, preferably even as a sterile barrier, so that contamination can be prevented as far as possible from penetrating into the interior of the connection tube 18 or the connection hose line 20.

[0081] Nevertheless, the casing or primary packaging should be opened as late as possible, respectively, when assembling the disposable device 10, in order to keep the exposure of the fluid connection 16 covered by the closure relative to the environment as short as possible. However, due to the closure, the exposure can be up to three hours in total. However, it is preferred to be less than two hours, more preferred to be less than one hour, and ideally less than half an hour.

[0082] During this time, each separation unit 12 is placed in its preset position in the rigid holder 14. The connection tube 18 and the connection hose line 20, if not already pre-installed, are brought into position. Only at the last moment before connecting the components, the cap 26 or the blind cover 40 is removed from the fluid connection 16 required for the respective connection. After removal of the cap 26 or the blind cover 40, the exposure of the respective open fluid connection 16 relative to the environment should be kept significantly shorter. Preferably, this period is less than two minutes, preferably less than one minute, and ideally less than 30 seconds. Under these premises, it is not absolutely necessary to carry out the installation in a clean room class better than ISO 8.

[0083] Generally, by the above means, the connection tube 18 is first connected to the separation unit 12 before the connection hose line 20 is connected to the connection tube 18. In any case, a self-contained system is finally produced.

[0084] If the assembly has already been carried out at the manufacturer, i.e. not at the later user, the assembled disposable device 10 is packaged as a whole in a packaging serving as a sterile barrier and delivered to the user.

[0085] After the setup or assembly of the disposable device 10 at the user, the blind cover 40 at the free hose end remains there until the connection hose line 20 is connected to the medium conveying or leading-out part in the course of the use.

[0086] As further safety measures, sterile gloves and a mask are proposed for the above-mentioned working steps when assembling the disposable device 10. Otherwise, clean room clothing is mandatory.

[0087] For the assembly of the disposable device 10 two persons are provided, in particular in order to achieve the desired short exposure of the opened fluid connection 16. The first person is responsible for unpacking and providing the components. The second person removes the cover 26 and the blind cover 40 from the fluid connection 16 and establishes the intended flow connection, that is, the second person works mainly at positions which are critical for the cleanliness in the interior of the components through which the medium flows.

[0088] Furthermore, the work surface, the tools and the storage containers are cleaned separately.

[0089] The disposable device 10 with its separation unit and its remaining components is described only exemplarily. In addition to or alternatively to the separation unit 12, further functional units can be provided which are not suitable for sterilization by gamma radiation, for example sensor devices with electronic data memories which can be damaged by gamma radiation.

[0090] Instead of the described cover 26, another closure with similar functionality is used for the separation unit 16 or for other functional units. For this purpose, an example is a plug consisting of silicone or a similar material with one or more cutouts which is placed at the fluid connection 16 of the separation unit 12. When heated in an autoclave, the plug expands and the cutouts form through-holes so that hot steam can enter the interior of the separation unit 12 through the thus formed through-holes. In the subsequent cooling, the plug shrinks again to the normal size so that the through-holes close and the intrusion of contaminants through the cutouts is avoided as far as possible. It is also possible to place an air- or hot-steam-permeable dust bag as protection around the fluid connection 16 and to fix it there.

[0091] For the (selective) connection of the separation unit 12 or of a functional unit, it is also possible to use a plurality of directly connectable, gamma-sterilizable distributor components which are placed directly on the end side of the separation unit 12 or of a functional unit.

[0092] List of reference signs

[0093] 10 disposable device

[0094] 12 separation unit

[0095] 14 holder

[0096] 16 fluid connection

[0097] 18 connecting tube

[0098] 20 (connection) hose line

[0099] 22 sterile air filter

[0100] 24 connector

[0101] 26 cover

[0102] 28 base body

[0103] 30 through hole

[0104] 32 set screw

[0105] 34 closure body

[0106] 36 operating element

[0107] 38 seal

[0108] 40 blind cover

Claims

1. A method for securing the microbiological cleanliness of a large-scale, single-use plant (10) for performing a bioprocess technology process in commercial production with large media throughputs, wherein the single-use plant (10) comprises at least one gamma-sterilizable component formed of a material suitable for sterilization by gamma radiation and a plurality of separation units in the form of filter capsules, chromatography columns or membrane adsorbers, at least one of the separation units containing a material unsuitable for sterilization by gamma radiation and thus not being gamma-sterilizable, wherein the components and the separation units respectively have areas which, when performing the bioprocess technology process, come into contact with process media, and wherein the method comprises the following steps: a) sterilizing the gamma-sterilizable components and gamma-sterilizable separation units by gamma radiation; b) protecting the media-contacting areas of the gamma-sterilizable components and gamma-sterilizable separation units respectively by sterile barriers; c) sterilizing the non-gamma-sterilizable separation units as subunits individually or in a composite by means of hot steam; d) protecting the media-contacting areas of the non-gamma-sterilizable separation units respectively by sterile barriers; e) removing the sterile barriers; and f) installing the gamma-sterilized components and gamma-sterilized separation units and the hot-steam-sterilized separation units in the single-use plant (10) immediately after removal of the sterile barriers, wherein the at least one gamma-sterilizable component comprises at least one rigid connecting tube (18) with fluid connections on which a plurality of separation units are connected after assembly of the single-use plant (10).

2. The method of claim 1, wherein, The time period between removal of a sterile barrier and installation of the respective gamma-sterilized component or gamma-sterilized separation unit or the respective hot-steam-sterilized separation unit is less than four minutes respectively.

3. The method of claim 1, wherein, The step of protecting the media-contacting areas of the gamma-sterilizable components and gamma-sterilizable separation units and / or non-gamma-sterilizable separation units respectively by sterile barriers comprises: additionally covering the media-contacting areas of the gamma-sterilized components or gamma-sterilizable separation units by at least one first closure and / or additionally covering the media-contacting areas of the non-gamma-sterilizable separation units by at least one second closure; the step of removing the sterile barriers comprises subsequently removing the first and / or second closures; and the step of installing the gamma-sterilized components or gamma-sterilized separation units or hot-steam-sterilized separation units in the single-use plant (10) is carried out immediately after removal of the first and / or second closures.

4. The method according to claim 3, characterized in that the time period between removal of the respective sterile barrier and installation of the respective gamma-sterilized component or gamma-sterilized separation unit provided with a first closure or the respective hot-steam-sterilized separation unit provided with a second closure is less than three hours respectively, and the time period between removal of the respective sterile barrier and installation of the respective gamma-sterilized component or gamma-sterilized separation unit provided with a first closure or the respective hot-steam-sterilized separation unit provided with a second closure is less than three hours respectively, and The time period between removal of the first or second closure and installation of the respective gamma-sterilized component or gamma-sterilized separation unit or heat-steam-sterilized separation unit is less than two minutes, respectively.

5. The method according to claim 3 or 4, characterized in that, The first and / or second closure forms a barrier that reduces the ingress of particles, which has a gap size of at most 100 pm.

6. The method according to any one of claims 1 to 4, characterized in that, Step b) is carried out before step a) and / or step d) is carried out before step c).

7. The method according to any one of claims 1 to 4, characterized in that, The sterile barrier for the heat-steam-sterilized separation unit comprises a closed envelope that completely surrounds the heat-steam-sterilized separation unit.

8. The method of claim 7, wherein, The envelope is formed from a water-impermeable but water-vapor-permeable nonwoven fabric.

9. The method according to any one of claims 1 to 4, characterized in that, The medium-contacting area of the non-gamma-sterilizable separation unit is covered by a second closure before sterilization with heat steam and until installation of the heat-steam-sterilized separation unit, wherein the second closure has at least one through-opening (30) that can be selectively released and closed.

10. The method according to any one of claims 1 to 4, characterized in that, The at least one non-gamma-sterilizable separation unit has a fluid connection (16) that is covered by a second closure.

11. The method of claim 10, wherein The following steps or measures: - positioning the second closure on the fluid connection (16) of the non-gamma-sterilizable separation unit; - if the through-opening (30) is closed, releasing the through-opening (30); - packaging the non-gamma-sterilizable separation unit into an envelope; - sterilizing the packaged separation unit with heat steam, in the case of a released through-opening (30); - after sterilization with heat steam: closing the through-opening (30) in the closed envelope; - unpacking the heat-steam-sterilized separation unit from the closed envelope; and - removing the second closure immediately before installation of the heat-steam-sterilized separation unit.

12. The method according to any one of claims 1 to 4, characterized in that, The medium-contacting area of the gamma-sterilizable component or gamma-sterilizable separation unit remains covered by a first closure before sterilization by gamma radiation and until installation of the gamma-sterilized component or gamma-sterilized separation unit.

13. The method of claim 12, wherein, The gamma-sterilizable component comprises a plurality of connectable distributor assemblies for connecting a plurality of separation units (12) and / or at least one connecting hose line (20), wherein the gamma-sterilizable component has at least one fluid connection (16) that is covered by the first closure.

14. The method of any one of claims 1 to 4, wherein, The sterile barrier for the gamma-sterilizable component or gamma-sterilizable separation unit comprises a closed main package that completely surrounds it.

15. The method of any one of claims 1 to 4, wherein, The heat-steam-sterilized separation unit and the gamma-sterilized component and the gamma-sterilizable separation unit are installed on a safety bench or in a clean room.

16. The method of claim 2, wherein, The time period between removal of the sterile barrier and installation of the respective gamma-sterilized component or gamma-sterilized separation unit or heat-steam-sterilized separation unit is less than two minutes, respectively.

17. The method of claim 2, wherein, The time period between removal of the sterile barrier and installation of the respective gamma-sterilized component or gamma-sterilized separation unit or heat-steam-sterilized separation unit is less than one minute, respectively.

18. The method of claim 2, wherein, The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the first closure is less than two hours.

19. The method of claim 4, wherein, The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the second closure is less than two hours.

20. The method of claim 4, wherein, The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the second closure is less than one hour.

21. The method according to claim 4, characterized in that The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the second closure is less than one hour.

22. The method according to claim 4, characterized in that The time period between removal of the first or second closure and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or heat-steam-sterilized separate unit is less than one minute.

23. The method according to claim 4, characterized in that The time period between removal of the first or second closure and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or heat-steam-sterilized separate unit is less than one half minute.

24. The method of claim 5, wherein, The gap size is at most 50 pm.

25. The method of claim 5, wherein, The gap size is at most 10 pm.

26. The method of claim 9, wherein, The second closure is a lid (26).

27. The method of claim 12, wherein, The first closure is a blind lid (40), a sterile connector or a housing.

28. The method of claim 15, wherein, The heat-steam-sterilized separate unit as well as the gamma-sterilized components and the gamma-sterilizable separate units are installed in areas of the clean room which are separated by walls. The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the first closure is less than two hours. The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the second closure is less than two hours. The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the second closure is less than one hour.

21. The method according to claim 4, characterized in that The time period between removal of the respective sterile barrier and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or the associated heat-steam-sterilized separate unit provided with the second closure is less than one hour.

22. The method according to claim 4, characterized in that The time period between removal of the first or second closure and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or heat-steam-sterilized separate unit is less than one minute.

23. The method according to claim 4, characterized in that The time period between removal of the first or second closure and installation of the associated gamma-sterilized component or gamma-sterilized separate unit or heat-steam-sterilized separate unit is less than one half minute. The gap size is at most 50 pm. The gap size is at most 10 pm. The second closure is a lid (26). The first closure is a blind lid (40), a sterile connector or a housing. The heat-steam-sterilized separate unit as well as the gamma-sterilized components and the gamma-sterilizable separate units are installed in areas of the clean room which are separated by walls.

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