Method for testing the integrity of a liquid processing device for sterilizing liquids and liquid processing device

Abstract

The invention relates to a method for testing the integrity of a liquid processing device (1) for sterilizing liquids (2), in particular liquids which cannot be sterilized in their final container, and to a liquid processing device (1).

Description

[0001] Method for testing the integrity of a liquid processing device for sterilizing liquids and liquid processing device

[0002] The invention relates to a method for testing the integrity of a liquid processing device for sterilizing liquids, in particular liquids which cannot be sterilized in their final container, and to a liquid processing device.

[0003] Testing the integrity of sterilization filter devices comprising sterilization filters is known.

[0004] According to the FDA's "Aspetic Processing Guidelines" from 2004, the integrity of sterilization filters should be tested before and after use.

[0005] It was also stated in the annex to the announcement of the Federal Ministry of Health on § 2 No. 3 of the Ordinance on the Manufacture of Medicinal Products and Active Pharmaceutical Ingredients of 12 March 2008 (BAnz. p.1217) in "Annex 1 to the EC Guide to Good Manufacturing Practice - Manufacture of Sterile Medicinal Products" that the integrity of the sterilization filter should be checked by a suitable method before and immediately after each use.

[0006] The task of the invention is therefore to provide an improved method for testing the integrity of a liquid processing device for sterilizing liquids, in particular liquids which cannot be sterilized in their final container, and a liquid processing device.

[0007] This task is solved in a method of the type mentioned at the beginning in that the liquid processing device comprises a sterilization device having a liquid inlet and a liquid outlet which can be f luidica lly connected to a filling device, wherein the liquid to be sterilized flows through the sterilization device on a sterilization path extending from the liquid inlet to the liquid outlet, and wherein a sterilization filter device comprising at least one sterilization filter is arranged on the sterilization path, and comprising a gas filter device having a gas filter and an integrity evaluation device, and wherein the method comprises the following method steps: a) cleaning in place of the liquid processing device, b) pressure hold test of the liquid processing device, c) first integrity test of the sterilization filter device, d) sterilization of the liquid processing device, e) second integrity test of the sterilization filter device, f) flow of the liquid to be sterilized through the sterilization device, and g) third integrity test of the sterilization filter device. Advantageously, the method enables an integrity test to be performed in a sterile environment.

[0008] In this case, the liquid processing device comprises a sterilization device comprising a liquid inlet and a liquid outlet which can be fluidically connected to a filling device, wherein the liquid to be sterilized flows through the sterilization device on a sterilization path extending from the liquid inlet to the liquid outlet, and wherein a sterilization filter device comprising at least one sterilization filter is arranged on the sterilization path, and with a gas filter device comprising a gas filter and with an integrity evaluation device. In this respect, the liquid processing device preferably has a line system comprising line segments which fluidically connects the sterilization device, the gas filter device, the integrity evaluation device and the pressure vessel unit to one another.

[0009] The integrity evaluation device is preferably configured as an integrity testing device, which is particularly preferably an Integritest® 5 from Merck, for example, which is suitable for testing the integrity of the sterilization filters of the sterilization device. The integrity evaluation device is also configured as a computer. Furthermore, the integrity evaluation device is in particular assigned to a control unit comprising a control functionality, is integrated into it or itself forms the control unit.

[0010] According to one embodiment of the preferred method in this respect, different cleaning agents are used for the cleaning in place of the liquid processing device according to method step a), which flow through the liquid processing device one after the other. Cleaning in place is also referred to as cleaning in place - CIP cleaning for short. Cleaning in place refers to a process for cleaning production systems and lines, whereby cleaning in place is carried out in a circular or continuous process without prior disassembly of the production systems and lines. The advantage of cleaning in place is that it can be carried out without major dismantling and conversion of the production systems and lines and is therefore very efficient.

[0011] For the localized cleaning of the liquid processing device, purified water, alkali solution, acid solution and sterile water for injection are used as cleaning agents, whereby the purified water, then the alkali solution, then the acid solution and then the sterile water for injection flow through the liquid processing device. Water for injections is water of extra high quality without significant contamination, the primary use of sterile water for injection being as a component for diluting other drugs (aseptic preparation of parenteral solutions). In this respect, the cleaning agent advantageously comprises temperatures in the range of 20 °C to 90 °C, the temperature being expediently 25 °C. Furthermore, the cleaning agent for cleaning in place of the liquid processing device comprises in particular an overpressure of 2 bar compared to the ambient pressure. Due to the sequential use of the various cleaning agents, the liquid processing device is pre-rinsed by the purified water comprising a neutral pH value. The alkali solution used as a cleaning agent has a pH value between 7.1 and 14, whereby organic soiling such as grease, protein compounds, soot, oils and so on can be removed. The more persistent the soiling, the higher the concentration of the alkali solution should be. The acid solution as a cleaning agent comprises a pH value of less than 7 and cleans inorganic and mineral soiling in particular, such as rust, limescale and so on. The same applies to the acid solution: the more persistent the soiling, the higher the concentration of the acid solution should be. Finally, the liquid processing device is rinsed again by the sterile water for injection, which comprises a neutral pH value, so that no cleaning agent residues remain in the liquid processing device.

[0012] Furthermore, the liquid processing device has a first conductivity measuring sensor for measuring the electrical conductivity, which is expediently arranged in a drainage manifold for the cleaning agent and is used to validate the cleaning in place of the liquid processing device. In particular, the electrical conductivity of the cleaning agent is measured with a second conductivity measuring sensor before cleaning the liquid processing device and compared with a measured electrical conductivity of the first conductivity measuring sensor, whereby the electrical conductivity of a first and a second conductivity measuring sensor are at least within a defined range of measured values at a temperature of 25 °C. It is particularly advantageous for the electrical conductivity to be measured exclusively in the cleaning step using sterile water for the injection, with the electrical conductivity of the first and second conductivity measuring sensors each being in the measured value range of 1.2 to 1.5 pS / cm at a temperature of 25 °C in order to validate the cleaning in place of the liquid processing device. By checking the electrical conductivity of the sterile water for injection as a cleaning agent finally flowing through the liquid processing device before cleaning the liquid processing device - i.e. before the cleaning agent enters the liquid processing device - and after the sterile water for injection as a cleaning agent has flowed through the liquid processing device, it is very easy to check and prove that the liquid processing device has been optimally cleaned.

[0013] According to an advantageous embodiment, the liquid processing device comprises a pressure vessel unit which can be connected to the liquid processing device, wherein the liquid processing device also expediently comprises an autoclave in which the pressure vessel unit can be cleaned and / or sterilized. The autoclave is also associated with the liquid processing device.

[0014] According to a further advantageous embodiment of the method, the liquid processing device furthermore has a pressure vessel unit which can be connected to the liquid processing device, the pressure vessel unit being cleaned and / or sterilized in a method step i), preferably in an autoclave, method step i) being carried out in particular before method step b) or before method step c). The pressure vessel unit is thus not cleaned and / or sterilized in place, i.e. out of place. Cleaning out of place is also called cleaning out of place - COP cleaning for short. Cleaning out of place is a cleaning process that is used when equipment parts, such as the pressure vessel unit in this case, cannot be cleaned in place or are difficult to clean. This means that the equipment parts must be dismantled before cleaning. They are then usually taken to a specific cleaning station, in this case an autoclave, or a specific area for cleaning and then reassembled after cleaning.

[0015] In this respect, the pressure vessel unit is preferably connected to the liquid processing device before process step b). In this way, the at least one pressure vessel unit is already mounted to the liquid processing device before the pressure hold test.

[0016] Furthermore, for cleaning the pressure vessel unit, preferably in the autoclave in process step i), different cleaning agents are preferably used, which flow through the pressure vessel unit one after the other. The cleaning agents used for this purpose are purified water, alkali solution, acid solution and sterile water for injection, with the purified water, then the alkali solution, then the acid solution and then the sterile water for injection conveniently flowing through the pressure vessel unit first. In this respect, the cleaning agent advantageously comprises temperatures in the range from 20 °C to 90 °C for cleaning out of place of the liquid processing device, the temperature being expediently 25 °C. Furthermore, the cleaning agent for cleaning out of place of the pressure vessel unit comprises in particular an overpressure of 2 bar compared to the ambient pressure. Due to the sequential use of the various cleaning agents, the liquid processing device is pre-rinsed by the purified water comprising a neutral pH value. The alkali solution used as a cleaning agent has a pH value between 7.1 and 14, whereby organic soiling such as grease, protein compounds, soot, oils and so on can be removed. The more persistent the soiling, the higher the concentration of the alkali solution should be. The acid solution as a cleaning agent comprises a pH value of less than 7 and cleans inorganic and mineral soiling in particular, such as rust, limescale and so on. The same applies to the acid solution: the more persistent the soiling, the higher the concentration of the acid solution should be. Finally, the liquid processing device is rinsed again by the sterile water for injection, which comprises a neutral pH value, so that no cleaning agent residues remain in the liquid processing device. Furthermore, the pressure vessel unit preferably has a third conductivity measuring sensor for measuring the electrical conductivity, which is used to validate the cleaning out of place of the pressure vessel unit. In particular, the electrical conductivity of the cleaning agent is measured with a fourth conductivity measuring sensor before cleaning the pressure vessel unit and compared with a measured electrical conductivity of the third conductivity measuring sensor, whereby the electrical conductivity of the third and fourth conductivity measuring sensors are at least within a defined range of measured values at a temperature of 25 °C. It is particularly advantageous for the electrical conductivity to be measured exclusively in the cleaning step using sterile water for the injection, with the electrical conductivity of the third and fourth conductivity measuring sensors each lying in the measured value range of 1.2 to 1.5 pS / cm at a temperature of 25 °C in order to validate the cleaning out of place of the pressure vessel unit. By checking the electrical conductivity of the sterile water for injection as a cleaning agent that finally flows through the pressure vessel unit before cleaning the pressure vessel unit - i.e. before the cleaning agent enters the pressure vessel unit - and after the sterile water for injection as a cleaning agent has flowed through the pressure vessel unit, it is very easy to check and verify that the pressure vessel unit has been optimally cleaned.

[0017] According to an additional advantageous embodiment of the preferred method, the pressure hold test of the liquid processing device is carried out with an overpressure of 2 bar to the ambient pressure, whereby the pressure hold test expediently lasts at least 10 minutes. Compressed air is preferably used as the medium for the pressure hold test. The pressure hold test ensures that the liquid processing device is configured to be leak-tight. Conveniently, the liquid processing device comprises at least one pressure measuring sensor for carrying out the pressure hold test.

[0018] In addition, a bubble pressure test is preferably performed for each sterilization filter of the sterilization filter device during each integrity test of the sterilization filter device, whereby each integrity test is expediently evaluated in the integrity evaluation device. This validates the integrity of the sterilization filters. The integrity test is carried out, for example, by means of a bubble point pressure test, diffusion test or pressure hold test. Preferably, the bubble point pressure test, also known as bubble point measurement or bubble point test, is used to test the quality of filter elements, especially membrane filters.

[0019] The bubble point is a simple and reliable way to characterize the properties of a sterilization filter element. For preparation, the pores of the filter element, which usually comprise a diameter of 0.22 pm during sterile filtration, are wetted with a buffer solution, which is most easily achieved by flushing a sterilization filter of the sterilization filter device under pressure. For hydrophilic filter elements in the form of membrane filters, water, in particular sterile water for injection, or a buffer solution similar to the liquid to be sterilized is typically used as the buffer solution, and for hydrophobic filter elements in the form of membrane filters, an alcohol / water mixture is expediently used.

[0020] For the bubble point pressure test, the sterilization filter is appropriately pressurized, preferably until 80% of the bubble point pressure specified by the manufacturer is reached. The pressure is then slowly increased up to the bubble point pressure and maintained for a defined period of time, in particular at least 5 min, preferably more than 10 min, particularly preferably at least 15 min. Compressed air is preferably used as a gaseous medium for this purpose. In order to expel the buffer solution from the pore, a force is required that is dependent on the pore diameter and corresponds to the pressure difference between the two sides of the filter:

[0021] Ap= (k • 4 o • cos0) / D with

[0022] Ap: pressure difference; k: correction factor for the pore shape c: surface tension of the buffer solution; Q: wetting angle of the membrane material (CTA: 50° - 55°; PAN: 52° - 58°; PESU: 65° - 70°, each for water as buffer solution);

[0023] D: Pore diameter

[0024] If a continuous air bubble leakage occurs after the membrane filter in the pressure vessel of the pressure vessel unit, the integrity test is considered failed. In such a case, the buffer solution comprises a different surface tension than the test liquid recommended by the manufacturer, the membrane filter has integrity but the wrong pore size, the temperature of the buffer solution is not correct, in particular too high, the membrane filter is incompletely wetted or there is a non-integer membrane of the membrane filter or a leaking system.

[0025] Other options for the integrity test are the diffusion test or the pressure hold test, which can be carried out as a variant of the diffusion test.

[0026] At a pressure difference below the bubble point pressure of the bubble pressure test, gas molecules diffuse through the water-filled pores of a wetted membrane filter according to Fick's law. The gas diffusion flow rate of a filter element configured as a membrane filter is proportional to the pressure difference and the total surface area of the filter element. To confirm the integrity of a filter element, the amount of gas diffusing through the membrane filter is measured at a pressure corresponding to about 80 % of the bubble point pressure.

[0027] First, the filter elements are thoroughly wetted with a suitable buffer solution during the diffusion test. The buffer solutions correspond to those used in the bubble point pressure test. For hydrophilic filter elements in the form of membrane filters, the buffer solution typically used is water, in particular sterile water for injection, or a buffer solution similar to the liquid to be sterilized, and for hydrophobic filter elements in the form of membrane filters, an alcohol / water mixture is used. The pressure on the upstream side of the filter element is then slowly increased to the test pressure recommended by the manufacturer, typically at least 80 % of the bubble point pressure. The system reaches equilibrium within a stabilization period. Finally, the gas flow on the filtrate side is determined for one minute using an inverted measuring cylinder or a flow meter.

[0028] The pressure hold test is a variant of the diffusion test. The pressure hold test requires a very accurate pressure gauge to detect pressure changes on the upstream side due to gas diffusion through the filter. As there is no need to determine the gas flow on the clean side of the filter, any risk of contamination of the sterile side of the filter element is eliminated. The pressure maintenance value depends on the diffusion flow rate and the inflow volume. It can be calculated using the following equation

[0029] Ap= (D-t-p_ai r pressure) / V

[0030] The following applies:

[0031] AP = pressure difference [bar]

[0032] D = diffusion rate [ml / min] t = time [min] pair pressure = air pressure [1 atm or 1013 mbar]

[0033] V = Inflow volume [ml]

[0034] According to a further advantageous embodiment of the method, the sterilization of the liquid processing device is carried out using a sterilization agent, wherein pure water vapour is expediently used as sterilization agent. The sterilization is expediently carried out as sterilization in place, which is also referred to as SIP sterilization (SIP: sterilization in place). In this respect, the liquid processing device preferably comprises temperature measuring sensors for measuring a temperature of the sterilization agent, wherein a temperature of greater than or equal to 121 °C is expediently used as the temperature of the sterilization agent. Particularly preferably, the sterilization of the liquid processing device with the sterilization agent in process step d) lasts for a period of at least 30 minutes. Sterilization is also preferably carried out at an overpressure of at least 2 bar above the ambient pressure, i.e. the atmospheric pressure of 1.013 bar.

[0035] Sterilization is a process in which living microorganisms, including their permanent forms (e.g. spores) and viruses, are removed from materials and objects. After the appropriate treatment, the sterilized materials and objects are referred to as "sterile". When sterilizing materials, e.g. food, pharmaceuticals or other solutions, ideally all microorganisms contained or adhering to them, including their permanent forms, are killed and viruses, prions also known as infectious proteins, plasmids and other DNA fragments are destroyed. In practice, complete sterilization cannot be achieved with 100% certainty. A reduction in the number of reproducible microorganisms by a certain factor (in powers of ten) is therefore required, depending on the area of application, or a certain probability of complete sterilization.

[0036] Furthermore, the sterilization of the liquid processing device comprises a first heating phase, a draining phase, a second heating phase and a stabilization phase, a holding phase and a cooling phase. In this respect, a heating phase lasts for a period of between 5 min and 15 min, whereby the duration does not expediently exceed 10 min. The emptying phase and / or the stabilization phase lasts between 1 min and 5 min. Preferably, the holding phase lasts for at least 30 minutes. Accordingly, it is preferred that water vapor flows through the liquid processing device at 121 °C and at least 2 bar pressure for at least 30 min. In this way, resistance level V can be achieved. Particularly preferably, the liquid processing device is flowed through with water vapor at 134 °C and at least 3 bar pressure for at least 60 min, so that resistance level VI is achieved.

[0037] In this respect, the part of the liquid processing device comprising the gas filter device is sterilized first and then the part of the liquid processing device comprising the sterilization filter device is sterilized or vice versa. According to a further preferred embodiment of the method, the liquid processing device has a liquid preparation device comprising the liquid to be sterilized and has a filling device, wherein before the liquid to be sterilized flows through the sterilization device, the liquid preparation device is fluidically connected to the liquid inlet and the filling device is fluidically connected to the liquid outlet.

[0038] In addition, the filling device has sterilized filling containers into which the liquid flowing through the sterilization device is filled by means of the filling device.

[0039] During sterile filtration, the microorganisms are separated from the liquid to be sterilized by filtration. Membrane filters with a pore diameter of 0.22 pm are usually used as sterilization filters, although membrane filters with a pore diameter of around 0.1 pm can also be used if necessary. Accordingly, only small molecules can pass through the membrane filters during sterile filtration, while larger particles such as bacteria are retained. The main applications are the sterile filtration of aqueous solutions, heatsensitive nutrient solutions, vitamin solutions, serums, virus vaccines, plasma fractions and protein solutions.

[0040] A selection of sterilization filters is listed below:

[0041] Merck Millipore, Durapore® 0.22 pm membrane, hydrophilic 10" CVGL cartridge or KVGL capsule

[0042] Merck Millipore, HydroCORR™: Aervent® 0.2 pm membrane, hydrophilic 10" CTGR cartridge or KTGR capsule

[0043] Sartorius, Sartoflour® 0.2 pm membrane, hydrophobic cartridge or capsule

[0044] According to an advantageous embodiment of the liquid processing device in this respect, the liquid processing device comprises a plurality of sterilization devices arranged functionally in parallel and a plurality of gas filter devices arranged functionally in parallel, wherein expediently the plurality of sterilization devices corresponds to the plurality of gas filter devices. Due to the plurality of sterilization directions and / or gas filter devices, the liquid processing device enables a quasi-continuous or continuous process for testing the integrity of a liquid processing device for sterilizing liquids, in particular liquids not in their final container.

[0045] Preferably, each liquid inlet expediently comprises a liquid inlet collection supply line and / or each liquid outlet expediently comprises a liquid outlet collection discharge line. The one common liquid inlet collector supply line and the one common liquid outlet collector discharge line reduce the investment costs.

[0046] In addition, each liquid inlet particularly preferably has a liquid inlet valve arrangement configured to release or close the sterilization device associated with the liquid inlet. This enables each sterilization device to be flowed through separately via the liquid inlet supply line. Furthermore, each liquid outlet has a liquid outlet valve arrangement which is configured to release or close the sterilization device associated with the liquid outlet, whereby each sterilization device can optionally be emptied alone or together with other sterilization devices.

[0047] According to a further advantageous embodiment of the liquid processing device, each gas inlet has a gas inlet valve arrangement comprising a gas inlet valve, which is configured to optionally release or close each gas filter device. This makes it possible to save investment costs and to control and / or regulate the liquid processing device in an improved manner, whereby each gas filter device can optionally be controlled alone or together with other gas filter devices, in particular to be released or closed.

[0048] Preferably, the liquid processing device is configured to carry out the method according to one of claims 1 to 31.

[0049] The invention is described in more detail below with reference to the accompanying drawing, which shows Figure 1 a process flow diagram of a first embodiment of a liquid processing device,

[0050] Figure 2 the process flow diagram of the first embodiment of the liquid processing device for cleaning in place of the liquid processing device,

[0051] Figure 3 the process flow diagram of the first embodiment of the liquid processing device for a pressure hold test of the liquid processing device,

[0052] Figure 4 the process flow diagram of the first embodiment of the liquid processing device, for an integrity test of the first sterilization filter of the sterilization filter device,

[0053] Figure 5 the process flow diagram of the first embodiment of the liquid processing device for an integrity test of the second sterilization filter of the sterilization filter device,

[0054] Figure 6 the process flow diagram of the first embodiment of the liquid processing device for a sterilization of the gas filter device,

[0055] Figure 7 the process flow diagram of the first embodiment of the liquid processing device for sterilization of the sterilization filter device,

[0056] Figure 8 the process flow diagram of the first embodiment of the liquid processing device for a sterilization of liquids, in particular liquids which cannot be sterilized in their final container, by means of the liquid processing device, and

[0057] Figure 9 a process flow diagram of a second embodiment of the liquid processing device.

[0058] Unless otherwise stated, the following description refers to all embodiments of a liquid processing device 1 illustrated in the drawing as well as a method for testing the integrity of a liquid processing device 1 for sterilizing liquids 2 which in particular cannot be sterilized in their final container. The liquid processing device 1 comprises a sterilization device 7 comprising a liquid inlet 4 which can be f luidica lly connected to a liquid container 3 containing a liquid 2 to be sterilized and a liquid outlet 6 which can be fluidica lly connected to a filling device 5. The liquid 2 to be sterilized is thereby produced in a liquid production device, not shown, which the liquid processing device 1 expediently also has. In addition, the filling device 5 has sterilized filling containers, not shown, into which the liquid 2 flowing through the sterilization device is filled by means of the filling device 5.

[0059] The liquid 2 to be sterilized can flow through the sterilization device 7 on a sterilization path 8 extending from the liquid inlet 4 to the liquid outlet 6. A sterilization filter device 10 comprising at least one sterilization filter 9 is arranged on the sterilization path 8. In the two embodiments of the liquid processing device 1 shown in Figs. 1 and 9, the sterilization filter device 10 comprises one sterilization filter 9 each, which are identified as sterilization filters 9a and 9b for easier differentiation. Each sterilization filter 9 has a liquid filter inlet 11, a retentate outlet 12 and a permeate outlet 13. In the following, device components are marked with a lowercase letter a, b, c ... to make it easier to distinguish between them. The sterilization filters 9 are preferably configured as membrane filters 14.

[0060] Downstream of the liquid inlet 4 and upstream of the liquid filter inlet 11a of the first sterilization filter 9a arranged on the sterilization path 8, a line segment 19 of a piping system 20 associated with the liquid processing device 1 is configured comprising valves 15, 16 and 17, which are in particular configured as a valve block 18. The line segment 19 is designated between the valves 15 and 16 as line segment 19a, between the valves 16 and 17 as line segment 19b and between the valve 17 and the liquid filter inlet 11a as line segment 19c. A valve block is conveniently referred to here as a block made of a high- strength material, such as metal, which accommodates several valves by installation or attachment. The connections required for their function are drilled into the block and are connected to the corresponding line segments of the line system 20. The valves 15, 16 and 17, which are configured in particular as valve block 18, are expediently manually or automatically controllable and / or adjustable valves. Downstream of the permeate outlet 13a of the first sterilization filter 9a arranged on the sterilization path 8 and upstream of the liquid filter inlet lib of the second sterilization filter 9b arranged on the sterilization path 8, a line segment 24 of the piping system 20 associated with the liquid processing device 1 is configured comprising valves 21 and 22, which are in particular configured as a valve block 23. The line segment 24 is designated between the permeate outlet 13a and the valve 21 as line segment 24a, between the valves 21 and 22 as line segment 24b and between the valve 22 and the liquid filter inlet lib as line segment 24c. The valves 21 and 22, which are configured in particular as a valve block 23, are also expediently manually or automatically controllable and / or adjustable valves. Furthermore, the sterilization filter device 10a has a first sampling device 25 arranged downstream of the permeate outlet 13a, by means of which the quality of the permeate 26 after the first sterilization filter 9b can be analyzed and checked. Expediently, the sampling device 25 is also configured as a manually or automatically controllable and / or adjustable valve.

[0061] Downstream of the permeate outlet 13b of the second sterilization filter 9b arranged on the sterilization path 8 and upstream of the liquid outlet 6, a line segment 29 of the piping system 20 associated with the liquid processing device 1 is configured comprising a valve 27, which is configured in particular as a valve block 28. Furthermore, the sterilization filter device 10b also has a second sampling device 30 arranged downstream of the permeate outlet 13b, by means of which the quality of the permeate 31 after the second sterilization filter 9b can be analyzed and checked. Expediently, the sampling device 30 is also configured as a manually or automatically controllable and / or adjustable valve.

[0062] In addition, each sterilization filter device 10 comprises a sensor 32 for measuring physical and / or chemical properties, which is arranged upstream of the liquid filter inlet 11 of the sterilization filter 9. The sensor 32 is configured as a pressure measuring sensor 33. The sterilization device 7 also has a further sensor 35 configured as a pressure measuring sensor 34, which is arranged downstream of the last sterilization filter device 10, in this case the second sterilization filter device 10b, namely between the permeate outlet 13b and the second sampling device 30. A line segment 43 of the line system 20 is connected to the retentate outlet 12a of the sterilization filter 9a via a valve 42, via which the retentate 44 can be discharged from the sterilization filter 9a into a further line segment 45. A line segment 47 of the piping system 20 is also connected to the retentate outlet 12b of the sterilization filter 9b via a valve 46, via which the retentate 48 can be discharged from the sterilization filter 9a into a further line segment 49.

[0063] In contrast to the first embodiment of the liquid processing device 1, the second embodiment of the liquid processing device 1 comprises a plurality of sterilization devices 7 arranged functionally in parallel. The second embodiment of the liquid processing device 1 shown in Fig. 9 comprises two sterilization devices 7. In embodiments of the liquid processing device 1 not shown, the sterilization device 7 comprises a different number of sterilization filter devices 10, namely in particular one sterilization filter device 10, three sterilization filter devices 10, four sterilization filter devices 10, five sterilization filter devices 10 or more sterilization filter devices 10. For easier differentiation, the sterilization devices 7 are identified as sterilization device 7.1 and sterilization device 7.2. The basic structure of the sterilization devices 7.1 and 7.2 is the same and corresponds to the structure of the sterilization device 7 according to the first embodiment. In the following, all components of a first device are labeled 1 and all components of a second device are labeled 2 for easier differentiation. However, each liquid inlet 4.1,4.2 of the corresponding sterilization device 7.1,7.2 is fluidically connected via a liquid inlet valve arrangement 186 comprising line segments 36.1,36.2 and a liquid inlet valve 37, wherein the liquid inlet valve 37 is in turn fluidically connectable to the liquid container 3. The sterilization device 7.1 or 7.2 associated with the liquid inlet 4.1 or 4.2 can be opened or closed by the liquid inlet valve 37. Each liquid outlet 6.1, 6.2 of the corresponding sterilization device 7.1, 7.2 is also fluidically connected via a liquid outlet valve arrangement 187 comprising line segments 38.1, 38.2 and a liquid outlet valve 39. The liquid outlet valve 39 can in turn be fluidically connected to the filling device 5, so that the sterilization device 7.1 or 7.2 assigned to the liquid outlet 6.1 or 6.2 can be released or closed by the liquid outlet valve 39. In addition to the sterilization device 7, the liquid processing device 1 also has a gas filter device 41 comprising a gas filter 40. A gas 50, in particular compressed air 51, can flow through the gas filter device 41 on a gas filter path 53 extending from a gas inlet 52 to the valves 16, 22, 27, 42 and 46. The gas filter 40 is arranged on the gas filter path 53. In the two embodiments of the liquid processing device 1 shown in Figs. 1 and 9, the gas filter device 41 comprises a gas filter 40 in each case. The gas filter 40 has a gas filter inlet 54, a retentate gas outlet 55 and a permeate gas outlet 56. The gas filter 40 is expediently also configured as a membrane filter 57.

[0064] Here too, in contrast to the first embodiment, the second embodiment in Fig. 9 comprises two gas filter devices 41. For easier differentiation, the gas filter devices 41 are labeled as gas filter devices 41.1 and gas filter device 41.2. Here too, the basic structure of the gas filter devices 41.1 and 41.2 corresponds to the structure of the gas filter device 41 already described above. The two gas filter devices 41.1 and 41.2 are fluidically connected to each other by means of a gas inlet valve arrangement 182 comprising a gas inlet valve 183 and line segments 184, 185, whereby each gas filter device 41.1, 41.2 can be opened or closed selectively and independently of the respective other gas filter device 41.1, 41.2. Here, line segment 184 fluidly connects valve 58.1 to gas inlet valve 183 and line segment 185 fluidly connects valve 58.2 to gas inlet valve 183.

[0065] Downstream of the gas inlet 52 and upstream of the gas filter inlet 54 of the gas filter 40 arranged on the gas filter path 53, a line segment 63 of a line system 20 associated with the liquid processing device 1 is configured comprising valves 58, 59, 60 and 61, which are in particular configured as a valve block 62. The line segment 63 is designated between the valves 58 and 59 as line segment 63a, between the valves 59 and 60 as line segment 63b, between the valves 60 and 61 as line segment 63c and between the valve 61 and the gas filter inlet 54 as line segment 63d. In this context, a valve block is expediently referred to as a block made of a high-strength material, such as metal, which accommodates several valves by installation or attachment. The connections required for their function are drilled into the block and are connected to the corresponding line segments of the line system 20. The valves 58, 59, 60 and 61, which are configured in particular as a valve block 62, are expediently manually or automatically controllable and / or adjustable valves.

[0066] Downstream of the permeate gas outlet 56 of the gas filter 40 arranged on the gas filter path 53 and upstream of the valves 16, 22, 27, 42 and 46, a line segment 67 of the piping system 20 associated with the liquid processing device 1 and comprising a valve 66 is configured. Between the permeate gas outlet 56 and the valve 66, the line segment 67 is referred to as line segment 67a and between the valve 66 and the valves 16, 22, 27, 42 and 46 as line segment 67b. Here, the branch from line segment 67b towards valve 16 is referred to as line segment branch 160, towards valve 42 as line segment branch 161, towards valve 22 as line segment branch 162, towards valve 46 as line segment branch 163 and towards valve 27 as line segment branch 164. The valve 66 is expediently a manually or automatically controllable and / or adjustable valve.

[0067] A line segment 69 of the pipeline system 20 is connected to the retentate gas outlet 56 of the gas filter 40 via a valve 68, via which the retentate gas 70 can be discharged from the gas filter 40 into a further line segment 71.

[0068] Furthermore, each gas filter device 41 comprises a sensor 64 arranged downstream of the permeate gas outlet 56 of the gas filter 40 for measuring physical and / or chemical properties, wherein the sensor 64 is configured as a pressure measuring sensor 65.

[0069] The liquid processing device 1 also comprises an integrity evaluation device 72. The integrity evaluation device 72 is preferably configured as an integrity testing device 73, which is expediently an Integritest® 5 from Merck, for example. Accordingly, the integrity evaluation device 72 is suitable for performing an integrity test of the sterilization filters 9 of each sterilization filter device 10.

[0070] Furthermore, the integrity evaluation device 72 is in particular associated with a control unit 74 comprising a control functionality, is integrated therein or itself forms the control unit 74. The integrity evaluation device 72 and / or the control unit 74 are expediently connected at least to all valves and / or sensors, in particular for bidirectional data exchange. The integrity evaluation device 72, but in particular the control unit 74, ensures that the liquid processing device 1 can be controlled and / or regulated in a fully automated manner. The integrity evaluation device 72 is connected to valve 58 by means of line segment 75 and to valve 59 by means of line segment 76. Valves 58 and 59 are expediently manually or automatically controllable and / or adjustable valves.

[0071] In contrast to the first embodiment, the second embodiment of the liquid processing device 1 also comprises two integrity evaluation devices 72, which are configured corresponding to the membrane filters 14 installed in the sterilization filter devices 10. For easier differentiation, the integrity evaluation devices 72 are labeled as integrity evaluation device 72.1 and integrity evaluation device 72.2.

[0072] In addition, the liquid processing device 1 has a buffer solution inlet 77 to which a line segment 80 of the piping system 20 comprising the valves 78 and 79 is connected downstream, wherein the line segment 80 opens into the two valves 15 and 21. Between the valves 78 and 79 the line segment 80 is referred to as line segment 80a, between the valves 79 and 21 the line segment 80 is referred to as line segment 80b and between the valves 79 and 15 the line segment 80 is referred to as line segment 80c. The valves 78 and 79 are preferably configured as block valves 81 and are expediently manually or automatically controllable and / or adjustable valves.

[0073] A first pressure vessel unit 82 of the liquid processing device 1 is expediently connectable to the buffer solution inlet 77. The first pressure vessel unit 82 comprises a pressure vessel 83 containing a buffer solution 150 and a conveying device 86, in particular having an electric drive unit 84 and connected to the pressure vessel 83 via a line segment 85, expediently in the form of a liquid pump 87, such as a centrifugal pump or the like. In the embodiment shown in Fig. 9, the first sterilization device 7.1 is connected to the first pressure vessel unit 82 via the buffer solution inlet 77.1 and the second sterilization device 7.2 is fed directly with a buffer solution 150 via the buffer solution inlet 77.2. Accordingly, the buffer solution inlet 77 can optionally be connected to a pressure vessel unit 82 or directly to a buffer solution 150.

[0074] In addition, the liquid processing device 1 further comprises an autoclave 148 in which the first pressure vessel unit 82 can be cleaned and / or sterilized.

[0075] The liquid processing device 1 additionally comprises a cleaning agent inlet 88 for cleaning agent 151 and a sterilization agent inlet 89 for sterilization agent 147, wherein the cleaning agent inlet 88 comprises a valve 90 and line segments 91 and 92 connected thereto, which open into the valve 17 and 60, respectively, and wherein the sterilization agent inlet 89 comprises the valve 90 and the line segments 91 and 92 connected thereto, which also open into the valve 17 and 60, respectively. The valve 90 is preferably a manually or automatically controllable and / or adjustable valve.

[0076] The liquid processing device 1 also has a drainage device 93, which, starting from valve 78, comprises a line segment 94 to which a valve 95 is connected, the valve 95 being configured in particular as a 3-way valve. From the valve 95, a line segment 96 goes into a first drain manifold 97 of the drainage device 93 and a line segment 98 goes into a second drainage manifold 99 of the drainage device 93. In addition to a sensor 100, which is appropriately configured as a temperature measuring sensor 101, the line segment 98 also comprises a condensation trap 102. The first drainage manifold 97 additionally comprises a sensor 141 which is suitable for measuring physical and / or chemical properties and is suitably configured as a conductivity measuring sensor 142.

[0077] Furthermore, starting from valve 15, the drainage device 93 has a line segment 102 to which a valve 103 is connected, which is suitably configured as a 4-way valve or as a valve block. A line segment 104 extends from valve 103 to the first drainage manifold 97 and a line segment 108, comprising a sensor 106 configured as a temperature measuring sensor 105 and a condensation trap 107 downstream of the sensor 106, extends to the second drainage manifold 99. In addition, the drainage device 93 has the line segment 45 to which a valve 109 is connected. The valve 109 is suitably configured as a 4-way valve or as a valve block. A line segment 110 extends from valve 109 to the first drainage manifold 97 and a line segment 111 to the second drainage manifold 99. The line segment 111 has a sensor 113 configured as a temperature measuring sensor 112 and a condensation trap 114 downstream of the sensor 113.

[0078] In addition, the drainage device 93 has the line segment 49 to which a valve 115 is connected, whereby the valve 115 is appropriately configured as a 4-way valve or as a valve block. A line segment 116 extends from valve 115 to the first drainage manifold 97 and a line segment 117 to the second drainage manifold 99, wherein the line segment 117 is connected via a sensor 119 configured as a temperature measuring sensor 118 and a condensation trap 120 downstream of the sensor 119.

[0079] The valves 103 and 109 are connected to each other via line segments 121 and 122, both of which open into a valve 123. The valve 123 is expediently also configured as a 4-way valve or as a valve block and is also f luidica lly connected to the valve 115 via the line segment 156. In addition, a further line segment 124 extends from valve 123 and is connected to a valve 125 configured in particular as a 3-way valve. Starting from valve 125, a line segment 126 extends to a valve 143, from which a line segment 144 extends to the first drainage manifold 97 and a line segment 127 extends to the second drainage manifold 99. The line segment 127 has a sensor 129 configured as a temperature measuring sensor 128 and a condensation trap 130 downstream of the sensor 129.

[0080] A second pressure vessel unit 145 comprising a pressure vessel 146 is connectable to the valve 143, wherein the second pressure vessel unit 145 is configured in particular to indicate bubble formation possibly occurring during the integrity test of the sterilization filters 9 of each sterilization filter device 10. Also, the second pressure vessel unit 145 is cleanable and / or sterilizable by the autoclave 148 or another autoclave 149 of the liquid processing device 1. In addition, the drainage device 93 comprises the line segment 71 to which a valve 131 configured expediently as a 3-way valve or as a valve block is connected. A line segment 132 extends from valve 131 to the first drainage manifold 97 and a line segment 133 to the second drainage manifold 99, wherein the line segment 133 has a sensor 135 configured as a temperature measuring sensor 134 and a condensation trap 136 downstream of the sensor 135.

[0081] In addition, the drainage device 93 comprises the line segment 137 extending towards the second drainage manifold 99 and having a sensor 139 configured as a temperature measuring sensor 138 and a condensation trap 140 downstream of the sensor 139.

[0082] The second sterilization device 7.2 shown in Fig. 9 and the second gas filter device 41.2 use the same drainage device 93 as the first sterilization device 7.1 and the first gas filter device 41.1 of the first embodiment of the first liquid processing device 1. Therefore, the liquid processing device 1 of the second embodiment also comprises only one drainage device 93. Here, the sterilization devices 7.1,7.2 and the gas filter devices 41.1,41.2 are f luidica lly connected to the drainage device 93 via corresponding line segments. For this purpose, valve 78.1 is fluidically connected to valve 95 via line segment 165, whereby valve 95 is now configured as valve block 166 or as a 4-way valve. Valve 103.1 is fluidically connected via line segment 167 to a valve 168 and thus opens into line segment 108 and via line segment 169 to the drainage manifold 97. Valve 123.1 is now fluidically connected via line segment 170 to valve 143, which is now also configured as a valve block 171 or as a 4-way valve. Furthermore, valve 109.1 is fluidically connected via line segment 172 to a 3-way valve 173 configured on line segment 111 and via line segment 174 to the line segment 110 leading into the drainage manifold 97. Valve 115.1 is fluidically connected via line segment 175 to a 3-way valve 176 configured on line segment 117 and via line segment 177 to the line segment 116 leading into the drainage manifold 97. Finally, valve 66.1 is fluidically connected via line segment 178 to valve 131, which is now configured as a valve block 179 or as a 4-way valve, and valve 61.1 is fluidically connected via line segment 180 to a valve 181 configured as a 3-way valve and arranged on line segment

[0083] 137. The liquid processing device 1 is used to carry out the method for testing the integrity of a liquid processing device 1 for sterilizing liquids 2 that cannot be sterilized in their final container, in particular.

[0084] Fig. 2 shows a process flow diagram of the first embodiment of the liquid processing device 1 for cleaning in place of the liquid processing device 1 after process step a). Process step a) is conveniently carried out as the first process step. The cleaning of the liquid processing device 1 is carried out as CIP cleaning.

[0085] In process step a), the part of the liquid processing device 1 shown in "bold" in Fig. 2 is cleaned using cleaning agents 151. In particular, purified water 152, alkali solution 153, acid solution 154 and sterile water for injection 155 are used as cleaning agents 151 in process step a). Here, alkali solutions 153 are alkaline solutions, also known as alkaline solutions, i.e. aqueous solutions in which the concentration of hydroxide ions OH- exceeds that of oxonium ions H3O+, resulting in a pH value of the alkali solution 153 of greater than 7. Acid solutions 154 are acidic solutions, also referred to as acids, i.e. aqueous solutions in which the concentration of the oxonium ions H3O+ exceeds that of the hydroxide ions OH-, resulting in a pH of the acid solution 154 of less than 7. Sterile water for injection 155 is water of extra high quality without significant contamination, which is appropriately used for the preparation of solutions to be administered by injection.

[0086] For the cleaning in place of the liquid processing device 1 according to method step a), the different cleaning agents 151 preferably flow through the liquid processing device 1 one after the other. Preferably, the purified water 152 flows through the liquid processing device 1 first, then the alkali solution 153, then the acid solution 154 and then the sterile water for injection 155. The purified water 152 is used for the basic cleaning of the liquid processing device. The alkali solution 153 is used for cleaning the liquid processing device 1 from organic impurities, whereas the acid solution 154 is used for cleaning the liquid processing device 1 from inorganic impurities. The sterile water for injection 155 is finally used for the final cleaning of the liquid processing device 1, so that the sterile water for injection 155 also rinses all residues of the previously used cleaning agents 151 from the liquid processing device 1.

[0087] The cleaning agents 151 for cleaning in place of the liquid processing device 1 comprise temperatures in the range from 20 °C to 90 °C, wherein the cleaning agent 151 for cleaning in place of the liquid processing device 1 is preferably used at an overpressure to the ambient pressure of 2 bar.

[0088] The respective cleaning agent 151 flows through the liquid processing device 1 according to the following exemplary scheme. The cleaning agent 151 enters the liquid processing device 1 via the cleaning agent inlet 88. It then flows through the line segments 92, 19b, 19a, 80c, 80a, 94 and 96 into the drainage manifold 97. The cleaning agent 151 then flows through the line segments 92, 19b, 19a, 102 and 104 into the drainage manifold 97. It then flows through the line segments 92, 19b, 19a, 121, 124, 126 and 144 into the drainage manifold 97 and then through the line segments 92, 19c, 43, 45 and 110 in the direction of the drainage manifold 97. Subsequently, the line segments 92, 19c, 67b, 71 and 132 are flowed through in the direction of the drainage manifold 97. The cleaning agent 151 then flows through the line segments 92, 19c, 24a, 45, 122, 124, 126 and 144 into the drainage manifold 97. The cleaning agent 151 then flows through the line segments 92, 19b, 19a, 80c, 80b, 45, 122, 124, 126 and 144 into the drainage manifold 97. This is followed by the cleaning of the line segments 92, 19b, 67b, 71 and 132, after which the cleaning agent flows through the line segments 92, 19b, 67b, 24b, 45, 122, 124, 126 and 144 in the direction of the drainage manifold 97. Subsequently, the line segments 92, 19b, 19a, 80c, 80b, 24b, 24c, 49, 116 29 are flowed through in the direction of the drainage manifold 97. This is followed by the flow through the line segments 92, 19b, 19a, 80c, 80b, 24b, 24c, 47, 49, 156, 124, 126, 144. Finally, the cleaning agent 151 flows through the line segments 91, 63c, 63d, 67a, 71 and 132 as well as the line segments 91, 63c, 63d, 69, 71 and 132 in the direction of the drainage manifold 97. The sequence of the line segments of the piping system 20 that are flowed through and thus cleaned is variable, i.e. any other combination of line segments can be flowed through by the cleaning agent 151 for cleaning. In order to specify the corresponding cleaning path, the valves are set manually or automatically by the control unit 74. The cleaning of the individual line segments is repeated with each of the cleaning agents 151, whereby the sequence of the line segments of the piping system 20 that are flowed through and thus cleaned is also variable with the different cleaning agents 151.

[0089] The cleaning in place of the liquid processing device 1 is validated using the conductivity measuring sensor 142 arranged in the drainage manifold 97 for measuring the electrical conductivity of the cleaning agent 151 flowing through the liquid processing device 1.

[0090] For the validation of the cleaning in place of the liquid processing device 1, the electrical conductivity of the cleaning agent 151 is measured before cleaning of the liquid processing device 1 using a further conductivity measuring sensor 157 at the cleaning agent inlet 88. The measured value of the further conductivity measuring sensor 157 resulting for the conductivity is compared with a measured electrical conductivity of the conductivity measuring sensor 142 arranged in the drainage manifold 97, whereby the cleaning in place is found to be in order if the electrical conductivity of the conductivity measuring sensor 157 and the conductivity measuring sensor 142 are each at least within a defined range of measured values at a temperature of 25 °C. Preferably, the electrical conductivity is measured exclusively when sterile water is used as the cleaning agent 151 for the injection 155. To validate the cleaning in place of the liquid processing device 1, the electrical conductivity of the conductivity measuring sensors 142,157 is expediently in the measured value range of 1.2 to 1.5 pS / cm at a temperature of 25 °C in each case.

[0091] Furthermore, for carrying out the method, the two pressure vessel units 82 and 145 are also cleaned in a method step i) preferably in an autoclave 148,149, the method step i) being carried out in particular before the method step b) or before the method step c). Accordingly, in contrast to the liquid processing device 1, the cleaning of the pressure vessel units 82,145 is not performed as CIP cleaning, but as COP cleaning. The cleaned pressure vessel units 82 and 145 are then expediently connected to the liquid processing device before process step b). For cleaning the pressure vessel units 82, 145 preferably in the autoclave 148, 149 in process step i), different cleaning agents 151 are also used as before for cleaning the liquid processing device 1, which flow through the respective pressure vessel unit 82, 145 one after the other. The cleaning steps are identical to the cleaning steps for the liquid processing device 1. Purified water 152, alkali solution 153, acid solution 154 and sterile water for injection 155 are used as cleaning agents 151, whereby expediently first the purified water 152, then the alkali solution 153, then the acid solution 154 and then the sterile water for injection 155 flow through the respective pressure vessel unit 82,145. The respective cleaning agent 151 for the cleaning out of place of the pressure vessel units 82,145 comprises temperatures in the range from 20 °C to 90 °C and expediently an overpressure to the ambient pressure of 2 bar.

[0092] For the validation of the cleaning out of place of the pressure vessel units 82,145, the electrical conductivity of the cleaning agent 151 is also measured with a conductivity measuring sensor 158 before the cleaning of the pressure vessel unit 82,145. The measured value of the conductivity measuring sensor 158 resulting for the conductivity is compared with a measured electrical conductivity of a further conductivity measuring sensor 159, which is arranged downstream of the conveying device 86, the cleaning out of place being found to be in order if the electrical conductivity of the two conductivity measuring sensors 158,159 are each at least within a defined range of measured values at a temperature of 25 °C. Preferably, the electrical conductivity is measured exclusively when sterile water is used as the cleaning agent 151 for the injection 155. To validate the cleaning out of place of the pressure vessel unit 82,145, the electrical conductivity of the two conductivity measuring sensors 158,159 is expediently each in the measured value range of 1.2 to 1.5 pS / cm at a temperature of 25 °C.

[0093] Fig. 3 shows the process flow diagram of the first embodiment of the liquid processing device 1 for a pressure hold test of the liquid processing device 1. To carry out the pressure hold test, in particular the pressure vessel units 82 are fluidically connected to the valve 78 via the buffer solution inlet 77 and the pressure vessel unit 145 is fluidically connected to the valve 125. In the method step b), the part of the liquid processing device 1 shown in "bold" in Fig. 3 is tested by means of a gas 50, expediently compressed air 51.

[0094] The process step b), namely the pressure hold test of the liquid processing device 1, is carried out with an overpressure to the ambient pressure of 2 bar, whereby the pressure hold test expediently lasts at least 10 min, but preferably 30 min. The pressure in the liquid processing device 1 is detected by means of the pressure measuring sensors 33a, 33b and 65. If the pressure in the liquid processing device 1 remains constant for the duration of the pressure hold test, the pressure hold test is deemed to have been passed.

[0095] For the pressure hold test, the line segments 19a, 19b, 19c, 24a, 24b, 24c, 29, 43, 47, 49, 63a, 63b, 63c, 63d, 67a, 67b, 69, 71, 80a, 80b, 80c, 91, 92, 94, 102, 121, 122, 124, 126 and 156 as well as the sterilization filters 9a, 9b and the gas filter 40 are pressurized with gas 50 of the corresponding pressure via the gas inlet 52.

[0096] After process step b), process step c) is preferably carried out, namely a first integrity test of the sterilization filter device 10, in this case of the two sterilization filter devices 10a and 10b. Process step c) performs an integrity test prior to sterilization, which is also referred to as a "pre-use" integrity test. In the integrity test, a bubble pressure test is preferably performed for each sterilization filter 9a, 9b of the sterilization filter device 10a, 10b. The corresponding process flow diagram of the first embodiment of the liquid processing device 1, for an integrity test of the first sterilization filter 9a of the sterilization filter device 10a is shown in Fig. 4.

[0097] For the integrity test of the first sterilization filter 9a, a buffer solution 150 is conveyed by means of the preferably motor-driven conveying device 86 from the pressure vessel 83 and via the buffer solution inlet 77 and the line segments 80a, 80c, 19a, 19b, 19c into the sterilization filter 9a for wetting the membrane filter 14a, the buffer solution 150 draining via the line segments 43, 24a, 45, 122, 124 into the pressure vessel 146 of the pressure vessel unit 145. For hydrophilic filter elements in the form of membrane filters 14, water 152, in particular sterile water for injection 155, or a buffer solution 150 similar to the liquid to be sterilized is typically used for this purpose as buffer solution 150, and for hydrophobic filter elements in the form of membrane filters 14, an alcohol / water mixture is expediently used.

[0098] Subsequently, the gas filter path 53, i.e. the line segments 63b, 63c, 63d 67a and 67b, of the gas filter device 41 is supplied with gas 50, expediently compressed air 51, i.e. compressed air, via the gas inlet 52 via the integrity evaluation device 72 by means of the line segments 75 and 76. Valves 16, 22, 46 and 27 are closed. Valve 42 is open in such a way that the compressed air can flow into the sterilization filter 9a.

[0099] After the sterilization filter 9a, the line segments 24a, 45, 122, 124 remain open on the permeate side so that gas 50 passing through the membrane filter 14a can flow into the pressure vessel 146 of the pressure vessel unit 145 connected to the valve 125.

[0100] For the bubble pressure test, the sterilization filter 9a is expediently pressurized, preferably until 80% of the bubble point pressure of the membrane filter 14a specified by the manufacturer is reached. The pressure is then slowly increased up to the bubble point pressure and maintained for a defined period of time, in particular at least 5 min, preferably more than 10 min, particularly preferably at least 15 min. In order to expel the buffer solution 150 from the pore, a force dependent on the pore diameter is required, which corresponds to the pressure difference between the two sides of the filter.

[0101] If a continuous air bubble leakage occurs after the membrane filter 14a in the pressure vessel 146 of the pressure vessel unit 145, the integrity test is considered failed. In such a case, for example, the buffer solution 150 comprises a different surface tension than the test liquid recommended by the manufacturer, the membrane filter 14a has integrity but the wrong pore size, the temperature of the buffer solution 150 is incorrect, in particular too high, the membrane filter 14a is incompletely wetted or there is a non-integer membrane of the membrane filter 14a or a leaking system. The first integrity test of the sterilization filter 9a is preferably evaluated simultaneously in the integrity evaluation device 72.

[0102] After the integrity test of the first sterilization filter 9a, the second sterilization filter 9b of the second sterilization filter device 10b is also subjected to an integrity test. The corresponding process flow diagram of the first embodiment of the liquid processing device 1 for an integrity test of the second sterilization filter 9b of the sterilization filter device 10b is shown in Fig. 5.

[0103] For the integrity test of the second sterilization filter 9b, a buffer solution 150 is also conveyed by means of the preferably motor-driven conveying device 86 from the pressure vessel 83 and via the buffer solution inlet 77 and the line segments 80a, 80b, 24b, 24c into the sterilization filter 9b for wetting the membrane filter 14b, the buffer solution 150 draining via the line segments 47, 29, 49, 156, 124 into the pressure vessel 146 of the pressure vessel unit 145. For hydrophilic filter elements in the form of membrane filters 14, purified water 152, in particular sterile water for injection 155, or a buffer solution 150 similar to the liquid to be sterilized is typically used for this purpose as buffer solution 150, and for hydrophobic filter elements in the form of membrane filters 14, an alcohol / water mixture is expediently used.

[0104] Subsequently, the gas filter path 53, i.e. the line segments 63b, 63c, 63d 67a and 67b, of the gas filter device 41 is supplied with gas 50, expediently compressed air 51, i.e. compressed air, via the gas inlet 52 via the integrity evaluation device 72 by means of the line segments 75 and 76. Valves 16, 22, 42 and 27 are closed. Valve 46 is open in such a way that the compressed air can flow into the sterilization filter 9b.

[0105] After the sterilization filter 9b, the line segments 29, 49, 156, 124 remain open on the permeate side so that gas 50 passing through the membrane filter 14b can flow into the pressure vessel 146 of the pressure vessel unit 145 connected to the valve 125. For the bubble pressure test, the sterilization filter 9b is expediently pressurized, preferably until 80% of the bubble point pressure of the membrane filter 14b specified by the manufacturer is reached. The pressure is then slowly increased up to the bubble point pressure and maintained for a defined period of time, in particular at least 5 min, preferably more than 10 min, particularly preferably at least 15 min. In order to expel the buffer solution 150 from the pore, a force dependent on the pore diameter is required, which corresponds to the pressure difference between the two sides of the filter.

[0106] If a continuous air bubble leakage occurs after the membrane filter 14b in the pressure vessel 146 of the pressure vessel unit 145, the integrity test is considered failed. In such a case, for example, the buffer solution 150 comprises a different surface tension than the test liquid recommended by the manufacturer, the membrane filter 14b has integrity but the wrong pore size, the temperature of the buffer solution 150 is incorrect, in particular too high, the membrane filter 14b is incompletely wetted or there is a non-integer membrane of the membrane filter 14b or a leaking system.

[0107] The second integrity test of the sterilization filter 9b is also expediently evaluated simultaneously in the integrity evaluation device 72.

[0108] After the two sterilization filters 9a and 9b of the sterilization device 7 of the liquid processing device 1 have been subjected to an integrity test, the liquid processing device 1 is now sterilized in process step d). In process step d), the part of the liquid processing device 1 shown in "bold" in Figs. 6 and 7 is sterilized by means of sterilization agent 147. The sterilization takes place as so-called sterilization in place, also known as SIP sterilization. In process step d), first a part of the liquid processing device 1 comprising the gas filter 40 of the gas filter device 41 is sterilized and then the remaining part of the liquid processing device 1 comprising the two sterilization filters 9 is sterilized. The corresponding process flow diagram of the first embodiment of the liquid processing device 1 for the part of the liquid processing device 1 comprising the gas filter 40 of the gas filter device 41 is represented in Fig. 6. Via the sterilization agent inlet 89, the sterilization agent 147 flows through the line segments 91, 63b, 63c, 63d, 67a, 69, 71, 133 and 137 towards the second drainage manifold 99 and the respective valves 60, 61, 68, 66, 90 and 131. In addition, the gas filter 40 of the gas filter device 41 is also sterilized by the sterilization agent 147. The sterilization agent 147 is expediently pure steam at a temperature of at least 121 °C. To measure the temperature of the sterilization agent 147, the line segment 133 has the sensor 135 configured as a temperature measuring sensor 134 and the line segment 137 has the sensor 139 configured as a temperature measuring sensor 138.

[0109] The sterilization for the part of the liquid processing device 1 comprising the gas filter 40 of the gas filter device 41 with the sterilization agent 147 in process step d) preferably lasts for a period of at least 30 min. The sterilization comprises a first heating phase, a draining phase, a second heating phase, a stabilization phase, a holding phase and a cooling phase.

[0110] Each heating phase lasts between 5 minutes and 15 minutes, whereby the duration should not exceed 10 minutes. The heating phase is completed when the temperature measuring sensor 134 and 139 constantly indicates a temperature of at least 121 °C. After the first heating phase, an emptying phase takes place, whereby the condensation trap 136, 140 installed downstream of the sensor 135, 139 is used for this purpose. The sterilization agent 147 is condensed in the condensation trap 136, 140 and then discharged into the second drainage manifold 99. The emptying phase lasts between 1 min and 5 min. This is followed by the second heating phase, which proceeds in the same way as the first heating phase. After the second heating phase, a stabilization phase takes place, which lasts between 1 min and 5 min. This is followed by a holding phase lasting at least 30 minutes. Here, the pure water vapor is expediently kept the sterilization agent 147 in the part of the liquid processing device 1 comprising the gas filter 40 of the gas filter device 41 for a period of at least 30 min. After the holding phase, the cooling phase takes place, in which the part of the liquid processing device 1 comprising the gas filter 40 of the gas filter device 41 cools down to ambient temperature. Subsequently, the remaining part of the liquid processing device 1 comprising the two sterilization filters 9 is sterilized. The corresponding process flow diagram of the first embodiment of the liquid processing device 1 for the remaining part of the liquid processing device 1 comprising the two sterilization filters 9 is represented in Fig. 7.

[0111] Via the sterilization agent inlet 89, the sterilization agent 147 flows through the line segments 92, 19a, 19b, 19c, 24a, 24b, 24c, 29, 43, 45, 47, 49, 67a, 69, 71, 80a, 80b, 80c, 94, 98, 102, 108, 111, 117, 121, 122, 124, 126, 127, 133 and 156 to the second drainage manifold 99 as well as the relevant valves 15, 16, 17, 21, 22, 27, 42, 46, 66, 78, 79, 90, 95, 103, 109, 115, 123, 125, 131 and 143. In addition, the two sterilization filters 9a, 9b of the sterilization filter devices 10a, 10b are also sterilized by the sterilization agent 147. The two sampling devices 25 and 30 are also sterilized. The sterilization agent 147 is expediently pure steam at a temperature of at least 121 °C. To measure the temperature of the sterilization agent 147, the line segment 133 has the sensor 135 configured as a temperature measuring sensor 134.

[0112] The sterilization for the part of the liquid processing device 1 comprising the two sterilization filters 9 with the sterilization agent 147 in process step d) preferably lasts for a period of at least 30 min. The sterilization comprises a first heating phase, a draining phase, a second heating phase, a stabilization phase, a holding phase and a cooling phase.

[0113] Each heating phase lasts between 5 minutes and 15 minutes, whereby the duration should not exceed 10 minutes. The heating phase is completed when the temperature measuring sensors 101, 105, 112, 118 and 128 constantly indicate a temperature of at least 121 °C. After the first heating phase, an emptying phase takes place, whereby the condensation traps 107, 114, 120, 130 and 136 installed downstream of the sensors 100, 106, 113, 119, 129 are used for this purpose. The sterilization agent 147 is condensed in the condensation traps 107, 114, 120, 130 and 136 and then discharged into the second drainage manifold 99. The emptying phase lasts between 1 min and 5 min. This is followed by the second heating phase, which proceeds in the same way as the first heating phase. After the second heating phase, a stabilization phase takes place, which lasts between 1 min and 5 min. This is followed by a holding phase lasting at least 30 minutes. Here, the pure water vapor is expediently held as sterilization agent 147 over the period of at least 30 min in the part of the liquid processing device 1 comprising the two sterilization filters 9. After the holding phase, the cooling phase takes place, in which the part of the liquid processing device 1 comprising the two sterilization filters 9 is cooled down to ambient temperature.

[0114] After process step d), process step e) is preferably carried out, namely a second integrity test of the sterilization filter device 10, in this case of the two sterilization filter devices 10a and 10b. Process step e) performs an integrity test after sterilization, which is also referred to as a "post-sterilization" integrity test. The "post-sterilization" integrity test carried out in process step e) is performed in the same way as the first "pre-use" integrity test already described.

[0115] After the "post-sterilization" integrity test in process step e), in process step f) the sterilization of liquids 2, which in particular cannot be sterilized in their final container, is carried out by means of the liquid processing device 1. The relevant process flow diagram of the first embodiment of the liquid processing device 1 for a sterilization of liquids 2, which in particular cannot be sterilized in their final container, by means of the liquid processing device 1 is shown in Fig. 8. Process step f) is also referred to as the production step.

[0116] In the production step, the liquid container 3 containing the liquid 2 to be sterilized is connected to valve 15. From there, the liquid 2 to be sterilized flows through the line segments 19a, 19b and 19c into the first sterilization filter 9a and therein through the membrane filter 14a. From the permeate outlet 13a, the permeate 26 then flows via the line segments 24a, 24b and 24c into the second sterilization filter 9b and therein through the membrane filter 14b. The permeate 31 then flows via the line segment 29 into the filling device 5 connected to valve 27, where the sterilized permeate 31 is filled. Furthermore, the gas filter path 53 is supplied with gas 50, in particular compressed air 51, via the gas inlet 52. The gas 50 is present at the valves 17, 21 and 27 in order to flush the sterilization path 8 with gas 50 after the permeate 31 has been filled and to convey the liquid 2 to be sterilized completely through the two sterilization filter devices 10a, 10b to the filling device 5.

[0117] After process step f), process step g) is preferably carried out, namely a third integrity test of the sterilization filter device 10, in this case of the two sterilization filter devices 10a and 10b. Process step g) carries out an integrity test after the production step, which is also referred to as a "post-use" integrity test. The "post-use" integrity test carried out in process step g) is analogous to the first "pre-use" integrity test or second "poststerilization" integrity test already described.

[0118] According to the preceding description, the method comprises the following method steps, namely a) a cleaning in place of the liquid processing device 1, b) a pressure hold test of the liquid processing device 1, c) a first integrity test of the sterilization filter device 10, d) a sterilization of the liquid processing device 1, e) a second integrity test of the sterilization filter device 10, f) a flow of the liquid 2 to be sterilized through the sterilization device 7, and g) a third integrity test of the sterilization filter device 10. Preferably, process steps a) to g) are carried out in the order following letters a) to g).

[0119] Fig. 9 represents a process flow diagram of a second embodiment of the liquid processing device 1. The liquid processing device 1 has a plurality of sterilization devices 7 arranged functionally in parallel, namely two sterilization devices 7.1, 7.2 in the second embodiment, and a plurality of gas filter devices 41 arranged functionally in parallel, namely two gas filter devices 41.1, 41.2 in the second embodiment. The plurality of sterilization devices 7 and gas filter devices 41 arranged functionally in parallel enables quasi-continuous operation of the liquid processing device 1, since - as shown in Fig. 9 - the first sterilization device 7.1 is cleaned, checked for its integrity and sterilized and in the second sterilization device 7.2 the liquid 2 to be sterilized is sterilized while flowing through and the permeate 31.2b is filled into the filling device 5.

Claims

1. Claims1. A method for testing the integrity of a liquid processing device (1) for sterilizing liquids (2), in particular liquids which cannot be sterilized in their final container, comprising a sterilization device (7) comprising a liquid inlet (4) and a liquid outlet (6) which can be fluidica lly connected to a filling device (5), wherein the liquid (2) to be sterilized flows through the sterilization device (7) on a sterilization path (8) extending from the liquid inlet (4) to the liquid outlet (6), and wherein a sterilization filter device (10) comprising at least one sterilization filter (9) is arranged on the sterilization path (8), and with a gas filter device (41) comprising a gas filter (40) and with an integrity evaluation device (72), and wherein the method comprises the following steps: (a) cleaning in place of the liquid processing device (1), b) pressure hold test of the liquid processing device (1), c) first integrity test of the sterilization filter device (10), d) sterilization of the liquid processing device (1), e) second integrity test of the sterilization filter device (10), f) transferring the liquid (2) to be sterilized through the sterilization device (7), and g) third integrity test of the sterilization filter device (10).

2. The method according to claim 1, wherein different cleaning agents (151) are used for the cleaning in place of the liquid processing device (1) according to step a), which flow through the liquid processing device (1) one after the other.

3. The method according to claim 2, wherein purified water (152), alkali solution (153), acid solution (154) and sterile water for injection (155) are used as cleaning agents (151), wherein expediently first the purified water (152), then the alkali solution (153), then the acid solution (154) and then the sterile water for injection (155) flow through the liquid processing device (1).

4. The method according to one of claims 2 or 3, wherein the cleaning agent (151) for cleaning in place of the liquid processing device (1) comprises temperatures in the range from 20 °C to 90 °C.

5. The method according to one of claims 2 to 4, wherein the cleaning agent (151) for the cleaning in place of the liquid processing device (1) comprises an overpressure of 2 bar to the ambient pressure.

6. The method according to one of the preceding claims, wherein the liquid processing device (1) comprises a first conductivity measuring sensor (142), which is expediently arranged in a drainage manifold (97) for the cleaning agent (151), for measuring the electrical conductivity, using which the cleaning in place of the liquid processing device (1) is validated.

7. The method according to claim 6, wherein the electrical conductivity of the cleaning agent (151) is measured with a second conductivity measuring sensor (157) before the cleaning of the liquid processing device (1) and is compared with a measured electrical conductivity of the first conductivity measuring sensor (142), the electrical conductivity of the first and second conductivity measuring sensors (142, 157) being at least within a defined range of measured values at a temperature of 25°C.

8. The method according to claim 7, wherein sterile water is used as the cleaning agent (151) for the injection (155) and, for validating the cleaning in place of the liquid processing device (1), the electrical conductivity of the first and second conductivitymeasuring sensors (142, 157) is in each case in the measured value range of 1.2 to 1.5 pS / cm at a temperature of 25 °C.

9. The method according to one of the preceding claims, wherein the liquid processing device (1) furthermore has a pressure vessel unit (82, 145) which can be connected to the liquid processing device (1), the pressure vessel unit (82, 145) being cleaned in a process step i) preferably in an autoclave (148, 149), the process step i) being carried out in particular before the process step b) or before the process step c).

10. The method according to claim 9, wherein the pressure vessel unit (82, 145) is connected to the liquid processing device (1) before process step b).

11. The method according to claim 9 or 10, wherein different cleaning agents (151) are used for cleaning the pressure vessel unit (82, 145), preferably in the autoclave (148, 149) in process step i), which flow through the pressure vessel unit (82, 145) one after the other.

12. The method according to claim 11, wherein purified water (152), alkali solution (153), acid solution (154) and sterile water for injection (155) are used as cleaning agents (151), wherein expediently first the water (152), then the alkali solution (153), then the acid solution (154) and then the sterile water for injection (155) flow through the pressure vessel unit (82, 145).

13. The method according to claim 11 or 12, wherein the cleaning agent (151) for the cleaning out of place of the liquid processing device (1) comprises temperatures in the range from 20 °C to 90 °C.

14. The method according to one of claims 11 to 13, wherein the cleaning agent (151) for the cleaning out of place of the liquid processing device (1) comprises an overpressure of 2 bar to the ambient pressure.

15. The method according to one of claims 7 to 14, wherein the pressure vessel unit (82, 145) comprises a third conductivity measuring sensor (159) for measuring the electrical conductivity, using which the cleaning of the pressure vessel unit (82, 145) is validated.

16. The method according to claim 15, wherein the electrical conductivity of the cleaning agent (151) is measured by a fourth conductivity measuring sensor (158) before the cleaning of the pressure vessel unit (82, 145) and is compared with a measured electrical conductivity of the third conductivity measuring sensor (159), the electrical conductivity of the first and second conductivity measuring sensors (158, 159) being at least within a defined range of measured values at a temperature of 25°C.

17. The method according to claim 16, wherein sterile water is used as the cleaning agent (151) for the injection (155) and, for validating the cleaning of the pressure vessel unit (82, 145), the electrical conductivity of the third and fourth conductivity measuring sensors (158, 159) is each in the measured value range of 1.2 to 1.5 pS / cm.

18. The method according to one of the preceding claims, wherein the pressure hold test of the liquid processing device (1) is carried out with an overpressure to the ambient pressure of 2 bar, the pressure hold test expediently lasting at least 10 min.

19. The method according to claim 18, wherein the liquid processing device (1) comprises at least one pressure measuring sensor (33, 34, 65) for carrying out the pressure hold test.

20. The method according to any one of the preceding claims, wherein a bubble pressure test is performed for each sterilization filter (9) of the sterilization filter device (10) at each integrity test of the sterilization filter device (10).

21. The method according to any one of the preceding claims, wherein each integrity test is evaluated in the integrity evaluation device (72).

22. The method according to any one of the preceding claims, wherein the sterilization of the liquid processing device (1) is carried out using a sterilization agent (147), wherein pure steam is expediently used as sterilization agent (147).

23. The method according to claim 22, wherein the liquid processing device (1) comprises temperature measuring sensors (101, 205, 128, 114, 118, 134, 138) for measuring a temperature of the sterilization agent (147), wherein a temperature of greater than or equal to 121 °C is expediently used as the temperature of the sterilization agent (147).

24. The method according to claim 22 or 23, wherein the sterilization of the liquid processing device (1) with the sterilization agent (147) in method step d) lasts for a period of at least 30 min.

25. The method according to one of claims 22 to 24, wherein the sterilization of the liquid processing device (1) comprises a first heating phase, a draining phase, a second heating phase and a stabilization phase, a holding phase and a cooling phase26. The method according to claim 25, wherein a heating phase lasts for a period of time between 5 min and 15 min, the period of time expediently not exceeding 10 min.

27. The method according to claim 25 or 26, wherein the emptying phase and / or the stabilization phase lasts for a period of between 1 min and 5 min.

28. The method according to one of claims 25 to 27, wherein the holding phase lasts for a period of at least 30 min.

29. The method according to one of the preceding claims, wherein first the gas filter device (41) and then the sterilization filter device (10) is sterilized or vice versa.

30. The method according to one of the preceding claims, wherein the liquid processing device (1) comprises a liquid preparation device comprising the liquid (2) to besterilized and a filling device (5), wherein before the liquid (2) to be sterilized flows through the sterilization device (7), the liquid preparation device is fluidica lly connected to the liquid inlet (4) and the filling device (5) is fluidica lly connected to the liquid outlet (6).

31. The method according to claim 30, wherein the filling device (5) has sterilized containers into which the liquid (2) flowing through the sterilization device (7) is filled by means of the filling device (5).

32. A liquid processing device (1) comprising a sterilization device (7) with a liquid inlet (4) and a liquid outlet (6) which can be fluidica lly connected to a filling device (5), wherein the liquid (2) to be sterilized flows through the sterilization device (7) on a sterilization path (8) extending from the liquid inlet (4) to the liquid outlet (6), and wherein a sterilization filter device (10) comprising at least one sterilization filter (9) is arranged on the sterilization path (8), and with a gas filter device (41) comprising a gas filter (40) and with an integrity evaluation device (72).

33. The liquid processing device (1) according to claim 32, wherein the liquid processing device (1) has a pressure vessel unit (82, 145) which can be connected to the liquid processing device (1).

34. The liquid processing device (1) according to claim 33, wherein the liquid processing device (1) further comprises an autoclave (148, 149) in which the pressure vessel unit (82, 145) can be cleaned and / or sterilized.

35. The liquid processing device (1) according to one of claims 32 to 34, wherein the liquid processing device (1) comprises a line system (20) comprising line segments which fl uidica I ly interconnects the sterilization device (7), the gas filter device (41), the integrity evaluation device (72) and the pressure vessel unit (82, 145).

36. The liquid processing device (1) according to any one of claims 32 to 35, wherein the liquid processing device (1) comprises a plurality of functionally parallel arrangedsterilization devices (7) and a plurality of functionally parallel arranged gas filter devices (41), wherein expediently the plurality of sterilization devices (7) corresponds to the plurality of gas filter devices (41).

37. The liquid processing device (1) according to claim 36, wherein each liquid inlet (4) has a liquid inlet valve arrangement (186) which is configured to release or close the sterilization device (7) associated with the liquid inlet (4).

38. The liquid processing device (1) according to claim 36 or 37, wherein each liquid outlet (6) has a liquid outlet valve arrangement (187) configured to release or close the sterilization device (7) associated with the liquid outlet (6).

39. The liquid processing device (1) according to any one of claims 36 to 38, wherein each gas inlet (52) comprises a gas inlet valve arrangement (182) comprising a gas inlet valve (183) configured to selectively release or close each gas filter device (41).

40. The liquid processing device (1) according to any one of claims 32 to 39, wherein the liquid processing device (1) is configured to perform the method according to any one of claims 1 to 31.

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