An integrated bioprocessing system for executing several bioprocesses in liquid immunocellular or naive cell cultures.

Abstract

The present invention relates to an integrated bioprocessing system for performing several bioprocesses on a liquid immunocellular cell culture or naive cell culture, wherein the integrated bioprocessing system (1) performs several different bioprocesses by following different protocols, the protocols defining the actions that the integrated bioprocessing system (1) performs on the cell culture for each bioprocess, the integrated bioprocessing system (1) detects at least one state of the cell culture via a sensor (6), the protocols defining the reactions performed by the integrated bioprocessing system (1) when the state of the cell culture deviates from the normal state defined in the protocol, and the integrated bioprocessing system (1) detects at least one state of the integrated bioprocessing system (1), particularly via a sensor (6). It is proposed that the protocols define the reactions performed by the integrated bioprocessing system (1) when the state of the integrated bioprocessing system (1) deviates from the normal state defined in the protocol.

Description

Technical Field

[0001] The present invention relates to an integrated bioprocessing system for performing several bioprocesses on a liquid immune cell culture or a naive cell culture as described in the general part of claim 1, and a method for operating the integrated bioprocessing system as described in the general part of claim 14.

[0002] The term "bioprocess" currently represents a biotechnology process, particularly a biotechnology process involving the use of immune cell cultures or naive cell cultures, especially stem cell cultures. One or more processing steps can be performed on each cell culture. Thus, a bioprocess in this sense can refer to a manufacturing process that includes a series of processing steps performed on a cell culture that ultimately leads to a final product.

[0003] Here, bioprocesses are in the fields of cell therapy and gene therapy for producing autologous T cells modified to express, for example, chimeric antigen receptors (CARs). These cells can be used to treat various types of hematological malignancies, including various types of leukemia (blood cancers). Other cell therapies based on naive cells, especially stem cells and their derivatives, are also of interest.

[0004] In biotechnological processes involving the use of liquid immune cell cultures or naive cell cultures, the starting materials are usually very heterogeneous with respect to their composition, as each donor or patient can be in a different state (e.g., regarding the progression of the disease, genetic constitution or immune system history). Thus, specific steps of the bioprocess need to be flexibly adapted and adjusted to each individual cell culture. Furthermore, each cell culture may respond differently to the specific processing steps applied and require individual adjustments within the processing steps, such as the amount of reagent added or the duration of the incubation step.

[0005] Therefore, depending on the characteristics of the cell culture and the bioprocess being carried out, various parameters, including, for example, the type, sequence, or configuration of processing steps performed for each immune cell culture, need to be adjusted to suit the individual characteristics of the cell culture.

[0006] In the field of bioprocesses for cell and gene therapy involving the allogeneic or in-house production of genetically modified immune cells, compliance with bioprocess regulatory requirements is crucial. Bioprocesses are typically highly regulated and require approval by regulatory authorities.

[0007] To ensure product safety, a quality design approach is typically pursued, which aims to reliably identify, explain, and control all sources of variability affecting the bioprocess by appropriate means. This includes ensuring that all aspects related to the bioprocess are understood and controlled as much as possible. In particular, it is necessary to identify aspects critical to product quality and evaluate their impact on the product, including deviations from their set points. In the resulting design space, deviations must be controlled to maintain compliance of the bioprocess with the approved bioprocess. Therefore, process data, including the types and quantities of materials used, process conditions, and any deviations, must be documented, and appropriate actions must be taken if deviations occur.

[0008] In recent years, integrated bioprocessing systems have been increasingly proposed. Such integrated bioprocessing systems allow for the simultaneous execution of several bioprocesses on different cell cultures, with the processing steps performed being tailored to each cell culture. By providing the integrated bioprocessing system with protocols that include workflows for each bioprocess, the automation of many unit operations becomes possible.

[0009] The known prior art that forms the basis of the present invention (International Publication No. 2017 / 221155A1) relates to an integrated bioprocessing system according to the general part of claim 1.

[0010] Known integrated bioprocessing systems have a control unit that can react to specific states of cell cultures and determine the next steps. When the system is used in a GMP process, the control unit is likely to impose strong limitations on the decisions it can make. Improving known integrated bioprocessing systems to the point where the quality of decisions made, whether by the system or the user, is very high, and where more decisions can be made by the integrated bioprocessing system without requiring user intervention, is a challenge.

[0011] This invention is based on the problem of improving known integrated bioprocessing systems to achieve further optimization with respect to a specified challenge.

[0012] The above-mentioned objective is achieved by the features of the characterization portion of claim 1.

[0013] A system that handles different protocols for different products, typically without necessarily considering bioprocesses, may have responses to some deviations in the manufacturing of the products coded into the protocols. For example, if a product fails quality testing, it may be discarded. Responses to deviations in the system's state, such as malfunctions of transport or functional devices for product manufacturing, are usually handled by the system itself, independently of the protocol. For example, if a transport device that removes products from a manufacturing station fails, the manufacturing station may be shut down to prevent product accumulation.

[0014] The main recognition of this invention is that the above cannot be transferred in a 1:1 ratio to an integrated bioprocessing system. Processing of cell cultures cannot be stopped without knowledge of the outcome of the cell culture. The standard fallback in such cases requires an operator. However, constant operator involvement is inefficient.

[0015] Therefore, the present invention is based on the recognition that the best response to deviations in the state of an integrated bioprocessing system depends on the circumstances within the protocol. For example, if a deviation in O2 control occurs at the start of the cell culture process, transferring to another incubator may be the correct response, but if the cell count is high enough to warrant harvesting, immediate harvesting may be the preferred response.

[0016] Furthermore, for example, if a protocol requires high-density cell proliferation and there is a decrease in O2 control, it may be necessary to respond by transferring cells to another incubator even in response to a small deviation, whereas in the case of a protocol that only performs low-density proliferation, the response may be slower due to the lower oxygen requirement.

[0017] All of these different reactions can respond to the same condition in an integrated bioprocessing system, namely a failure of the O2 control system or incubator. However, the "correct" or preferred reaction depends on the protocol.

[0018] Therefore, it is proposed to include a response to the state of the integrated bioprocessing system in the protocol. The integrated bioprocessing system can then respond to the same deviation in different ways depending on the protocol. Thus, decisions regarding what the integrated bioprocessing system should do may depend on both the monitored cell culture parameters and the state of the integrated bioprocessing system, as well as the progress of the protocol execution and any history of the cell culture, such as past measurements of the integrated bioprocessing system related to the cell culture.

[0019] A further advantage arises from the fact that the state of the cell culture typically lags behind any deviations in the state of the integrated bioprocessing system. For example, if there is a failure in temperature control, the cell count may be normal at the time the failure occurs and may remain normal for some time (e.g., several hours), but with the proposed solution, the integrated bioprocessing system can handle the deviation before the cell culture itself enters an observable deviation state.

[0020] Furthermore, it is difficult to approve the impact on different protocols because the protocol may pass regulatory approval while the integrated bioprocessing system mechanism automatically addresses deviations from the integrated bioprocessing system, and therefore the results cannot be fully known.

[0021] The present invention relates to an integrated bioprocessing system for performing several bioprocesses on a liquid immunocellular cell culture or naive cell culture, wherein the integrated bioprocessing system performs several different bioprocesses by following different protocols, the protocols defining the actions that the integrated bioprocessing system performs on the cell culture for each bioprocess, the integrated bioprocessing system detects at least one state of the cell culture via sensors, the protocols defining the reactions performed by the integrated bioprocessing system if the state of the cell culture deviates from the normal state defined in the protocol, and the integrated bioprocessing system detects at least one state of the integrated bioprocessing system in particular via sensors.

[0022] The term “state of the integrated bioprocessing system” should be understood to include any functional, physical, and / or software state of the integrated bioprocessing system that is not measured as the state of the cell culture. Any measurement that directly targets the cell culture, such as a temperature measurement in direct proximity to the cell culture by a temperature sensor attached to a receptacle that houses and moves with the cell culture, is not a measurement of the state of the integrated bioprocessing system. For example, a general temperature measurement of an incubation chamber that indicates the incubation chamber is defective and, at the same time, affects the cell culture with a certain delay, is a measurement of the state of the integrated bioprocessing system. Any state that is inseparable from the state of the cell culture and the integrated bioprocessing system is, by definition, the state of the cell culture and not the state of the integrated bioprocessing system. Here, preferably, the state of the integrated bioprocessing system is detected by a sensor.

[0023] More specifically, it is proposed that the protocol defines the reactions performed by the integrated bioprocessing system when the state of the integrated bioprocessing system deviates from the normal state defined in the protocol.

[0024] In the highly preferred embodiment described in claim 2, at least one protocol covers the entire measurement space of the sensor. Preferably, this applies to multiple or all sensors. Thus, it does not cover only individual states or specific trigger events of the integrated bioprocessing system.

[0025] As described in the above O2 control example (Claim 3), the protocol or the progress of the operation may affect the reaction.

[0026] Claim 4 clarifies that different protocols may include different responses to the same state of an integrated bioprocessing system.

[0027] The embodiment according to claim 5 relates to partitioning the measurement space of the sensor so as to cover the entire measurement space. Some partitions may be linked to the user action according to claim 6.

[0028] In a preferred embodiment according to claim 7, the user action can be saved. Also, the partition may be adaptable by the integrated bioprocessing system by learning from the user action. The saved data or the automatic adaptation makes it possible to improve the protocol over time.

[0029] Claim 8 states that the state of the integrated bioprocessing system may or may not be linked to the cell culture. Claims 9 and 10 provide preferred embodiments of such states.

[0030] In a preferred embodiment according to claim 11, the entire measurement space of the integrated bioprocessing system can be covered and the protocol can be made the main or only source of response to deviations. The complexity of this solution can be managed by first mapping all or almost all states of the new protocol to user intervention and then improving the protocol over time.

[0031] According to claim 12, in case of a deviation of the integrated bioprocessing system, the integrated bioprocessing system may react before this deviation has a significant impact on the cell culture.

[0032] In a preferred embodiment according to claim 13, if the deviation concerns a plurality of cell cultures that may be following different protocols, the integrated bioprocessing system prioritizes the response. For example, if the transport mechanism fails, all cell cultures may be affected. Some may require immediate care, while others may be able to stay in an incubator, etc. without problems for several days.

[0033] Equally important, another teaching described in claim 14 relates to a method for operating an integrated bioprocessing system.

[0034] Here, it is essential that the protocol defines the reactions that the integrated bioprocessing system will perform if the state of the integrated bioprocessing system deviates from the normal state defined in the protocol.

[0035] All explanations given regarding the proposed integrated bioprocessing system are fully applicable.

[0036] Claim 15 relates to a method for adapting a protocol over time.

[0037] Embodiments of the present invention will be described below with reference to the drawings. [Brief explanation of the drawing]

[0038] [Figure 1] This diagram shows an integrated bioprocessing system that performs several bioprocesses on cell cultures. [Figure 2] This is a snapshot showing the tests for deviations and possible responses.

[0039] The integrated bioprocessing system 1 shown in the figure is preferably adapted to perform a bioprocess for the production of genetically modified T cells. Here, the T cells are genetically modified to express a chimeric antigen receptor (CAR). Thus, the term "CAR-T cells" refers to T cells that have been genetically modified to express a CAR. The genetically modified CAR-T cells, the product of the bioprocess, can be administered to a patient and used to initiate or restart cancer treatment in the patient. As the bioprocess is carried out, the initial immune cell cultures are processed gradually. All the descriptions given are primarily directed towards such bioprocesses. However, it can be pointed out that these descriptions are also quite applicable to other bioprocesses.

[0040] The term "liquid immune cell culture" should be understood broadly, referring to an immune cell culture containing at least one type of immune cell suspended as particles in any type of liquid. As described below, a liquid immune cell culture may contain other cell types that are not immune cells. Therefore, the term "liquid immune cell culture" refers to a liquid immune cell culture at any stage in a bioprocess. Consequently, the types and fractions of immune cells present in a liquid immune cell culture change as certain immune cells are enriched or depleted from the liquid immune cell culture and / or as immune cells are genetically modified during the bioprocess applied.

[0041] The term "immune cells" generally refers to different types of white blood cells. Therefore, the term "immune cells" includes various cells, such as, but not limited to, dendritic cells, T lymphocytes (also called T cells), B lymphocytes, natural killer cells, macrophages, etc. Immune cells may also include subtypes of immune cells, such as tumor-infiltrating lymphocytes or different types of T cells. A specific type of immune cell subtype can be classified based on the type of antigen present on the cell surface. Therefore, the term "immune cells" may refer, for example, to T cells containing the surface antigen CD4 ("CD4+ T cells"). Typically, a specific type of immune cell, such as T cells, preferably a specific subtype of immune cell, such as CD4+ T cells, is selectively enriched by the bioprocess, while other immune cells, such as macrophages, and / or other cell types that are not immune cells, such as red blood cells, and / or other subtypes of immune cells, such as CD8+ T cells, are depleted from the liquid immune cell culture. The enriched immune cells are called targeted immune cells, and all other components that are depleted from the liquid immune cell culture are called "impurities." Furthermore, as mentioned above, target immune cells can be genetically modified.

[0042] The term "naive cell" refers to cells that can still differentiate into different target cell types. In particular, stem cells and their derivatives before they have fully differentiated into a specific cell type are naive cells. The term also includes naive immune cells.

[0043] The term "liquid" should also be understood in a broad sense, referring to any liquid and / or particulate liquid processed within the integrated bioprocessing system 1. Therefore, the term "liquid" may refer to culture media, waste, liquid immune cell cultures, by-products obtained during bioprocessing, samples and / or initial immune cell cultures.

[0044] Preferably, the initial immune cell culture is obtained by a process called "leukocyte apheresis," in which immune cells are obtained from the patient. Additionally or alternatively, the initial immune cell culture may also be obtained from the patient's tissue. The initial immune cell culture may also be obtained from one or more non-patient donors.

[0045] Depending on the origin of the initial cell culture and the bioprocesses performed, the initial cell culture, particularly the type, quantity, and distribution of impurities, as well as the target immune cells or naive cells, can vary.

[0046] Currently, any initial immune cell culture used in a bioprocess is preferably used for only one patient, preferably the patient from whom the cell culture first arose, or for a small number of patients, e.g., up to 10 patients. Otherwise, the bioprocess described currently yields only cell cultures for a single patient or a small number of patients, and cell cultures for other patients are derived from different bioprocesses. Therefore, the proposed integrated bioprocessing system 1 is used to parallelize small-scale bioprocesses, where preferably, the bioprocesses are carried out in accordance with GMP.

[0047] An integrated bioprocessing system 1 is proposed for carrying out several bioprocesses on liquid immunocellular cell cultures or naive cell cultures. The integrated bioprocessing system 1 carries out bioprocesses by controlling several components of the integrated bioprocessing system 1 to perform several unit operations. The integrated bioprocessing system 1 may include a transport mechanism 2 for transporting cell cultures between different stations for unit operations. Here, the integrated bioprocessing system 1 preferably maintains the cell cultures in a sealed environment, one per cell culture. The sealed environment can be adapted throughout the bioprocessing process, for example, by tube welding. Therefore, it is not necessary to sterilize the entire system or use a cleanroom for the integrated bioprocessing system 1. Here, preferably, the integrated bioprocessing system 1 includes a first interface 3 through which cell cultures can enter the integrated bioprocessing system 1 and / or a second interface 4 through which cell cultures can exit the integrated bioprocessing system 1. The integrated bioprocessing system 1 transports cell cultures from a first interface 3 to at least one, preferably more, locations where unit operations are performed, preferably then to a second interface 4. Here, preferably, no user intervention is required, planned, or performed between the first and second interfaces 4 during normal operation. The integrated bioprocessing system 1 may include an enclosure 5 that functionally protects the space between the interfaces from user intervention during normal operation. The first and second interfaces 4 may be the same interface.

[0048] Unit operations are fundamental process steps for achieving specific physical and / or chemical changes in a cell culture. Common examples of unit operations include enrichment, selection, activation, and genetic modification.

[0049] The integrated bioprocessing system 1 performs several different bioprocesses by following different protocols. Exemplarily, the protocols can describe all steps from the cell culture entering the integrated bioprocessing system 1 to the cell culture leaving the integrated bioprocessing system 1.

[0050] The protocol defines the actions that the integrated bioprocessing system 1 performs on cell cultures for each bioprocess. The protocol can also describe further actions, such as transport actions and actions on additional media. Actions may include unit actions, transport actions, etc.

[0051] The integrated bioprocessing system 1 detects at least one state of a cell culture via a sensor 6. The integrated bioprocessing system 1 may include a sensor 6 for detecting the state of the cell culture. The integrated bioprocessing system 1 may include a mechanism for taking a sample from the cell culture and analyzing the sample.

[0052] The protocol defines the reactions that the integrated bioprocessing system 1 will perform if the state of the cell culture deviates from the normal state defined in the protocol. For example, if the cell count is too low at a certain point in time, further incubation may be performed.

[0053] The integrated bioprocessing system 1 further detects at least one state of the integrated bioprocessing system 1, particularly via the sensor 6.

[0054] The state of a cell culture may include parameters of the cell culture, such as cell count, cell size distribution, cell culture viability, cell culture temperature, and cell culture density. These parameters may also include measurements of the culture medium containing the cells and / or the medium removed from the cell culture.

[0055] The states of the integrated bioprocessing system 1 may include conditions such as a malfunction of the transport mechanism 2, a complete failure of the external power supply, a malfunction of the incubator, or a shortage of supplies. Preferably, at least one of the states of the integrated bioprocessing system 1 is not temperature.

[0056] It is essential that the protocol defines the reactions performed by the integrated bioprocessing system 1 when the state of the integrated bioprocessing system 1 deviates from the normal state defined in the protocol.

[0057] A reaction is an action that occurs in response to a deviation. A normal state does not need to be explicitly declared as such. The protocol pathway resulting from a deviation leads to either a non-reaction, unsuccessful completion of the bioprocess, or otherwise a suboptimal outcome.

[0058] Figure 1 shows the integrated bioprocessing system 1. As an example, two bioprocesses being performed are shown in enlarged views. In detail, the enlarged views show cartridges 7 containing cell cultures on which unit operations are being performed, connected to two receptacles 8 for transporting culture media and / or cell cultures through the integrated bioprocessing system 1. If no deviations are present, both protocols proceed along the normal pathway 9 in line with normal conditions.

[0059] Figure 2 shows a snapshot over time, including the determination of two bioprocesses. From left to right, Figure 2 shows that at a given point in time, the integrated bioprocessing system 1 analyzes the readings of sensor 6. The dotted lines represent the cell culture state line and the integrated bioprocessing system 1 state line. For example, the integrated bioprocessing system 1 tests for a first deviation 10 in the protocol of the first bioprocess of the two bioprocesses and a second deviation 11 in the protocol of the second bioprocess of the two bioprocesses. If only one deviation is present, the integrated bioprocessing system 1 performs either the reaction of the first protocol 12 or the reaction of the second protocol 13.

[0060] However, if there are deviations in both protocols, and for example both deviations cannot be processed simultaneously, the integrated bioprocessing system 1 enters a prioritization routine 14 and prioritizes the deviations based on information from the protocols.

[0061] Here, preferably, at least one protocol, and more particularly multiple protocols, define the response of the integrated bioprocessing system 1 to at least one sensor 6, and more particularly to a portion, and more particularly to the whole, of the measurement space of multiple sensors 6 per protocol. The measurement space of sensor 6 includes all possible values ​​of sensor 6. However, the measurement space may be limited to values ​​that can actually occur. For example, the measurement space of temperature sensor 6 does not need to include 0K or 5000K. By defining the measurement space of multiple sensors 6 in the protocol, many states of the integrated bioprocessing system 1 can be handled. Sensor 6 can include hardware and / or software sensors 6. Here, the sensor 6 that detects the state of the integrated bioprocessing system 1 preferably includes or is a sensor 6 permanently connected to the integrated bioprocessing system 1.

[0062] Here, preferably, at least one sensor 6, and in particular, the plurality of sensors 6 per protocol, detect one or more states of the integrated bioprocessing system 1. Generally, whenever a sensor 6 is referred to herein, unless otherwise specified, it is preferably a sensor 6 that detects the state of the integrated bioprocessing system 1. Generally, whenever the term "at least one" is referred to, this term may be replaced with "at least two" or "at least three" in preferred embodiments.

[0063] Furthermore, at least one protocol may define different responses to the same state of the integrated bioprocessing system 1 depending on the progress of the protocol. For example, a failure of transport mechanism 2 may be handled differently depending on whether the cell culture is currently being transported, must be transported immediately, or does not need to be transported within the next day.

[0064] Preferably, at least one protocol defines different responses to the same state of the integrated bioprocessing system 1 as the protocol progresses. For example, if incubation has just started or is about to end, a failure of the transport mechanism 2 may be handled differently during the incubation operation.

[0065] Therefore, in a preferred embodiment, different protocols may define different responses to the same state of the integrated bioprocessing system 1, preferably under the same circumstances, and more preferably even when all other conditions are equivalent. For example, two protocols for immunotherapy using similar cell cultures in the same incubator at the same point in time during the protocol, entering the incubator at approximately the same time, remaining in the incubator for approximately the same period, and even performing the same operations during the protocol, may define different responses to incubator failure. Thus, different protocols may also define different responses to the same state of the integrated bioprocessing system 1 during the same type of operation.

[0066] In a preferred embodiment, it is proposed that at least one measurement space of sensor 6 and / or multiple measurement spaces of sensor 6 be partitioned into at least two, preferably at least three, more preferably at least four different partitions having different reactions. Partitioning the measurement spaces is a particularly easy way to handle the measurement spaces. For example, the temperature of a cell culture may need to be maintained between 35°C and 38°C according to a protocol. This may be a normal partition. Furthermore, partitions between 34°C and 35°C and between 38°C and 40°C may have relevant reactions performed by the integrated bioprocessing system 1, such as emergency cooling or heating. The remaining measurement spaces may have partitions having relevant reactions that may highlight the cell culture in the integrated bioprocessing system 1 or immediately alert the operator via a critical emergency routine, such as draining the cell culture from the integrated bioprocessing system 1 via an emergency interface.

[0067] Preferably, the measurement space of one identical sensor 6 is partitioned into different partitions with different protocols, and / or depending on the progress of the protocols and / or depending on the progress of the protocol's operation. As described, the protocol partitions can change over time to better adapt the protocols to different possible states. Over time, the protocols can include various responses to different possible states, reducing the need for user intervention.

[0068] According to one embodiment, it is proposed that at least one response of one partition includes notification to the user, and / or at least one response of one partition does not include notification to the user.

[0069] After notifying the user, the integrated bioprocessing system 1 can receive a reaction to be performed directly or indirectly from the user. The integrated bioprocessing system 1 performs the reaction and stores the received reaction in relation to the template and the state of the integrated bioprocessing system 1 that led to the notification to the user. The stored information can later be displayed to the user or used for analysis. The integrated bioprocessing system 1 can additionally or alternatively adapt the template based on the received reaction, particularly to ensure that the same state does not lead to a notification to the user in the future.

[0070] The integrated bioprocessing system 1 may include a state in which at least one state is indirectly linked to the state of a cell culture, and / or a state in which at least one state of the integrated bioprocessing system 1 is not linked to the state of a cell culture.

[0071] One or more states of an integrated bioprocessing system 1 indirectly linked to a cell culture may include energy input to the cell culture, particularly heating or cooling energy to the cell culture, and / or volume or mass input, particularly gas flow rate and / or base and / or ammonium addition rate. The term "indirectly linked" means that the states generally affect the biological state of the cell culture by being states that describe, in particular, the provision of culture medium or energy.

[0072] One or more states of the integrated bioprocessing system 1 not linked to a cell culture include the state of the transport mechanism 2 of the integrated bioprocessing system 1, in particular availability, and / or the presence of a predefined receptacle 8, in particular without a cell culture, and / or consumables at a predefined location, and / or the state of the integrated bioprocessing operation station 15 used to carry out bioprocesses according to a template.

[0073] In summary, the state of a cell culture may include one or more of the following: cell density compared to a known trajectory, cell type distribution compared to a desired distribution, cell characteristic distribution, in particular the proportion of genetically modified cells, pH value, dissolved oxygen value, oxygen renewal rate, oxygen uptake rate, glucose concentration, carbon dioxide concentration, carbon dioxide evolution rate, cell viability, enzyme activity, lactate concentration, and / or ammonium ion concentration.

[0074] The indirectly connected state may include one or more of the following: oxygen supplied to the cell culture, heat supplied to the cell culture, energy supplied to the cell culture, or volume supplied to the cell culture. Preferably, the indirectly connected state has a time lag between the change in the state of the integrated bioprocessing system 1 and the state of the cell culture. The time lag may be specified in the protocol.

[0075] An unconnected state could include a state in which a part of the integrated bioprocessing system 1 that is not currently affecting the cell culture is notified of a defect in the transport mechanism 2 for transporting the cell culture to the next station, in this case the transport robot.

[0076] According to one embodiment, in at least one protocol, the entire measurement space of all sensors 6 of the integrated bioprocessing system 1 that detect the state of the cell culture is assigned to the protocol, preferably the entire measurement space of all sensors 6 of the integrated bioprocessing system 1 that detect the state of the integrated bioprocessing system 1 is linked to the state of the cell culture, and more preferably the entire measurement space of all sensors 6 of the integrated bioprocessing system 1 that detect the state of the integrated bioprocessing system 1 related to the execution of the protocol is covered by the protocol. States of parts not used in the protocol do not need to be covered if the protocol can be executed independently of those states.

[0077] If the state of the integrated bioprocessing system 1 deviates from the normal state defined in the protocol, the response should preferably be carried out before the deviation results in a deviation in the state of the cell culture. The lag described above can be used to protect the cell culture in the event of a system deviation. Where the lag and the question of how quickly the deviation significantly affects the cell culture may depend on the protocol, the proposed solution can protect the cell culture proactively. Preferably, the response is carried out before the deviation results in any change in the state of the cell culture.

[0078] According to one embodiment, if a change in the state of the integrated bioprocessing system 1 affects multiple cell cultures, it is proposed that the integrated bioprocessing system 1 derives prioritization of reactions in the protocol from the cell culture protocols and executes the reactions according to the prioritization. This embodiment is shown in Figure 2 as described above. For example, if an incubator containing several cell cultures malfunctions, some cell cultures may require immediate attention, while others may be able to be maintained in the incubator for a long period without further means. The integrated bioprocessing system 1 can then determine, for example, the order in which to transfer the cell cultures from the incubator based on prioritization. Prioritization may be based on the time lag between the change in the state of the integrated bioprocessing system and the change in the state of the cell cultures of different protocols.

[0079] Another equally important teaching relates to a method for operating an integrated bioprocessing system 1 to perform several bioprocesses on a liquid immunocellular cell culture or naive cell culture, wherein the integrated bioprocessing system 1 performs several different bioprocesses by following different protocols, the protocols defining the actions that the integrated bioprocessing system 1 performs on the cell culture for each bioprocess, the integrated bioprocessing system 1 detects at least one state of the cell culture via a sensor 6, the protocols defining the reactions performed by the integrated bioprocessing system 1 if the state of the cell culture deviates from the normal state defined in the protocol, and the integrated bioprocessing system 1 detects at least one state of the integrated bioprocessing system 1, in particular via a sensor 6.

[0080] According to this further instruction, it is essential that the protocol defines the reactions performed by the integrated bioprocessing system 1 when the state of the integrated bioprocessing system 1 deviates from the normal state defined in the protocol.

[0081] All descriptions given with respect to the proposed integrated bioprocessing system 1 are fully applicable.

[0082] According to one embodiment, it is proposed that at least one protocol be adapted over time so that the number of compartments increases and / or the reactions within the compartments change, particularly so that the number of compartments requiring user notification decreases, preferably the protocol is adapted at least partially automatically, and / or the integrated bioprocessing system 1 stores information about user actions in relation to protocols requiring user action, and the stored information is output to the user to adapt the protocol.

[0083] The changes can take two distinct forms: on the one hand, the response of the integrated bioprocessing system 1 may be more finely segmented, i.e., the measurement space may be increasingly progressively sorted into better harmonized responses; on the other hand, the response of the integrated bioprocessing system 1 to a particular state may be updated, for example, if there is evidence that there is a better way to recover from deviation than the method of the protocol. One or both types of changes may be implemented.

Claims

1. An integrated bioprocessing system for performing several bioprocesses on a liquid immunocellular cell culture or naive cell culture, wherein the integrated bioprocessing system (1) performs several different bioprocesses by following different protocols, and the protocols define the actions that the integrated bioprocessing system (1) performs on the cell culture for each of the bioprocesses. The integrated bioprocessing system (1) detects at least one state of the cell culture via the sensor (6), The protocol defines a reaction to be performed by the integrated bioprocessing system (1) if the state of the cell culture deviates from the normal state defined in the protocol. The integrated bioprocessing system (1) detects at least one state of the integrated bioprocessing system (1) in particular via the sensor (6), The protocol defines the reactions to be performed by the integrated bioprocessing system (1) when the state of the integrated bioprocessing system (1) deviates from the normal state defined in the protocol. An integrated bioprocessing system characterized by [features].

2. The integrated bioprocessing system according to claim 1, wherein at least one protocol, in particular multiple protocols, defines the response of the integrated bioprocessing system (1) to a portion, in particular the whole, of the measurement space of at least one sensor (6), in particular multiple sensors (6) per protocol, preferably the at least one sensor (6), in particular the multiple sensors (6) per protocol, detects one or more states of the integrated bioprocessing system (1).

3. The integrated bioprocessing system according to claim 1 or 2, characterized in that at least one protocol defines the response of the integrated bioprocessing system (1) to the same state in a different manner as the protocol progresses, preferably at least one protocol defines the response of the integrated bioprocessing system (1) to the same state in a different manner as the operation of the protocol progresses.

4. An integrated bioprocessing system according to any one of claims 1 to 3, characterized in that different protocols define different responses to the same state of the integrated bioprocessing system (1), preferably, that different protocols define different responses to the same state of the integrated bioprocessing system (1) during the same type of operation.

5. An integrated bioprocessing system according to any one of claims 2 to 4, characterized in that the measurement space of at least one of the sensors (6) and / or the measurement spaces of a plurality of sensors (6) are partitioned into at least two, preferably at least three, more preferably at least four different partitions having different reactions, preferably the measurement space of one same sensor (6) is partitioned into different partitions in different protocols and / or in accordance with the progress of the protocols and / or in accordance with the progress of the operation of the protocols.

6. An integrated bioprocessing system according to any one of claims 1 to 5, characterized in that at least one reaction of one compartment includes notification to the user, and / or at least one reaction of one compartment does not include notification to the user.

7. The integrated bioprocessing system according to claim 6, characterized in that the integrated bioprocessing system (1) receives a response to be performed after notifying the user, the integrated bioprocessing system (1) performs the response, the integrated bioprocessing system (1) stores the received response in relation to the template and the state of the integrated bioprocessing system (1) that brought about the notification to the user, and / or the integrated bioprocessing system (1) adapts the template based on the received response, in particular so that the same state does not bring about a notification to the user in the future.

8. The integrated bioprocessing system according to any one of claims 1 to 7, characterized in that at least one state of the integrated bioprocessing system (1) includes a state indirectly linked to the state of the cell culture, and / or at least one state of the integrated bioprocessing system (1) includes a state not linked to the state of the cell culture.

9. The integrated bioprocessing system according to claim 8, characterized in that one or more states of the integrated bioprocessing system (1) indirectly connected to the cell culture include energy input to the cell culture, particularly heating or cooling energy to the cell culture, and / or volume or mass input, particularly gas flow rate.

10. The integrated bioprocessing system according to claim 8 or 9, characterized in that one or more states of the integrated bioprocessing system (1) not connected to the cell culture include the state of the transport mechanism (2) of the integrated bioprocessing system (1), in particular usefulness, and / or the presence of a particularly predefined receptacle (8) that does not contain the cell culture, and / or consumables at a particularly predefined location, and / or the state of the operating station (15) of the integrated bioprocessing used to carry out the bioprocess according to the template.

11. An integrated bioprocessing system according to any one of claims 1 to 10, characterized in that in at least one protocol, the entire measurement space of all sensors (6) of the integrated bioprocessing system (1) for detecting the state of the cell culture is assigned to the protocol, preferably the entire measurement space of all sensors (6) of the integrated bioprocessing system (1) for detecting the state of the integrated bioprocessing system (1) is linked to the state of the cell culture, and more preferably the entire measurement space of all sensors (6) of the integrated bioprocessing system (1) for detecting the state of the integrated bioprocessing system (1) related to the execution of the protocol is covered by the protocol.

12. The integrated bioprocessing system according to any one of claims 1 to 11, characterized in that the reaction when the state of the integrated bioprocessing system (1) deviates from the normal state defined in the protocol occurs before the deviation results in a deviation from the state of the cell culture, preferably before the deviation results in any change in the state of the cell culture.

13. The integrated bioprocessing system according to any one of claims 1 to 12, characterized in that, when a change in the state of the integrated bioprocessing system (1) affects multiple cell cultures, the integrated bioprocessing system (1) derives a priority order for the reactions in the protocol from the protocol for the cell cultures and executes the reactions according to the priority order.

14. A method for operating an integrated bioprocessing system (1) for performing several bioprocesses on a liquid immunocellular cell culture or naive cell culture, wherein the integrated bioprocessing system (1) performs several different bioprocesses by following different protocols, the protocols define the actions that the integrated bioprocessing system (1) performs on the cell culture for each of the bioprocesses, The integrated bioprocessing system (1) detects at least one state of the cell culture via the sensor (6), The protocol defines a reaction to be performed by the integrated bioprocessing system (1) if the state of the cell culture deviates from the normal state defined in the protocol. The integrated bioprocessing system (1) detects at least one state of the integrated bioprocessing system (1) in particular via the sensor (6), The protocol defines the reactions to be performed by the integrated bioprocessing system (1) when the state of the integrated bioprocessing system (1) deviates from the normal state defined in the protocol. A method characterized by the following.

15. The method according to claim 14, characterized in that at least one protocol is adapted over time so that the number of compartments increases and / or the reactions within the compartments change, in particular so that the number of compartments requiring user notification decreases, preferably the protocol is adapted at least partially automatically, and / or the integrated bioprocessing system (1) stores information about user actions in relation to the protocol requiring the user action, and the stored information is output to the user in order to adapt the protocol.

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