Method for carrying out a bioprocess

Abstract

The invention relates to a method for conducting a bioprocess with a digital control unit (1) of a bioprocess device (2), wherein the digital control unit (1) comprises a local data storage (4) and a local processor unit (5), wherein bioprocess data (16) are generated by the digital control unit (1). It is proposed that a documentation routine (22) and a signing routine (24) are executed in a data security routine (21), that documentation data (23) are generated from the bioprocess data (16) in the documentation routine (22), and that a cryptographic private key (25) is extracted from private key data (20) in the signing routine (24) and that the documentation data (23) are digitally signed with the cryptographic private key (25) by generating a digital signature (26), that the documentation routine (22) is executed continuously during the bioprocess, and that the signing routine (24) is executed discontinuously in several signing cycles during the bioprocess according to a signing policy (P) defining a triggering event (e i ) for initiating the signing routine (22).

Description

Technical Field

[0001] The present invention relates to a method for implementing a biological process according to the general part of claim 1, a digital control unit for a biological process apparatus for controlling a biological process according to claim 21, a control system according to claim 22, a data processing system according to claim 23, a computer program product according to claim 24, and a computer-readable storage medium according to claim 25. Background Technology

[0002] The term "bioprocess" currently refers to biotechnology and biopharmaceutical processes that involve the manufacture of desired therapeutic biological products (such as biologics, vaccines, components for cell or gene therapy) or non-therapeutic biological products (such as pigments, biofuels, or nutritional supplements). Such biological products can be manufactured from living cells, or the cells themselves can be biological products, or the biological product can be the result of cell-free manufacturing based on cellular components of natural or non-natural origin.

[0003] "Bioprocess apparatus" includes at least one device or a combination of two or more devices involved in a bioprocess, such as a bioreactor, digital control unit (DCU), filtration equipment, chromatographic analysis equipment, centrifuge, freeze dryer, and analytical equipment, which may be disposable or reusable equipment.

[0004] To at least partially automate biological processes, methods for implementing biological processes using digital control units have come into play. An example of such a digital control unit, which serves as the starting point of this invention, is shown in DE1 0237082A1. Known digital control units include all electronic components for controlling biological processes, receiving sensor data, and communicating with a user via a user interface. This allows for the execution of biological process control routines, wherein biological process data is generated to document the real-world execution of the desired biological process.

[0005] The aforementioned bioprocess data is particularly important, for example, if a new drug product undergoes compliance procedures before entering the market. Such compliance procedures typically require proof that the corresponding processes in the bioprocess laboratory conform to predefined rules. This is especially important during clinical trials, due to the quality control standards and administrative measures required by the relevant national drug regulatory agency, such as the FDA, for the approval process of new drugs. However, this involves not only the experimental phase, where documentation of process steps and sensor data is primarily relevant, but also the manufacturing phase, where documentation of process quality plays a crucial role according to GMP standards. GMP, or Good Manufacturing Practice, is the standard required to comply with guidelines recommended by agencies such as the FDA, which control the authorization and licensing of the manufacture and sale of pharmaceuticals. These guidelines define minimum manufacturing requirements that must be met to ensure that the corresponding product is of high quality for its intended use. Compliance with GMP standards is overseen globally by regulatory agencies.

[0006] In any of the above situations, the integrity of biological process data is essential. This means that it must be ensured that the biological process data has not been manipulated, whether arbitrarily or unintentionally.

[0007] To ensure the integrity of biological process data, it has been proposed to submit the data in an online calendar and externally sign it using a generally known signing method (US 8,719,576B2). This known concept leaves room for the signing of the corresponding biological process data. This is not only an advantage but also a disadvantage.

[0008] In the aforementioned scenarios, several drawbacks typically arise while ensuring data integrity. The primary drawback is the increased complexity of data acquisition during biological processes and the verification of data integrity by recipients during compliance processes. Signatures must be explicitly initiated during or at the end of a biological process, and the corresponding dataset must be verified using appropriate digital signatures to ensure data integrity during compliance processes. Given that biological process data can be collected over extended periods by various collaborative laboratory units, and that recipients of biological process data can be constructed across multiple recipient units during compliance processes, signing biological process data has become an overall inefficient and complex administrative task. Summary of the Invention

[0009] The object of this invention is to provide an apparatus that allows for increased efficiency in the signature process.

[0010] The above-mentioned problem is solved by the features of the characterizing portion of claim 1 relative to the features of the general portion of claim 1 for carrying out biological processes.

[0011] First, it has been found that during biological processes, signing is completed in several signing cycles based on a predefined signing strategy. The result is that the biological process data in the biological process dataset is segmented, and each segment is signed within its corresponding signing routine. Second, it has been found that this segmentation can be easily adapted to the specific needs of the biological process and / or the receiver, thereby increasing the efficiency of subsequent processing of the biological process data.

[0012] A signature strategy is proposed, which automatically initiates signature routines during each signature cycle. This includes defining triggering events to initiate signature routines, resulting in a particularly simple implementation.

[0013] The digital control unit, which at least partially implements the proposed method, includes a local data storage device and a local processor unit, which are currently considered core components for digital data processing. Parts of the proposed method can be well implemented by external components. Parts of the proposed method, particularly the signature routine, can also be initiated by the digital control unit and possibly executed by external units.

[0014] Throughout this document, "external" means a unit or step located outside of the digital control unit.

[0015] The term "initiation" in relation to a routine means that the execution of the routine begins immediately or with a certain time lag. In any case, the initiation of a routine always leads to the subsequent execution of the routine.

[0016] The digital control unit according to the present invention generates biological process data, which describes the biological processes as will be explained. This biological process data forms the basis for the documentation required for the aforementioned compliance processes.

[0017] In detail, the private key data is stored in the digital control unit or any other unit, such as an external signature unit, which forms the basis for executing the data security routine. The local processor unit can at least initiate this data security routine, so that control of the entire data security routine remains within the local processor unit.

[0018] Within the data security routines, a documentation routine is executed. This documentation routine generates documentation data from the biological process data. This documentation data undergoes signing, which will be explained below.

[0019] A signature routine is initiated within a data security routine. In this routine, a cryptographic private key is extracted from the private key data. Then, a digital signature is generated, and the document compilation data is digitally signed using the cryptographic private key. In short, the signature routine performs a digital signature of the document compilation data based on asymmetric cryptography, which is well-known in the art. By utilizing the signature routine executed within a trusted unit, a high level of security regarding data integrity can be achieved, in this case, with regard to the signature routine itself.

[0020] If the private key data includes a cryptographic key or is even the same as the cryptographic private key, then extracting the cryptographic private key from the private key data, as mentioned above, is particularly simple. However, extraction can be more complex. For example, the cryptographic private key can be derived from the private key data based on unpredictable random numbers.

[0021] Because data security routines can be designed to require minimal data processing to generate documentation data, the proposed solution can be implemented using a wide variety of existing digital control units without adding any additional hardware. This not only offers a cost advantage but also facilitates the integration of the proposed solution into existing laboratories.

[0022] To achieve the proposed solution, a documentation routine is executed continuously during the biological process, and a signing routine is executed discontinuously during the biological process in several signing cycles according to a signing policy that defines triggering events for initiating the signing routine.

[0023] The statement "continuously" regarding the documentation routine means that the documentation routine continuously generates biological process data after it is initiated. The statement "discontinuously" regarding the signature routine means that the digital signature is generated only when the aforementioned triggering event occurs.

[0024] According to a preferred embodiment of claim 2, the digital control unit further includes a bioprocess interface for sending and receiving bioprocess control data, the bioprocess interface including an actuator interface for sending actuator data to at least one actuator to influence the bioprocess and a sensor interface for receiving sensor data related to the bioprocess from at least one sensor. For example, a stirrer or valve can be such an actuator, and the associated corresponding actuator data can be a stirring frequency in revolutions per minute (rpm) or a fluid flow rate in milliliters per minute (mL / min). Exemplary sensors can be biomass sensors, pH sensors, or oxygen sensors reflecting the corresponding data. According to this embodiment, the digital control unit also includes a user interface for displaying at least a portion of the bioprocess data to a user and for receiving user control command data. Especially during the experimental phase, the user interface provides the user with the possibility of influencing the bioprocess during both the experimental development and manufacturing phases. Common exemplary parameters set by the user are stirring speed, temperature, pH, oxygen saturation, etc.

[0025] According to another preferred embodiment of claim 3, the digital control unit is configured to execute a bioprocess control routine via a local processor unit to control the bioprocess. Here, all automation occurs if necessary. In the bioprocess control routine, the digital control unit receives sensor data from sensors. Additionally, in the bioprocess control routine, the digital control unit generates actuator data based on user control command data and / or sensor data, and controls the actuators by sending the actuator data to the actuators, thereby influencing the bioprocess. This control can derive the actuator data based on simple logical operations between user control command data and / or sensor data. It can also be based on a control loop that derives the actuator data to achieve a certain target value. Finally, it can be based on sequence control, which is typically implemented by software as described below. Thus, the digital control unit can, on the one hand, provide coordination functions for the entire bioprocess, and on the other hand, it can simply be an execution tool executing requests from at least one other control unit.

[0026] In the bioprocess control routine, the digital control unit also generates bioprocess data from actuator data and / or sensor data and / or user control command data.

[0027] Claims 4 to 12 relate to preferred signature strategies that are primarily based on triggering events related to the biological process itself. According to claim 4, at least one triggering event is defined as an event directly related to the biological process. The expression "directly" means that the corresponding triggering event is based on information inherent to the biological process. Examples are changes in biological process steps, biological process stages, and biological process states. Where the triggering event is directly related to the biological process, the probability that the segmentation of the biological process data into the signed biological process dataset will be executed in accordance with the actual manner of subsequent compliance procedures is high.

[0028] According to claims 13 and 14, in the documentation routine, biological process data is divided into data blocks, which are then processed in a hashing step. According to a preferred embodiment, the data blocks are hashed in the form of a tree structure, such as a Merkle tree. The signatures of the documentation data, which may include the complete hash tree structure or may only include the hash root, require minimal data processing in either case, as described above.

[0029] Claim 15 clarifies that, during a biological process, the digital control unit continuously receives sensor data from sensors and also continuously sends actuator data to the actuators within the biological process control routine, thereby influencing the biological process. This allows the biological process control routine to implement control strategies, such as feedback strategies with near real-time control loops.

[0030] As described above, the segmentation of biological process data into biological process datasets is generated by the definition of triggering events. These biological process datasets form the basis of the signature routines according to claims 16 and 17. In claim 17, subsequent biological process datasets are correlated with each other in a predefined manner. This can be an overlap of subsequent biological process datasets or the inclusion of identifiers of corresponding previous biological process datasets. This ensures that no data between two subsequent biological process datasets is omitted in the signature routine.

[0031] The digital signature generated based on the document compilation data can be stored in the local data storage device of the digital control unit. It can also be stored in any other data storage device connected to the digital control unit via a data transmission interface. Both possibilities are the subject of claim 18, illustrating that after the signature routine is executed, unnoticed manipulation of the biological process data as described above is impossible, rendering the storage location of the digital signature ineffective.

[0032] Claims 19 and 20 relate to preferred variations concerning the initiation and execution of signature routines. While the digital control unit initiates and executes the complete signature routine according to claim 19, according to claim 20, the digital control unit only initiates the signature routine to be executed by an external signature unit. In this context, the expression "to be executed" means that the aforementioned initiation is carried out such that the corresponding routine (here, the documentation routine) is executed by the corresponding external unit (here, the documentation unit). For this purpose, in the initiation, a request can be sent, for example, from the initiating unit (here, the local processor unit) to the execution unit (here, the documentation unit) via a data connection.

[0033] In both cases, the digital control unit remains under the control of the signature routine, ensuring that the signature routine can be easily synchronized with the biological process via the aforementioned triggering events.

[0034] According to another teaching of claim 21, the proposed digital control unit is claimed to be configured to perform the methods described above for carrying out biological processes. Reference may be made to all explanations given regarding the proposed methods.

[0035] Another teaching of claim 22, which is equally important, relates to a control system having the proposed digital control unit and an external document preparation unit and / or an external signature unit to perform the proposed method described above. Furthermore, all explanations given regarding the proposed method may be referenced.

[0036] Another teaching of claim 23 relates to a data processing system for implementing the proposed method, and in particular for implementing the corresponding routines. Preferably, the data processing system includes at least a local data storage device and a local processor unit for the digital control unit. All interpretations given regarding the proposed digital control unit are equally applicable to the proposed data processing system.

[0037] According to another teaching of claim 24, which is of equal importance, a computer program product for the proposed data processing system is thus claimed. The computer program product is configured to implement the proposed method, and in particular, to implement the above-described routines. Furthermore, all interpretations given for the proposed method fully apply to the proposed computer program product.

[0038] Another teaching of equal importance to claim 25 thus claims protection for a computer-readable storage medium on which the computer program is stored. Similarly, all interpretations given for the proposed method are fully applicable to the proposed readable storage medium.

[0039] Finally, the proposed bioprocess apparatus will be able to be protected in the following way: The proposed bioprocess apparatus preferably includes a bioreactor and all components and / or equipment for performing the corresponding upstream and downstream treatment stages.

[0040] The upstream processing stage of a bioprocess typically comprises all actions and workflows from the development, optimization, screening, and selection of strains or cell lines to their culture and the manufacture of the desired bioproduct from cells or cell components. This culture can be conducted at various scales (microliters to thousands of liters) using different reactor settings and geometries (rocking motion, stirred tanks, bubble cap towers, fixed beds, etc.) by applying different operating modes (batch, batch feed, continuous, especially perfusion, or combinations thereof). The culture is typically monitored, analyzed, and controlled based on various sensor technologies (soft, electrochemical, biochemical, optical, etc.; offline, online, atline). Typically, after the manufacture of the desired bioproduct, it is purified. Here, the culture medium is separated from the desired bioproduct (e.g., monoclonal antibodies, polyketides, enzymes, vaccines).

[0041] Downstream processing stages of biological processes typically encompass a variety of techniques and methods for the recovery, purification, analysis, and characterization of the desired biological product. These involve methods such as cell disruption, sedimentation, centrifugation, precipitation, crystallization, extraction, filtration, pH and conductivity adjustment of the liquid, enzymatic or chemical modification, dilution, buffer exchange, evaporation, adsorption, and chromatographic analysis. Analytical and characterization steps may be included to ensure the purified biological product meets critical quality attributes (e.g., antibody glycosylation patterns, endotoxin concentrations). Final formulation steps involving buffer exchange, drying, freeze-drying, or crystallization may be performed to bring the purified biological product to a state suitable for storage and distribution before filling and packaging.

[0042] Another preferred variation includes means for performing the upstream process, which is continuously connected to the downstream means.

[0043] All explanations given regarding the proposed process, the proposed digital control unit, the proposed control system, the data processing system, the computer program product, and the computer-readable storage medium are fully applicable to the biological process device. Attached Figure Description

[0044] Embodiments of the present invention will now be explained with reference to the accompanying drawings. The drawings show:

[0045] Figure 1 It is a proposed digital control unit for executing the proposed control system for carrying out the proposed method for biological processes.

[0046] Figure 2 according to Figure 1The working principle of the digital control unit includes biological process control routines and data security routines.

[0047] Figure 3 It is based on Figure 2 An overview of the triggering events based on the preferred signature strategy.

[0048] Figure 4 It is a hash tree structure a) such as in according to Figure 2 The data security routines generated in b) and the corresponding hash tree structure based on manipulated biological process data. Detailed Implementation

[0049] The proposed bioprocess device 2 has a digital control unit 1 for controlling bioprocesses, such as the culture of microorganisms or mammalian cells using a bioreactor 3 and components (not shown) for corresponding upstream and downstream treatments.

[0050] like Figure 1 As shown, the digital control unit 1 includes a local data storage device 4 and a local processor unit 5 for data processing. Units 4 and 5, namely the local data storage device 4 and the local processor unit 5, are implemented as electronic components. It can be noted that the local processor unit 5 preferably includes only one data processor that performs all the functions of the digital control unit 1; however, it can be assumed that the local processor unit 5 includes more than one data processor that interacts with each other to perform all the functions of the digital control unit 1.

[0051] like Figure 1 As shown, the digital control unit 1 includes a bioprocess interface 6 for sending and receiving bioprocess control data. Specifically, the bioprocess interface 6 includes an actuator interface 7 for sending actuator data 8 to at least one actuator 9, 10 to influence the bioprocess. Actuators 9, 10 should be understood as any component that can be controlled to be actuated to influence the bioprocess. In this document and preferably, actuator 9 is a stirrer including an impeller 9a within the bioreactor 3, while actuator 10 is preferably a valve for introducing fluid, preferably nutrient solution, into the bioreactor 3. Other possible actuators are pumps, liquid handling units, heating and / or cooling systems, etc. It can be noted that the bioprocess device 2 may include any number of actuators 9, 10, all of which can be controlled by actuator data 8. Furthermore, the bioprocess device is not limited to upstream equipment.

[0052] The bioprocess interface 6 also includes a sensor interface for receiving sensor data 12 related to the bioprocess from at least one sensor 13, 14, 15. Such sensors 13, 14, 15 can be any sensor related to describing the bioprocess, such as a biomass sensor, pH sensor, or oxygen sensor. The functionality of those sensors can be well provided by soft sensors, also known as “virtual sensors.” Soft sensors derive sensor values ​​from other sensing sources based on a data model. Depending on the application, there are various possibilities for implementing the necessary data processing hardware assigned to the respective soft sensors.

[0053] Sensors 13, 14, and 15, as described above, may have their own sensor interfaces that allow them to connect to the bioprocess interface 6, preferably its sensor interface 11, for transmitting sensor data 12. Depending on their operating principle, sensors 13, 14, and 15 may be connected to the sensor interface 11 of the bioprocess interface 6, for example, via electrical, optical, pneumatic, or hydraulic connections. Figure 1 In the preferred embodiment shown, and by way of example only, electrical connections are illustrated. Again, the bioprocess device 2 may include any number of sensors 13, 14, 15, all of which provide sensor data to the digital control unit 1.

[0054] The digital control unit 1 generates biological process data 16, which describes the biological process and will be described below. The biological process data 16 is added to [the system / system] immediately after its generation. Figure 2 The continuous data stream S shown.

[0055] The digital control unit 1 also includes a user interface 17 for displaying at least a portion of the biological process data 16 to the user and for receiving user control command data 18. These user control command data 18 may be commands to start and stop the biological process and / or to set certain control parameters (such as the stirring speed of the impeller 9a assigned to the actuator 9).

[0056] Furthermore, the digital control unit 1 is configured to execute the biological process control routine 19 via the local processor unit 5 to control the biological process. This also... Figure 2 As shown in the diagram. In the bioprocess control routine 19, the digital control unit 1 receives sensor data 12 from corresponding sensors 13, 14, and 15. In the bioprocess control routine 19, the digital control unit 1 also generates actuator data 8 based on user control command data 18 and / or sensor data 12, and controls actuators 9 and 10 by sending actuator data 8 to actuators 9 and 10, thereby influencing the bioprocess. In the bioprocess control routine 19, the digital control unit 1 generates bioprocess data 16 based on actuator data 8 and / or sensor data 12 and / or user control command data 18.

[0057] The biological process control routine 19 is preferably based on control software running on the local processor unit 5, which can be configured as a sequence program that may include rules for controlling actuators 9, 10, control loops, etc.

[0058] As described above, according to the present invention, data integrity regarding biological process data 16 is ensured by applying asymmetric cryptography, which is preferably controlled by a digital control unit 1 and preferably executed by an external signature unit s. For this purpose, firstly, private key data 20 is stored in a local data storage device 4 or in an external signature unit s. Secondly, the digital control unit 1 is configured to initiate a data security routine 21 via a local processor unit 5. The data security routine 21 relies on security software, which is also preferably running on the local processor unit 5.

[0059] The security routine 21 includes a documentation routine 22. Specifically, the digital control unit 1 is configured to initiate the documentation routine 22 within the data security routine 21 via the local processor unit 5. This documentation routine 22 is executed by either the local processor unit 5 or an external documentation unit d. In this documentation routine 22, documentation data 23 is generated from the biological process data 16 via the local processor unit 5 or the external documentation unit d, and this documentation data 23 is digitally signed.

[0060] The key point of this invention is that the data security routine 21 includes a signature routine 24. Therefore, the digital control unit 1 is preferably configured to initiate the signature routine 24 so that it is preferably executed in the data security routine 21 by an external signature unit s. In the signature routine 24, the external signature unit s extracts a cryptographic private key 25 from the private key data 20 and signs the document compilation data 23 with the cryptographic private key 25 by generating a digital signature 26.

[0061] Documentation routine 22 is executed continuously during the biological process, while signature routine 24 is executed discontinuously during the biological process according to signature policy P, which defines a triggering event e for initiating signature routine 24. i The signature strategy P is in Figure 3 Only the event e is indicated as the triggering event. i The corresponding group. Each triggering event e i This leads to the initiation of signature routine 24. This is in Figure 2 As shown in the image.

[0062] Here, and preferably, the digital control unit 1 has a housing 27, which should be robust against manipulation as described above. Alternatively or supplementary, the digital control unit 1 is a mobile unit that can be moved through the laboratory along with the local processor unit 5 and the local data storage device 4. Alternatively or supplementary, it is assumed that the local processor unit 5 and the local data storage device 4 are here, and preferably, connected to the sensors 13, 14, 15 and / or actuators 9, 10 via cables and / or short-range wireless communication. Again, alternatively or supplementary, the user interface 17 may also include a user display and user input devices, particularly a touchscreen, each of which is located in or on the housing 27 of the digital control unit 1.

[0063] Preferably, the digital signature 26 generated by signing the document compilation data 23 is stored in the local data storage device 4. Alternatively or supplementarily, the digital control unit 1 may include a data transmission interface 28, wherein the digital control unit 1 transmits the digital signature 26 and / or the document compilation data 23 and / or the biological process data 16 or portions thereof to an external data storage device 29, which may typically be a process control system, or itself may be another digital control unit. Here, and preferably, the external data storage device 29 is a so-called "multi-fermentation tank" control system (MFCS), which includes a local processor unit and the local data storage device itself. The MFCS also provides a centralized process management system that dispatches requests to the digital control unit 1; however, this is not applicable to this particular invention.

[0064] Preferably, the external document preparation unit d and / or external signature unit s are provided by the laboratory process control system 30 or the cloud service instance 31. Figure 1 Two alternatives are shown, while Figure 2 The example shown only illustrates alternatives to the document compilation unit d and / or signing unit s provided by cloud service instance 31. This demonstrates a high degree of flexibility in implementing the signing routine.

[0065] A further preferred approach is to use a Message Authentication Code (MAC) to establish a data connection between the digital control unit 1 on one side and the external document preparation unit d and / or external signature unit s on the other side. This not only encrypts the relevant data but also ensures data integrity. The latter can be achieved by having the digital control unit 1 individually sign the relevant data using a cryptographic private key stored in the local data storage device 4 before transmitting these data to the external signature unit s.

[0066] Regarding the aforementioned triggering event e i The definition of depends on the specific application, and multiple variations may be advantageous.

[0067] Preferably, at least one triggering event e iThis is defined as an event directly related to a biological process. Specifically, this can relate to the assigned steps of a biological process. i Biological processes and / or biological process states and / or biological process stages. This basic structure of biological processes can be correlated with... Figure 3 The diagrams are obtained through different variations. Although Figure 3 a) shows the sequence of biological process steps, but Figure 3 b), 3c) each show graphs representing the variable m, here representing the biomass m per volume relative to time t. Thus, Figure 3 b) and 3c) represent the stages and states of the biological process as explained.

[0068] like Figure 3 As shown in a), at least one triggering event e i Defined relative to at least one biological process step. According to Figure 3 In a preferred embodiment of a), such biological process steps w i This could be an equilibration step and / or sample injection step and / or washing step and / or elution step of the chromatographic column used in the downstream process stage. Particularly preferred is at least one triggering event e. i Defined as a step in a biological process w i To another change.

[0069] In another preferred embodiment, at least one triggering event e is defined in a time-based manner. i Preferably, at least one triggering event e i Defined as a time point relative to a step in a biological process. At least one triggering event e i A triggering event e is defined as a periodic repetition with a predefined time interval. i This is also advantageous. It is particularly preferred in cases where biological process steps are repeated periodically and / or where strictly defined standard operating procedures for production are followed.

[0070] In another preferred embodiment, at least one triggering event e i Defined as changes between stages of a biological process. For example... Figure 3 As shown in b), as an example, such a bioprocess stage can be a batch culture stage and / or a batch-feed culture stage and / or a continuous culture stage and / or any other cell culture stage in a bioreactor.

[0071] In another preferred embodiment, the corresponding triggering event e i This can be defined as a change in the state of a biological process. Here, and preferably, at least one triggering event e i It is defined as a change from one biological process state to another. For example... Figure 3As shown in c), such biological process states can be cell growth states, including but not limited to hysteresis states, logarithmic states, quiescent states, and death states, or any other state within any culture of cells in bacterial or fungal fermentation processes, mammalian cell cultures, or bioreactors.

[0072] like Figure 3 As shown in a), at least one triggering event e i Based on biological process steps w i The start or end point is defined, for example, the start or end point of a protein purification step using a chromatographic column. Figure 3 As shown in b), at least one triggering event e i It can be defined based on the start or end of a biological process phase. The latter can be the start or end of batch culture and / or batch-feed culture and / or continuous culture of cells.

[0073] Finally, at least one triggering event e i It can be defined based on biological process control data, here and preferably sensor data and / or user control command data and / or actuator data. This also applies to Figure 3 Variations shown in b) and 3c). One example could be the adjustment of at least one actuator 9, 10, such as a stirrer, which is adjusted by a user via control command data 18 given by the bioprocess user interface 17. This may be necessary, for example, in order to re-establish the oxygen level required by the bioprocess if the oxygen partial pressure drops below a critical predefined threshold.

[0074] like Figure 2 As shown, document compilation routine 22 includes dividing biological process data into 16 data blocks d. i Steps and hash data blocks d i To generate data block d i hash h i The steps, wherein, according to data block d i hash h i Generate document compilation data 23. Preferably, the document compilation routine 22 includes hashing data blocks d in the form of a tree structure using a standard hash function. i hash h i The steps. Figure 4 a) shows the resulting hash tree H. Here, and preferably, the tree structure is a Merkle tree structure.

[0075] A particularly preferred option is data block d. i The hash is structured into a root hash h0, from which document compilation data 23 is generated. In a particularly simple variant, the document compilation data 23 is identical to the root hash h0.

[0076] A key advantage of the above hashing is the following fact: data block d i Any and all modifications will result in corresponding modifications to the hash root h0, making the hashed data block d... i Any modifications can be easily detected. Another advantage is the fact that simply introducing the hash root h0 into the document compilation data 23 results in simple data processing with low data processing requirements.

[0077] Various algorithms can be applied to the hashes described above. Preferably, hash algorithms "SHA-1", "SHA-2", and "BLAKE2" can be used. For the signatures described above, preferably, elliptic curve digital signature algorithms, particularly the signature algorithm "ECDSA", can be used.

[0078] To minimize the chances of manipulating the biological process data 16, the documentation routine 22 can preferably be executed by the digital control unit 1 during the control of the biological process in the biological process control routine 19. This can also be accomplished by the external signature unit s as described above.

[0079] Herein and preferably, during at least a portion of a single biological process, the digital control unit 1 continuously receives sensor data 12 from sensors 13, 14, 15 in the biological process control routine 19, and continuously transmits actuator data 8 to actuators 9, 10, thereby influencing the biological process. The term "continuously" generally means herein that the receiving of sensor data 12 and the transmission of actuator data 8 are ongoing and systematic, preferably periodically repeated.

[0080] Each signature routine 24 is preferably based on the assigned biological process dataset ds i These biological process datasets ds i exist Figure 3 As shown in the image. Figure 3 b), 3c) Here, and preferably, the subsequent biological process dataset ds is shown. i ds i+1 They overlap with each other. Alternatively, or as an alternative, the corresponding previous biological process datasets ds i The identifier can be added to the corresponding subsequent biological process dataset ds i+1 In both cases, a certain amount of redundancy is integrated into the biological process dataset ds. i This ensures that no data is omitted in the corresponding signature routine 24.

[0081] Preferably, the digital signature 26 generated by signing the document compilation data 23 is received from the digital control unit 1 via the bioprocess interface 6 and stored in the local data storage device 4. Alternatively or supplementarily, the digital control unit 1 may include a data transmission interface 28, wherein the digital control unit 1 transmits the digital signature 26 and / or the document compilation data 23 and / or the bioprocess data 16 or portions thereof to an external data storage device 29, which is typically a process control system 30, or itself may be another digital control unit. Preferably, the external data storage device 29 is a so-called "multi-fermentation tank" control system (MFCS), which includes a local processor unit and the local data storage device itself. The MFCS also provides a centralized process management system that dispatches requests to the digital control unit 1; however, this is not applicable to this particular invention.

[0082] To further prevent manipulation of the biological process data 16, it is also preferable to protect the sensor data 12 and / or user control command data 18 from external manipulation after they are received by the digital control unit 1. This can be accomplished through control measures or mechanical measures. Control measures may be, for example, specific designs of control software and / or security software that make it impossible to access the relevant data via the user interface 17. In this sense, mechanical measures involve designing the digital control unit 1 in a mechanically robust manner.

[0083] In the bioprocess control routine 19, as described above, the digital control unit 1 generates bioprocess data 16 based on sensor data 12 and / or actuator data 8 and / or user control command data 18. According to the easiest method, that data is arranged sequentially based on a specific rule that defines which of that data will be assigned to the documentation data 23. Preferably, each data item in the bioprocess data 16 includes at least the aforementioned individual timestamp, data item name, and data item value.

[0084] Typically, it is preferred that the generation of biological process data 16 is continuous, preferably periodic, relative to time periods or data volume. Additionally, during document compilation routine 22, the biological process data 16 is divided into data blocks d. i The steps are preferably performed sequentially. Furthermore, it is preferable to continuously execute the data block d during document preparation routine 22. i The hashing of biological process data 16. This continuous generation and segmentation into data blocks d. i Hash is advantageous because the timeframe in which data manipulation is still possible is reduced to a minimum.

[0085] As its core function, the digital control unit 1 controls biological processes by communicating with actuators 9 and 10 and sensors 13, 14, and 15. To this end, the digital control unit 1 is configured to execute feedback routines to implement the control loop described above, thereby influencing the biological processes. This control loop can be used to maintain certain sensor data 12 stable by correspondingly controlling actuators 9 and 10.

[0086] The proposed solution is particularly advantageous when biological process data generated in a biotechnology environment during a biological process needs to be transferred from the sender to the receiver. As an example, at least biological process data 16 and a digital signature 26 are sent to the receiver. The sender may be an operator of the biotechnology environment in which the corresponding biological process has been performed. The receiver may be a government organization applying compliance procedures to the biological process in question.

[0087] Based on the digital signature 26 of the document compilation data 23, the recipient of the biological process data 16 can verify the integrity of this biological process data 16. For this to be possible, the public key corresponding to the private key 25 must also be made available to the recipient. The public key can be provided to the recipient by the sender of the biological process data 16 via a peer-to-peer data connection or using a Trusted Key Infrastructure (TKI).

[0088] Using the aforementioned public key, the recipient can decrypt the digital signature 26 to receive the document compilation data 23, which can be... Figure 4 The hash root h0 or the complete hash tree H shown in a) is now applied to the received biological process data 16 to generate a hash tree, which is referred to below as the "verification hash tree V" and its... Figure 4 As shown in b).

[0089] However, in Figure 4 In the example shown, the biological process data d4 has been manipulated, resulting in hashes h4′, h34′, h1234′, and h0′ that differ from the original hashes h4, h34, h1234, and h0. If the document compilation data 23 is based solely on the hash root h0, the receiver knows at least some data blocks d. i It is corrupted. If document compilation data 23 is based solely on the complete hash tree H, the receiver can even deduce that data block d4 is corrupted by comparing hash tree H and verifying hash tree V.

[0090] The above example demonstrates that by having the digital control unit 1 control the signature routine 24, data integrity can be verified with high reliability while maintaining high flexibility in the signing process itself.

[0091] As described above, data security routine 21 can be executed on various hardware units in various ways, two of which are indicated below:

[0092] According to the first preferred embodiment, the entire data security routine 21 is executed by the digital control unit 1. Private key data 20 is stored in the local data storage device 4. The data security routine 21 is executed by the local processor unit 5. The document preparation routine 22 is executed by the local processor unit 5 within the data security routine 21. In the document preparation routine 22, the digital control unit 1 generates document preparation data 23 from the biological process data 16. In this case, the signing routine 24 is executed by the local processor unit 5 within the data security routine 21. In the signing routine 24, the digital control unit 1 extracts the cryptographic private key 25 from the private key data 20, and the digital control unit 1 signs the document preparation data 23 with the cryptographic private key 25 by generating a digital signature 26.

[0093] According to the second preferred embodiment, at least signature routine 24 is executed in the external unit, particularly in the external signature unit s. Here, private key data 20 is stored in the external signature unit s, wherein data security routine 21 is initiated by the local processor unit 5. Then, document compilation routine 22 is initiated by the local processor unit 5 in data security routine 21 for execution by either the local processor unit 5 or the external document compilation unit d. In this document compilation routine 22, document compilation data 23 is again generated from biological process data 16 by either the local processor unit 5 or the external document compilation unit d, wherein signature routine 24 is initiated by the local processor unit 5 in data security routine 21 for execution by the external signature unit. In signature routine 24, the external signature unit extracts the cryptographic private key 25 from the private key data 20 and digitally signs the document compilation data 23 with the cryptographic private key 25 by generating digital signature 26.

[0094] According to another independent teaching, this requires protection for the digital control unit 1, which is configured to perform the proposed method. All the explanations given above are fully applicable to this teaching.

[0095] Based on another teaching, a control system having the proposed digital control unit 1 and external document preparation unit d and / or external signature unit s is thus proposed. Again, please refer to all the explanations given previously.

[0096] Finally, the independent teachings relate to a data processing system for implementing the above methods, preferably including a local data storage device 4 and a local processor unit 5, to a computer program product for a data processing system, and to a computer-readable storage medium on which the computer program product is stored.

Claims

1. A method for implementing a biological process using a digital control unit (1) of a biological process device (2), in, The digital control unit (1) includes a local data storage device (4) and a local processor unit (5), wherein biological process data (16) is generated by the digital control unit (1). in: In the data security routine (21), the documentation routine (22) and the signature routine (24) are executed. In the documentation routine (22), documentation data (23) is generated from biological process data (16), and in the signing routine (24), a cryptographic private key (25) is extracted from the private key data (20), and the documentation data (23) is digitally signed using the cryptographic private key (25) by generating a digital signature (26). The document preparation routine (22) is executed continuously during the biological process, and the signature routine (24) is executed discontinuously during the biological process in several signature cycles according to a signature policy (P), the signature policy defining a triggering event (ei) for initiating the signature routine (22).

2. The method according to claim 1, characterized in that, The digital control unit (1) includes a bioprocess interface (6) for sending and receiving bioprocess control data, the bioprocess interface (6) including an actuator interface (7) for sending actuator data (8) to at least one actuator (9, 10) to influence the bioprocess, the bioprocess interface (6) including a sensor interface (11) for receiving sensor data (12) related to the bioprocess from at least one sensor (13, 14, 15), and the digital control unit (1) including a user interface (17) for displaying at least a portion of the bioprocess data to a user and for receiving user control command data (18).

3. The method according to claim 2, characterized in that, A biological process control routine (19) is executed by the local processor unit (5) to control the biological process. In the biological process control routine (19), the sensor data (12) is received by the digital control unit (1) from the sensors (13, 14, 15). In the biological process control routine (19), the actuator data (8) is generated by the digital control unit (1) based on the user control command data (18) and / or the sensor data (12). The actuators (9, 10) are controlled by the digital control unit (1) by sending the actuator data (8) to the actuators (9, 10), thereby influencing the biological process. In the biological process control routine (19), the biological process data (16) is generated by the digital control unit (1) from the actuator data (8) and / or the sensor data (12) and / or the user control command data (18).

4. The method according to claim 1, characterized in that, At least one triggering event (e i An event is defined as an event directly related to the biological process in question.

5. The method according to claim 1, characterized in that, The biological process is assigned biological process steps (w) i ) and / or assigned a biological process stage and / or assigned a biological process state, and at least one triggering event (e i Regarding at least one biological process step (w i () and / or at least one biological process stage and / or at least one biological process state are defined.

6. The method according to claim 1, characterized in that, Define at least one triggering event in a time-based manner (e i ).

7. The method according to claim 6, characterized in that, At least one triggering event (e i () is defined as a point in time relative to a step in a biological process.

8. The method according to claim 6, characterized in that, At least one triggering event (e i ) is defined as a triggering event that repeats periodically over a predefined time period (e i ).

9. The method according to any one of claims 5-8, characterized in that, At least one triggering event (e i It is defined based on predefined changes in the biological process stage and / or the biological process state.

10. The method according to any one of claims 1-8, characterized in that, At least one triggering event (e i Based on biological process steps (w i The start or end of a biological process can be defined by the start or end of a biological process phase.

11. The method according to any one of claims 2-3, characterized in that, At least one triggering event (e i It is defined based on the biological process control data.

12. The method according to claim 11, characterized in that, At least one triggering event (e i It is defined based on the sensor data and / or the user control command data and / or the actuator data.

13. The method according to any one of claims 1-8, characterized in that, The document compilation routine (22) includes dividing the biological process data (16) into data blocks (d i The steps and hashing of the data block (d) i ) to generate the data block (d i The hash of (h) i The steps of ), and the document compilation data (23) is from the data block (d i The hash of (h) i Generated by ).

14. The method according to claim 13, characterized in that, The document compilation routine (22) includes processing the data blocks (d) in tree structure form, particularly in Merkle tree structure form. i The hash of (h) i Hash to hash root (h) o The steps in ) and the document compilation data (23) are from the hash root (h o Generated by ).

15. The method according to any one of claims 2-3, characterized in that, During a single biological process, the digital control unit (1) continuously receives sensor data (12) from the sensors (13, 14, 15) in the biological process control routine (19) and continuously sends actuator data (8) to the actuators (9, 10) to influence the biological process.

16. The method according to any one of claims 1-8, characterized in that, Each signature routine is based on the assigned biological process dataset (ds i )of.

17. The method according to claim 16, characterized in that, Subsequent biological process datasets (ds i ds i+1 ) overlap with each other, and / or the corresponding prior biological process datasets (ds i The identifier is added to the corresponding subsequent biological process dataset (ds). i+1 ).

18. The method according to any one of claims 1-8, characterized in that, The digital signature (26) generated by signing the document compilation data (23) is received from the digital control unit (1) via the bioprocess interface (6), particularly the data transmission interface (28), and stored in the local data storage device (4), and / or the digital control unit (1) initiates the transmission of the digital signature (26) and / or the document compilation data (23) and / or the bioprocess data (16) or a portion thereof via the data transmission interface (28) to an external data storage device (29), particularly a laboratory process control system.

19. The method according to any one of claims 1-8, characterized in that, The private key data (20) is stored in the local data storage device (4). The data security routine (21) is executed by the local processor unit (5). The document preparation routine (22) is executed by the local processor unit (5) in the data security routine (21). In the document preparation routine (22), the document preparation data (23) is generated by the digital control unit (1) from the biological process data (16). The signature routine (24) is executed by the local processor unit (5) in the data security routine (21). In the signature routine (24), the digital control unit (1) extracts the cryptographic private key (25) from the private key data (20). The document preparation data (23) is signed by the digital control unit (1) using the cryptographic private key (25) by generating a digital signature (26).

20. The method according to any one of claims 1-8, characterized in that, The private key data (20) is stored in an external signature unit. The data security routine (21) is initiated by the local processor unit (5). The document preparation routine (22) is initiated by the local processor unit (5) in the data security routine (21) and executed by the local processor unit (5) or the external document preparation unit. In the document preparation routine (22), the local processor unit (5) or the external document preparation unit generates document preparation data (23) from the biological process data (16). The signature routine (24) is initiated by the local processor unit (5) in the data security routine (21) and executed by the external signature unit. In the signature routine (24), the cryptographic private key (25) is extracted by the external signature unit from the private key data (20), and the document preparation data (23) is digitally signed with the cryptographic private key (25) by generating a digital signature (26).

21. A digital control unit for a bioprocess device (2) for controlling biological processes, in, The digital control unit (1) includes a local data storage device (4) and a local processor unit (5). The digital control unit (1) includes a bioprocess interface (6) for sending and receiving bioprocess control data. The biological process interface (6) includes an actuator interface (7) for sending actuator data (8) to at least one actuator (9, 10) to influence the biological process. The biological process interface (6) includes a sensor interface (11) for receiving sensor data (12) related to the biological process from at least one sensor (13, 14, 15). The digital control unit (1) generates biological process data (16). The digital control unit (1) includes a user interface (17) for displaying at least a portion of the biological process data to the user and for receiving user control command data (18). The digital control unit (1) is configured to execute a biological process control routine (19) via the local processor unit (5) to control the biological process, wherein in the biological process control routine (19), the digital control unit (1) receives sensor data (12) from the sensors (13, 14, 15). In the biological process control routine (19), the digital control unit (1) generates actuator data (8) based on the user control command data (18) and / or the sensor data (12), and controls the actuators (9, 10) by sending the actuator data (8) to the actuators (9, 10), thereby influencing the biological process. In the biological process control routine (19), the digital control unit (1) generates the biological process data (16) from the actuator data (8) and / or the sensor data (12) and / or the user control command data (18). Its features are: The private key data (20) is stored in a local data storage unit or an external signature unit. The digital control unit (1) is configured to initiate a data security routine (21) via the local processor unit (5). The digital control unit (1) is configured to initiate a documentation routine (22) in the data security routine (21) via the local processor unit (5) for execution by either the local processor unit (5) or an external documentation unit (d), in which the local processor unit (5) or the external documentation unit (d) generates documentation data (23) from the biological process data (16). The digital control unit (1) is configured to initiate a signature routine (24) in the data security routine (21) via the local processor unit (5) for execution by either the local processor unit (5) or an external signature unit. In the signature routine (24), the local processor unit (5) or the external signature unit extracts the cryptographic private key (25) from the private key data (20) and digitally signs the document compilation data (23) with the cryptographic private key (25) by generating a digital signature (26). The document preparation routine (22) is executed continuously during the biological process, and the signing routine (24) is executed discontinuously during the biological process in several signing cycles according to a signing policy (P), the signing policy (P) defining triggering events (e) for initiating the signing routine (22). i Furthermore, the digital control unit (1) is configured to initiate the signature routine (24) discontinuously.

22. A control system having a digital control unit (1) according to claim 21 and an external document preparation unit and / or an external signature unit to perform the method according to any one of claims 1 to 20.

23. A data processing system for implementing the method according to any one of claims 1 to 20.

24. A computer program product for use in the data processing system according to claim 23.

25. A computer-readable storage medium thereon preferably storing, in a non-volatile manner, the computer program product according to claim 24.

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