Method and system for configuring and / or setting up a downstream process for processing biomass

Abstract

The present invention relates to a computer-implemented method for configuring and / or setting up and / or controlling a downstream process for treating biomass, the method comprising: receiving at least one measurement of at least one characteristic of an upstream process and / or at least one measurement of at least one characteristic of a downstream processing stage or operation used to obtain biomass to be processed in the downstream process; determining at least one downstream process parameter based on the received at least one measurement; and configuring and / or setting and / or controlling at least one downstream processing stage or processing operation based on the determined at least one downstream process parameter. The invention further relates to computer program products and systems for configuring and / or setting up and / or controlling downstream processes, methods and systems for processing biomass.

Description

[Technical Field]

[0001] The technical field of the present application is methods and systems for configuring, setting up and / or controlling downstream processes for biomass processing, and in particular, one aspect of the present application relates to interconnections between upstream and downstream processes for biomass processing and / or interconnections between processing stages of a downstream process that includes multiple processing stages. [Background technology]

[0002] A biomass-to-product process (bioprocess) is a process that uses cells and / or their components to obtain a desired product. A bioprocess typically includes several distinct stages or operations, such as a cell growth stage, a cell harvest stage, a media preparation stage, a separation stage, a chromatography stage, a filtration stage, an agitation stage, etc.

[0003] Bioprocessing is generally divided into upstream and downstream processes. Upstream processes (the upstream portion of a bioprocess) refer to the initial part of a bioprocess, where cell cultures, microorganisms, etc. are grown. Upstream processes include multiple steps or stages. For example, upstream processes include culture inoculation, culture growth, fermentation, etc. Downstream processes (the downstream portion of a bioprocess) typically involve processing the biomass produced by the upstream process to obtain a final product that meets specific quality and purity requirements. Downstream processes typically include multiple stages, such as multiple purification stages in which waste, impurities, and / or other undesirable substances are removed. For example, downstream processes may include primary recovery to remove cells and / or debris, separation stages (e.g., by centrifugation), filtration stages, chromatography stages, buffer exchange stages, material retention stages, viral inactivation stages, other purification stages, etc. Each stage of an upstream and downstream process may include multiple substages. Each individual stage or operation has one or more process parameters or settings that must be configured, set, and / or controlled to obtain the desired final product. Summary of the Invention [Problem to be solved by the invention]

[0004] Configuring or setting up and controlling the various stages of a complex bioprocess presents various challenges. It is an object of the present invention to provide improved methods and systems for configuring, setting up and / or controlling a bioprocess. [Means for solving the problem]

[0005] The objects of the present invention are achieved by a method for configuring and / or setting and / or controlling a downstream process for processing biomass, a respective computer program product, a system for configuring and / or setting and / or controlling a downstream process, a method for processing biomass, and a system for processing biomass, as set forth in the claims.

[0006] In particular, according to a first aspect of the present disclosure, there is provided a computer-implemented method for configuring and / or setting up a downstream process for treating biomass, the method comprising: receiving at least one measurement of at least one characteristic of an upstream process used to obtain biomass to be processed in a downstream process; determining at least one downstream process parameter based on the received at least one measurement; Includes.

[0007] Based on the determined at least one downstream process parameter, the downstream process, more specifically at least one processing stage or processing operation of the downstream process, is configured and / or set up, such that the downstream process is performed in accordance with at least the determined downstream process parameter.

[0008] According to a second aspect of the present disclosure, there is provided a computer-implemented method for controlling a downstream process for treating biomass, the method comprising: receiving at least one measurement of at least one characteristic of an upstream process used to obtain biomass to be processed in a downstream process; determining at least one downstream process parameter based on the received at least one measurement; controlling at least one processing stage or operation of a downstream process based on the determined at least one downstream process parameter; Includes.

[0009] In particular, the control may be predictive control, based on measurements of at least one characteristic of an upstream process.

[0010] The biomass to be treated includes bacteria, yeast, mold, animal cells, plant cells, etc. Other substances contained therein include compounds, proteins (enzymes, etc.), various additives, etc.

[0011] Downstream processing of biomass produces biopharmaceuticals. Non-limiting examples of such products include recombinant and non-recombinant proteins, vaccines, gene vectors, DNA, RNA, antibiotics, secondary metabolites, growth factors, cells for cell therapy or regenerative medicine, and semi-synthetic products (e.g., artificial organs). A variety of production systems are used to facilitate this process, including animal cells (e.g., CHO, HEK, PerC6, VERO, MDCK), insect cells (e.g., SF9, SF21), microorganisms (e.g., E. coli, S. cerevisiae, P. pastoris), algae, plant cells, cell-free expression systems (e.g., cell extracts, recombinant ribosomal complexes), primary cells, stem cells, native and genetically engineered patient-specific cells, and cell-based systems such as matrix-based cell systems.

[0012] As previously mentioned, an upstream process is a bioprocess that grows cell cultures, microbial cultures, etc., thereby producing biomass that is further processed in downstream processes to obtain an end product that meets requirements for purity, quality, etc. Typically, the upstream and downstream processes each include multiple stages, each configured to perform a particular processing operation or group of processing operations. For example, an upstream process may include one or more stages or unit operations, such as culture inoculation, culture growth, fermentation, etc.

[0013] Downstream processing includes one or more stages or unit operations, such as a primary recovery stage where cells and / or debris are removed, a separation stage (e.g., by centrifugation), a filtration stage, a chromatography stage, a buffer exchange, a material retention stage, a viral inactivation stage, or other purification stages. As used herein, the term "purification process / operation" (also referred to as "clarification process / operation") refers to any process / operation associated with the processing of a biopharmaceutical during which at least one fraction of the product being processed is separated or filtered from the remainder of the product, resulting in a purified (clarified) intermediate or final product with desired properties. Exemplary purification processes / operations include filtration (depth filtration, viral filtration, viral inactivation, tangential flow filtration, sterile filtration, prefiltration, etc.), centrifugation, chromatography, etc. Similarly, the term "purification stage" (also referred to as "clarification stage") refers to any processing stage during which at least one fraction of the product being processed is separated or filtered from the remainder of the product. Representative separation stages are filtration stages, depth filtration stages, viral filtration stages, viral inactivation stages, centrifugation stages, tangential flow filtration stages, sterile filtration stages, chromatography stages, purification stages, etc. The term "filter" when used in connection with a purification process, stage or operation refers to a device used in the respective purification process, stage or operation to effect separation or filtration.

[0014] Each of the upstream and downstream process stages includes multiple sub-stages, and each individual stage or operation has one or more process parameters or settings that must be configured, set, and / or controlled to achieve the desired intermediate or final product.

[0015] Examples of downstream process end products include, but are not limited to, recombinant or non-recombinant proteins, vaccines, gene vectors, DNA, RNA, antibiotics, secondary metabolites, growth factors, and the like.

[0016] In the methods according to the first and second aspects, at least one characteristic of the upstream process used to obtain the biomass to be treated in the downstream process (upstream characteristic) is measured, and each one or more measurements are used to configure and / or set up and / or control the downstream process. The at least one upstream characteristic may be a characteristic characterizing cells, contaminants, products, etc. and / or a process parameter of the upstream process. The at least one upstream characteristic may be a characteristic characterizing any stage, treatment, or operation of the upstream process.

[0017] Measurement of at least one characteristic of the upstream process can be performed online or offline. In the context of this specification, the term "online" also includes in-line and at-line measurements. At-line measurements require more time and manual effort than in-line measurements. However, at-line measurements do not involve the level of time, analysis, and manual effort required for offline measurements.

[0018] Online measurements (e.g., in-line measurements) typically do not require the removal of product samples, although in some cases, online measurements (e.g., at-line measurements) require the removal or diversion of samples of the product being produced. Online measurements are performed using probes, sensors, or measurement devices placed in the processed product and / or the vessel holding the processed product (e.g., bioreactor). Online measurements are performed at predetermined intervals throughout the process and correspond to process parameters with defined confidence intervals. Examples of online measurements include pH, conductivity, temperature, broth volume, antifoam concentration, cell density, cell turbidity, cell viability, flow sensor parameters including sensor quality, and spectroscopic data indicating, for example, total protein concentration, metabolite and / or media concentrations, tubing and / or bioreactor pressure values, etc.

[0019] Offline measurements require a sample of the processed product to be diverted for further analysis. Sometimes offline measurements are performed once per batch. Examples of offline measurements include cell viability, total protein concentration obtained by offline measurement or offline sample, lactate dehydrogenase or other enzyme activity, upstream product quality (e.g., monoclonal antibodies), aggregation level of upstream products, product concentration, DNA / HCP concentration, and titer.

[0020] The measured value of at least one upstream characteristic can be used to configure and / or set and / or control a downstream process. For example, the measured value is transmitted by wireless transmission over a computer network (e.g., the Internet) or by any other suitable communication means to a receiving device involved in the downstream process. The receiving device may be part of a system for configuring and / or set and / or control the downstream process, or may itself be part of a system for configuring and / or set and / or control the entire biological process (i.e., both the upstream process and the downstream process).

[0021] Based on the measurement of at least one upstream characteristic, one or more settings, i.e., one or more downstream process parameters, are determined, for example, by a suitable programmed computer system including one or more processing devices (processors), which may be part of a system for configuring and / or setting and / or controlling a downstream process (downstream process configuration, setting and / or control system).

[0022] The determined downstream process parameters are stored in a database or other suitable data storage unit. The database may further store additional process parameters or data, such as, for example, a (functional) relationship or law linking at least one upstream characteristic and its value with at least one downstream parameter or setting. The functional relationship or law linking at least one upstream characteristic and its value with at least one downstream parameter or setting may be obtained by various means, for example, based on historical data and / or using mathematical models. For example, various statistical methods may be utilized to obtain the functional relationship, including, but not limited to, various regression analysis methods, machine learning methods, etc.

[0023] The stored process parameters, optionally together with additional parameters or data and functional laws, are used by a downstream process configuration, setup and / or control system to automatically setup, configure and / or control at least one downstream processing stage or processing operation. The database is therefore accessible by the respective devices and / or control units via a suitable computer network.

[0024] The database is implemented as a cloud database, i.e., a database running on a cloud computing platform. In other words, the database is accessible over the Internet through a provider that makes shared processing resources and data available to computers and other devices on demand. The database is implemented using a virtual machine image or a database service. The database may use an SQL-based data model or a NoSQL data model.

[0025] The database may provide access control such that some process parameters are accessible by multiple users of the database or respective control devices, and some process parameters are private and accessible only by a limited number of users or one specific user of the respective control devices.

[0026] In the context of this specification, the term "determining" includes any of the following: calculating, setting, changing, and / or adjusting at least one downstream process parameter, i.e., a setting for at least one process parameter of a downstream process. The term "receiving" includes any of the following: acquiring the respective data (measurement of at least one upstream characteristic), receiving wirelessly transmitted data, receiving data transmitted via a computer network such as the Internet, WLAN, etc., reading data from a permanent or temporary storage unit (e.g., a database), or receiving or obtaining data by any suitable means. Data can be received via a suitable interface, i.e., an interface of a computer system. Controlling at least one processing stage or operation (e.g., centrifugation, filtration, chromatography, pumping, storage, etc.) includes controlling at least one piece of processing equipment and / or control device (i.e., actuator) associated with the respective processing stage or operation according to a predetermined downstream process parameter. The at least one control device may be part of a control system that configures, sets, and / or controls the downstream process. Control is exercised during downstream processes, more specifically, as each processing stage or processing operation is carried out using each processing equipment.

[0027] According to the first and second aspects, the downstream process is automatically set up, configured, and / or controlled based on measurements of at least one characteristic of the upstream process used to obtain the biomass to be processed in the downstream process. Advantages of the proposed method for controlling the downstream process include reducing the number of labor-intensive and error-prone manual operations, thereby reducing the overall error rate; optimizing processing time; simplifying the downstream setup and control process; improving the quality of the output product; and reducing waste. Furthermore, the upstream and downstream processing stages can be optimally synchronized, thereby reducing idle and non-productive time and improving process efficiency. Furthermore, logistics and inventory management can be improved.

[0028] Various features or characteristics of the upstream process can be measured (e.g., automatically) and the measurements used in the downstream process.

[0029] For example, the at least one upstream process characteristic may include viable cell density, biomass, capacitance, cell viability, and / or cell turbidity. Based on the measured upstream values, at least one downstream parameter setting is determined. Determining the at least one downstream process parameter may include, for example: Selecting a clarification (purification) stage or operation; determining at least one process parameter of a selected clarification (purification) stage or operation and / or determining a dilution parameter of the biomass based on the received at least one measurement of viable cell density, biomass, capacitance, and / or cell viability; Includes.

[0030] Selection of a clarification (purification) operation includes selecting between a filtration stage or operation and a centrifugation stage or operation, wherein: If a filtration stage or operation is selected, the at least one process parameter includes at least one of the following parameters: type of filtration stage or operation, number of filters, filter area, pressure, flow rate, amount of diatomaceous earth, and treatment time; If a centrifugation stage or operation is selected, the at least one process parameter includes processing time, processing volume, and centrifugal force.

[0031] For example, a measured viable cell density (VCD) of an upstream process may be multiplied by the throughput to determine the total amount of biomass to be processed in a downstream process. Based on the determined amount of biomass, the amount of biomass requiring separation or clarification can be determined. The amount of biomass requiring separation or clarification can also be determined based on measured turbidity, measured biomass, or any other suitable measurable characteristic.

[0032] Depending on the biomass that needs to be separated or clarified, the separation method and / or system suitable for the cell separation stage can be determined. The separation method and respective system can be, for example, a filtration method / system and a centrifugation method. Furthermore, among the filtration methods, different types of filtration can be selected, such as depth filtration, dynamic body feed filtration, etc.

[0033] The functional relationships or laws linking the biomass requiring separation with the respective clarification operation settings (such as separation methods and / or systems) are stored in a database or other suitable storage medium and are used to configure, set up, and / or control downstream processes. For example, as the amount of biomass requiring separation increases, the following separation methods and / or systems and their respective stages are selected in this order: depth filtration, dynamic body feed filtration, or centrifugation. Further, other separation settings such as the number of filters, filter area, and / or processing time are determined. Furthermore, the dilution level of the biomass being processed is determined to facilitate the separation process.

[0034] Additionally or alternatively, downstream clarification (purification) operation settings (e.g., g-force of centrifugation stages, processing time, etc.) are determined based on cell viability. For example, for cells that are to maintain a high target viability, a lower g-force of the centrifugation stage / operation is selected compared to the g-force of damaged or apoptotic cells. Additionally or alternatively, downstream clarification (purification) operation settings are determined based on the targeted degree of sedimentation. For example, the higher the targeted degree of sedimentation (independent of cell viability), the higher the g-force of the centrifugation operation and / or the longer the processing time.

[0035] In one example, the at least one upstream process characteristic includes a titer. Determining at least one downstream process parameter includes determining at least one process parameter of the chromatography run based on the received titer measurements, the at least one process parameter including one or more of dimensioning, load, cycle time, flow rate, number of chromatography columns, column exchange sequence, loading scenario and / or sequence. A (functional) relationship or law linking the measured upstream titer and the at least one process parameter of the chromatography stage or run is stored in a database or other suitable storage unit and used to configure, set up and / or control the downstream process.

[0036] High titers multiplied by throughput yields large amounts of product. Generally, the higher the titer, the less volume is loaded onto the chromatography column during the loading step. Therefore, with increasing upstream titers, larger size and / or greater number of chromatography columns and / or greater number of cycles can be configured in the downstream process.

[0037] For example, in batch processing, the titer measurement is multiplied by the throughput to determine the total amount of product (biomass) to be processed in downstream processes, e.g., purified by Protein A chromatography. Based on the determined total amount of biomass, the chromatography settings (e.g., chromatography column dimensioning or size, load capacity, etc.) required to process the biomass within a given time are determined and set accordingly. Alternatively, for a given size or dimension of the chromatography column, the processing time (e.g., number of cycles) is determined and set accordingly. Furthermore, the amount of buffer is determined and set accordingly.

[0038] For continuous processes, the titer and volumetric flow rate determine the number of chromatography columns required to ensure continuous processing of the biomass flow from the upstream process to the downstream process, and activate or connect them. Additionally or alternatively, the titer may determine the number of cycles and / or the timing of chromatography column replacement (e.g., due to column aging after a predetermined number of cycles). Furthermore, the titer may determine at least one recipe for the downstream process (e.g., at least one recipe according to ISA88). Determining a recipe may involve creating a new recipe or modifying or adjusting an existing recipe. Creating, modifying, or adjusting a recipe may involve, for example, determining volumetric flow rates, loading amounts, and / or other parameters. As used herein, the term "recipe" refers to a set of information required to uniquely define a specific product production requirement or work task (see also the definition of the term "recipe" in ANSI / ISA-88.00.01-201o, "Batch Control Part 1: Models and Terminology," Chapter 6, point 6.1, p. 55).

[0039] In one example, the at least one upstream process characteristic includes host cell-derived protein (HCP) and / or DNA concentration. Determining includes determining at least one process parameter of an anion or cation exchange chromatography stage or run, wherein the at least one process parameter includes one or more of a chromatography column and / or membrane adsorber volume, a buffer volume, a number of cycles, and a processing time. For example, as HCP increases, the size or capacity of the AEX or CEX column increases.

[0040] Furthermore, the consumption of one or more media required for downstream processing of the biomass (e.g., in an anion exchange (AEX) chromatography operation or a cation exchange (CEX) chromatography stage or operation) is determined. Based on the determined consumption, the inventory of the respective media can be automatically controlled, additional amounts can be automatically ordered, and / or the estimated amount of media to be stocked can be modified. This significantly reduces the number and error rate of labor-intensive and error-prone manual operations. Furthermore, logistics and inventory management are significantly improved.

[0041] A (functional) relationship or law linking upstream host cell-derived protein (HCP) and / or DNA concentrations with at least one process parameter of an anion or cation exchange chromatography stage or operation is stored in a database or other suitable storage unit and used to configure, set up, and / or control the downstream process.

[0042] In one example, the at least one upstream process characteristic includes a type and / or amount of at least one contaminant. Determining the at least one downstream process parameter includes determining at least one downstream process parameter including one of a biomass dilution parameter, a cycle time, and a processing column size parameter based on the received measurements of the type and / or amount of the at least one contaminant.

[0043] The at least one upstream process characteristic includes, for example, an amount of antifoam agent and / or an amount of block polymer. Determining the at least one downstream process parameter includes determining at least one downstream process parameter including one of a biomass dilution parameter, a cycle time, and a processing column size parameter based on the measured value of the type and / or amount of antifoam agent or block polymer received.

[0044] For example, the type and / or amount of at least one contaminant, such as the amount of antifoam and / or anti-stick polymer, in an upstream process affects the viscosity, thereby affecting the characteristics or steps of the downstream process. For example, higher levels of antifoam and / or anti-stick polymer require higher parameter settings in the downstream process, such as longer cycle times, processing column sizes, etc. Furthermore, information about the amount of antifoam and / or anti-stick agent is used to determine the dilution level, where a higher level of antifoam and / or anti-stick polymer in the upstream process results in a higher dilution level in the downstream process.

[0045] Furthermore, antifoam agents (AF) and anti-blocking polymers can cause filter blocking. Therefore, in downstream processes, the amount of antifoam agent and / or anti-blocking polymer is kept as low as possible in each step of the downstream process. This can be achieved, for example, by dilution and / or the use of more filters and / or filters with larger surface areas that contain increased amounts of antifoam agent and / or anti-blocking polymer.

[0046] The (functional) relationship or law linking the amount and / or type of upstream contaminant with at least one downstream process parameter, such as dilution, cycle time, treatment time, etc., is stored in a database or other suitable storage unit and used to configure, set up, and / or control the downstream process.

[0047] In one example, the at least one upstream process characteristic includes a pH value and / or an amount (buffer capacity) of at least one pH corrective agent. Determining the at least one downstream process parameter includes determining the amount and / or type of at least one pH corrective agent to use in the downstream process based on the received pH value measurement and / or the amount of the at least one pH corrective agent. Generally, a particular processing step has an optimal pH value or pH range. The higher the measured pH value is compared to the optimal or target pH value, the more base / base concentration is required, and the settings of the respective downstream process are set or configured accordingly. Similarly, the lower the measured pH value is compared to the optimal or target pH value, the more acid / acid concentration is required, and the settings of the respective downstream process are set or configured accordingly.

[0048] For example, the pH value and / or the amount (buffer capacity) of at least one pH corrective agent of an upstream process are used to determine the necessary or optimal amount and / or type of pH corrective agent for operation of a Protein A chromatography unit in a downstream process. As an example, a combination of the pH value (basic pH value) and the pH corrective agent is used to determine the necessary or optimal amount and / or type of pH corrective agent for a downstream process.

[0049] Based on the determined amount and / or type of at least one pH corrective agent for the downstream process, the amount, flow rate, timing, and other parameters of the delivery of the pH corrective agent in the downstream process are automatically set, configured, and / or controlled, for example, by controlling the respective pumps and / or buffer reservoirs. Therefore, the error rate is reduced, preparation time is optimized, and process control is simplified. Furthermore, inventory management of the pH corrective agent can be improved.

[0050] Furthermore, it is possible to determine whether to start a downstream process or not to start it at all based on the pH value of the upstream process and / or the amount (buffer capacity) of at least one pH correcting agent. For example, if the measured pH value is not within a predetermined threshold, the downstream process is stopped and not started.

[0051] A (functional) relationship or law linking the upstream pH value and at least one downstream process parameter, such as the amount of at least one pH corrector, the amount and / or type of at least one pH corrector, is stored in a database or other suitable storage unit and is used to configure, set up and / or control the downstream process.

[0052] Various other upstream process characteristics are measured and the measurements are used to determine (e.g., set a change in) at least one downstream process parameter: the at least one upstream process characteristic includes, for example, amounts of lipids and / or epidermal growth factor (Long® EGF) and / or peptides and / or other media, and determining the at least one downstream process parameter includes determining at least one clarification (purification) operating parameter or setting (e.g., size and / or number and / or loading cycle of chromatography columns, etc.) based on the received measurements of the amounts of lipids and / or epidermal growth factor and / or peptides and / or other media; and / or the at least one upstream process characteristic includes at least one critical quality attribute (CQA), and determining the at least one downstream process parameter includes determining whether to initiate a downstream process based on the received measurement value of the at least one critical quality attribute; and / or the at least one upstream process characteristic includes a process temperature, and determining the at least one downstream process parameter includes determining cooling or heating of a process fluid for a downstream process based on the received process temperature; and / or the at least one upstream process characteristic includes turbidity, and determining at least one downstream process parameter includes determining at least one clarification (purification) operational parameter or setting (e.g., size and / or number and / or loading cycle of chromatography columns, volume of dilution solution, etc.) based on the received turbidity measurements; and / or the at least one upstream process characteristic includes a buffer system and / or buffer capacity of the medium, and determining the at least one downstream process parameter includes determining a pH adjustment parameter based on a measurement of the buffer system and / or buffer capacity of the received medium; and / or the at least one upstream process characteristic includes a throughput, and determining the at least one downstream process parameter includes determining a dimensioning of the downstream process based on the received throughput measurements (throughput is typically a global parameter that is used (together with other measured parameters) to determine the settings and / or function of one or more (e.g., all) downstream process steps); and / or The at least one upstream characteristic includes conductivity, and determining the at least one downstream process parameter includes determining a dilution parameter based on the received conductivity measurements (e.g., for at least one downstream processing stage, based on the measured upstream conductivity and a predetermined optimal or target conductivity, a corresponding measure such as an amount of dilution may be determined to achieve an optimal or target level of conductivity for a given DSP processing step).

[0053] The respective (functional) relationship between the measured at least one upstream characteristic and the at least one downstream parameter is stored in a database or other suitable storage unit and used to configure, set up and / or control a downstream process.

[0054] In one example, receiving includes receiving a plurality of measurements of a respective plurality of characteristics. At least one parameter of the downstream process is determined based on the received plurality of measurements. Using the measurements of the plurality of measured characteristics, better and more accurate configuration, setup, and / or control of the downstream process can be performed.

[0055] Non-limiting examples include at least two of the following characteristics: the amount of biomass or product being processed (e.g., expressed by wet cell weight or turbidity), viable cell concentration, cell viability, turbidity, and particle distribution of the product / biomass being processed, e.g., depending on the fraction of larger and smaller particles. For the same level of viability, the number of filters and / or filter area increase with increasing wet cell weight or turbidity and / or viable cell concentration. Furthermore, the filter area is determined depending on the particle distribution of the product / biomass being processed, e.g., depending on the fraction of larger and smaller particles.

[0056] According to a third aspect of the present disclosure, there is provided a computer program product comprising instructions that, when executed by a computer, cause the computer to perform the method of any of the above aspects and examples.

[0057] According to a fourth aspect of the present disclosure, there is provided a system configured to set up and / or configure and / or control a downstream process for processing biomass to obtain a product, the system comprising at least one processor configured to perform the method of any of the above aspects and examples. Accordingly, the above description of embodiments, examples, technical effects and advantages related to the above aspects and examples also apply to the system according to the fourth aspect of the present disclosure.

[0058] In particular, the system may comprise a receiving device (which may be part of or connected to the at least one processor) configured to receive at least one measurement value of at least one characteristic of an upstream process used to obtain biomass to be treated in the downstream process, and further configured to determine, by the at least one processor, at least one downstream process parameter based on the received at least one measurement value.

[0059] Furthermore, the system is configured to configure and / or set and / or control at least one processing stage or unit processing operation of a downstream process by at least one processor based on the determined at least one downstream process parameter. The at least one processor may be a general-purpose processor or a special-purpose processor. A distributed computing system, such as a cloud-based computing system, may be utilized. A system for configuring and / or set and / or control a downstream process for processing biomass to obtain a product is also referred to as a downstream process configuration and / or control system.

[0060] The system for setting up and / or configuring and / or controlling a downstream process further comprises a data storage unit for storing the determined at least one downstream process parameter, for example a database similar to the databases described in connection with the first and second aspects of the present disclosure.

[0061] The system for setting and / or configuring and / or controlling a downstream process further includes at least one device (actuator) controlled by a processor, wherein the at least one processor and the at least one actuator are configured to jointly realize a determined configuration and / or setting and / or control of the downstream process (i.e., at least one downstream processing stage or operation). The actuator is, for example, a valve that enables connection or disconnection of a particular stage or operation of the downstream process, or a group of stages or operations of the downstream process, in the flow path of the downstream process. Additionally or alternatively, the actuator can affect pressure, temperature, dilution, or other parameters of a particular stage or operation of the downstream process, a group of processing stages or operations, or any other unit along the process flow path.

[0062] The system for setting up and / or configuring and / or controlling a downstream process further includes one or more probes, sensors, or measurement devices for monitoring one or more parameters of the downstream process. Measurements are taken continuously or at specified intervals throughout the downstream process. The measurements are used by one or more control devices to control (e.g., using a feedback control loop) at least one piece of equipment associated with the downstream process.

[0063] Furthermore, the measurements can be used to set, configure and / or control at least one process parameter of the upstream process used to obtain the biomass to be treated in the downstream process, i.e., the exchange of measurement data between the upstream process and the downstream process is bidirectional.

[0064] According to a fifth aspect of the present disclosure, configuring and / or setting up a downstream process for processing biomass according to the method of any one of the above embodiments and examples; processing the biomass using a downstream process so configured and / or set up; and A method for processing biomass is provided, comprising:

[0065] The descriptions of embodiments, examples, technical effects and advantages related to the previous aspects also apply to the method according to the fifth aspect of the present disclosure.

[0066] The method comprises: carrying out an upstream process to obtain biomass to be processed in a downstream process; measuring at least one characteristic of the upstream process; Further includes:

[0067] As described above in relation to the first and second aspects, the measurement of at least one characteristic of the upstream process may be performed online (eg, in-line or at-line) or offline.

[0068] According to a sixth aspect of the present disclosure, there is provided a system configured to process biomass, the system comprising: at least one system for setting up and / or configuring and / or controlling a downstream process according to the fourth aspect and embodiment, the system including at least one processor configured to perform a method for configuring and / or setting up and / or controlling a downstream process for processing biomass according to any one of said aspects and embodiments; and at least one process (treatment stage) configured to process biomass by using a downstream process so configured and / or set up;

[0069] As described above in connection with the first and second embodiments, the at least one processing stage may be a filtration stage, a chromatography stage, an agitation stage, a hold-up measurement stage, or any other suitable stage, and may include respective equipment for performing one or more processing operations associated with the respective processing stage, and one or more control devices for controlling the equipment associated with the respective processing stage based on control signals from at least one processor of a system that configures and / or controls a downstream process.

[0070] The system for processing biomass further includes one or more probes, sensors, or measuring devices for monitoring one or more parameters of a downstream process in at least one processing stage. Measurements are performed continuously throughout the process or at specified intervals. The measurements are used by one or more control devices to control at least one piece of processing equipment associated with each processing stage (e.g., by utilizing a feedback control loop and / or predictive control). Measurement of the at least one process parameter of the downstream process is performed in-line, online, at-line, or offline.

[0071] The system: at least one processing stage configured to perform an upstream process, thereby obtaining biomass to be processed in a downstream process; at least one measurement device for measuring at least one characteristic of the upstream process; Further includes:

[0072] As described above in relation to the first and second aspects, the measurement of at least one characteristic of the upstream process may be performed online (e.g., in-line or at-line) or offline. Furthermore, the above description of embodiments, examples, technical effects and advantages related to the above aspects also apply to the system according to the sixth aspect of the present disclosure.

[0073] The principles, methods, and devices described above can be used not only to integrate upstream and downstream processes, but also to integrate different sub-processes, processing stages, and / or different devices, systems, or units within one type of process, e.g., within an upstream process or a downstream process.

[0074] For example, measurement data / values ​​associated with at least one characteristic or parameter of one particular processing stage, device, and / or unit can be used to configure, set, and / or control another processing stage, device, or unit, e.g., before or after the one processing stage. Processing stages can be, for example, a cell growth stage, cell harvesting stage, agitation stage, media preparation stage, buffer exchange stage, perfusion stage, kSep, bag test stage, chromatography stage, filtration stage, etc. Measurement data / values ​​associated with one particular processing stage, device, and / or unit can also be used to control the particular processing stage, device, and / or unit (e.g., via a feedback control loop).

[0075] For example, measurement data / measurements obtained in a chromatography stage, and more specifically in a single run of a chromatography stage or operation, can be used to optimally configure and / or set (i.e., parameterize) and / or control a subsequent processing stage or operation, such as virus activation. In such applications, the cyclical operation of the chromatography stage can be challenging from a process control perspective. The proposed method alleviates this difficulty.

[0076] The exchange of data is bidirectional, so that measurement data of a second processing stage subsequent to the first processing stage can be used to configure, set and / or control the first processing stage.

[0077] Thus, according to a seventh aspect of the present disclosure, there is provided a computer-implemented method for configuring and / or setting up and / or controlling a process comprising a plurality of processing operations or stages for processing biomass to obtain a product, the method comprising: receiving at least one measurement of at least one characteristic of a first of the plurality of processing stages or operations; determining at least one process parameter of a second of the plurality of processing stages or operations based on the received at least one measurement; and configuring and / or setting and / or controlling a second of the plurality of processing stages or operations based on the determined at least one downstream process parameter.

[0078] In particular, controlling utilizes predictive control techniques based on measurements of at least one characteristic of the upstream process.

[0079] As noted above, a first of the plurality of processing stages or operations may be an upstream or downstream processing stage or operation, and a second of the plurality of processing stages or operations may be a downstream processing stage or operation. In one example, both first of the plurality of processing stages or operations may be downstream processing stages or operations. Furthermore, the second processing stage or operation may follow the first processing stage or operation or may precede the first processing stage or operation. Furthermore, two or more processing stages or operations may be configured, configured, and / or controlled based on measurements of one or more other processing stages or operations. In other words, there may be two or more first processing stages or operations and / or two or more second processing stages or operations.

[0080] As discussed above in connection with measuring upstream characteristics, measuring at least one characteristic of a processing stage or operation (upstream and / or downstream) can be performed online or offline, making the measurement available for configuring and / or setting up and / or controlling a downstream process. The at least one characteristic characterizes any property of any processing stage or operation, or operation(s) performed by a processing stage or operation, the product before, during, or after processing in any processing stage, and other process conditions. Exemplary characteristics include, but are not limited to, pressure, volumetric flow rate, volumetric flow rate, turbidity, viscosity, product amount and / or concentration, contaminant amount and / or concentration, cell viability, and temperature.

[0081] As noted above, a downstream process typically includes multiple (i.e., at least two, typically three or more) cascaded downstream processing stages or operations, such as, for example, multiple purification stages. Individual processing stages or operations can be connected in parallel, sequentially, or through a mixture of both parallel and sequential connections. In exemplary implementations of the first through seventh aspects, individual downstream processing stages or operations can be separately connected and disconnected, for example, by using respective control devices (actuators) such as valves. Thus, the downstream process as a whole can have a modular structure, allowing individual processing stages or operations, or groups of processing stages or operations, to be connected or disconnected in response to at least one process parameter determined based on at least one measured value. For example, one or more additional processing stages or operations (such as one or more purification stages or operations) can be added or removed from the current processing stages or operations that make up the downstream process based on the at least one process parameter.

[0082] The at least one process parameter therefore includes the number and / or type of downstream processing stages or operations to be connected or disconnected. Configuring and / or setting up and / or controlling therefore includes connecting or disconnecting the determined number and / or type of downstream processing stages or operations. Furthermore, any other parameters of the connected downstream stages or operations and / or product streams entering or leaving the downstream stages, such as pressure, dilution, temperature, additives, etc., are configured, set up, and / or controlled based on the at least one determined downstream process parameter. For example, based on measurements, at least one parameter characterizing the dimensioning of the determined number and / or type of downstream processing stages or operations is determined and used by the setting, configuration, and / or control. The at least one dimensioning parameter depends on the particular downstream processing stage and includes, for example, filter area, filter flow rate, retention time, binding capacity, flow rate, amount of additive, processing time, processing volume, centrifugal force, etc. Thus, one or more downstream stages or operations can be flexibly adapted to the output (eg, concentration, cell density, viability, titer, etc.) of an upstream process or of a previous downstream processing stage or operation.

[0083] In one example, the at least one connectable processing stage or operation is a purification stage or operation, such as a filtration stage (e.g., a depth filtration stage, a viral filtration stage, a viral inactivation stage, a tangential flow filtration stage, a sterile filtration stage, a pre-filtration stage, etc.), a chromatography stage, a centrifugation stage, etc. Additionally or alternatively, the at least one connectable processing stage includes a further processing stage, such as a temporary or permanent storage stage or operation, an agitation stage or operation, etc. During the purification stage, at least one property of the filter and / or product before, during, and / or after undergoing the purification process is measured. Based on the measurement, further purification stages (e.g., additional filters, pre-filters, chromatography columns, etc.) are dynamically / actively connected or disconnected during the purification process and / or the properties of the product targeted for the particular purification operation are changed / adapted.

[0084] Furthermore, the foregoing descriptions of embodiments, examples, technical effects, and advantages associated with the first to sixth aspects above also apply to the method according to the seventh aspect of the present disclosure.

[0085] According to an eighth aspect of the present disclosure, there is provided a computer program product comprising instructions which, when executed by a computer, cause the computer to perform the method of the seventh aspect.

[0086] According to a ninth aspect of the present disclosure, there is provided a system for configuring and / or setting up and / or controlling a process for treating biomass to obtain a product, the system comprising at least one processor configured to carry out the method according to the seventh aspect.

[0087] The system according to the ninth aspect of the present disclosure is configured in the same or similar manner and includes the same or similar components as the systems described in connection with the first to sixth aspects and examples. For example, the downstream configuration and / or control system further includes a receiving device for receiving measurement signals from at least one sensor measuring at least one upstream and / or downstream process characteristic. The system further includes at least one sensor for measuring at least one upstream and / or downstream process characteristic.

[0088] At least a characteristic of the process is measured upstream (i.e., at the input), downstream (i.e., at the output), and / or within a particular processing stage or operation. For example, a sensor measures at least one characteristic of at least one processing stage or operation (a first processing stage) of multiple processing stages or operations of an upstream or downstream process and / or at least one characteristic of a product supplied to or output from the first processing stage. The measurements are provided to a processor, which can determine at least one process parameter and configure, set up, and / or control at least one second processing stage based on the received measurements.

[0089] The system for configuring and / or setting and / or controlling a process for treating biomass further comprises at least one device (actuator) controlled by the at least one processor that helps to realize the determined configuration and / or setting and / or control. The at least one actuator may be, for example, a valve.

[0090] The at least one processor determines, e.g., using predictive control techniques based on at least one measurement received from a sensor, how many processing stages to connect and / or how to configure, set, and / or control the processing stages, and generates respective control signals to the at least one actuator.

[0091] The at least one actuator may be, for example, a valve associated with a particular processing stage, and the control signal may open or close the valve to disconnect or connect the respective processing stage. Additionally or alternatively, the control unit may issue control signals to the respective actuators to control the pressure, dilution, temperature, and / or other process characteristics and product characteristics supplied to the at least one second processing stage. Thus, the entire process may be optimally configured, set up, and / or controlled, reducing failures.

[0092] The system further includes a data storage unit (e.g., a database) for storing the determined at least one downstream process parameter and / or measurement value and / or rules linking the measurement value to the process parameter; and / or a receiving device for receiving the at least one measurement value and / or at least one sensor for obtaining the at least one measurement value.

[0093] Exemplary processors, receiving devices, sensors, and other devices such as actuators and data storage units are described above in relation to the first to sixth aspects and examples, and the descriptions also apply to the seventh to ninth aspects.

[0094] According to a tenth aspect of the present disclosure, there is provided a method for processing biomass to obtain a product, the method comprising: configuring and / or setting and / or controlling a process for treating biomass according to the method of the seventh aspect of the present disclosure; processing the biomass using a downstream process so configured and / or set up and / or controlled; Includes.

[0095] According to an eleventh aspect of the present disclosure, there is provided a system configured to process biomass to obtain a product, the system comprising: at least one system for configuring and / or setting and / or controlling according to the ninth aspect and embodiments above, comprising a processor configured to perform a method for configuring and / or setting and / or controlling a process for treating biomass according to the seventh aspect of the present disclosure; at least one process stage configured to process biomass by using a process so configured and / or set up; Includes.

[0096] The above description of embodiments, examples, technical effects and advantages associated with the first through sixth aspects and examples above also apply to the seventh through eleventh aspects of the present disclosure. Furthermore, the principles described above may be applied to any level of process granularity, such as to sub-stages of a particular processing stage. [Effects of the Invention]

[0097] The exchange of data (one-way or two-way) between various processing stages, devices and / or units, or between upstream and downstream processes, has advantages including, but not limited to: ·Optimal synchronization of processes within various processing stages, devices and / or units or between upstream and downstream processes; · Reduced idle, non-productive time and increased processing efficiency; ·Improved yield and / or quality of the final product; ·Reducing waste; ·Optimize consumption and / or storage of medium; · Optimize inventory management and logistics.

[0098] Furthermore, by adapting (setting, configuring and / or controlling) the individual processes and by modularly connecting and / or controlling the individual processing stages, one or more of the following advantages are realized: · Avoiding or reducing product losses, for example due to blocked filters, and avoiding or reducing the need for complex and costly product recovery procedures; · Optimizing processes at processing stages after and / or before connection of the process workflow, for example, optimizing pressure ranges, adapting to variations in filter capacity tolerances and / or product properties at different stages of the process workflow; · Avoid over-dimensioning and the associated increased costs; · Reduce dead volume; · Maintaining and / or adapting the flow of throughput before and through connecting processing stages in the process workflow.

[0099] The above advantages of flexible modular connection and / or control of downstream processing stages or operations apply to both batch and continuous processes. A typical continuous process is the perfusion process involved in the production of biopharmaceuticals, during which the product is released to a subsequent processing stage continuously or at any time interval.

[0100] In particular, in the case of prior art continuous processes operating over long processing time ranges (e.g., greater than 8 hours), it was often necessary to over-increase the throughput of individual stages of the process to ensure sufficient capacity over the entire processing time. This entails a number of drawbacks. For example, if a fairly large entire filter area is immediately switched on or activated at the beginning of the process, the product flow is relatively attenuated due to a large dead volume relative to the flow rate. Furthermore, particularly during start-up, the relatively long residence time within a particular purification stage (e.g., filtration stage, chromatography stage, etc.) can hinder or complicate process monitoring by sensors located at the outlet of the purification stage. This means that when processing decisions need to be made based on sensor monitoring at the output of a purification stage, a portion of the product must often be discarded due to a lack of measurements (the so-called dead volume of the purification stage). This increases costs, especially when disposable technology (e.g., disposable filters) is employed.

[0101] Furthermore, a large filter area in a purification stage relative to the fluid flow can result in insufficient input pressure, resulting in uneven flow distribution within the purification stage (e.g., within a filtration stage), which in turn negatively impacts efficiency, process stability, reliability, and safety, especially for chromatography stages.

[0102] Furthermore, the product streams fed to a particular purification stage or group of purification stages exhibit variations in the product as well as filter materials and characteristics. In traditional downstream processing methods, such variations are addressed by over-dimensioning the individual purification stages, which leads to the technical problems discussed above.

[0103] The flexible configuration, setup and / or control of the downstream processes described above, which include multiple (individually) connectable and / or controllable stages or operations, particularly multiple individually connectable and / or controllable purification stages or operations, overcomes one or more of the above-mentioned problems of conventional biological treatment methods described above and provides the above-mentioned advantages.

[0104] For example, the exact amount of filter material for a given overall process is predetermined and flexibly changed as needed, eliminating the need to over-dimension the system and reducing or completely avoiding the drawbacks associated with over-dimensioning.

[0105] Additionally, the adaptive connection and disconnection of processing stages and sub-stages (e.g., purification stages and sub-stages) during process execution makes it possible for the first time to run large-scale batch processes in continuous mode, which is otherwise not possible with such long processing times.

[0106] Furthermore, the active and flexible connection and disconnection and / or control of the individual treatment stages and sub-stages allows balancing of the volumetric flow rates of the individual treatment stages and sub-stages, thereby enabling the disposal of intermediate storage tanks.

[0107] Furthermore, when using disposable vessels and components such as disposable bioreactors, connectors, sensors, and filter elements, automatic connection and disconnection of individual processing stages and substages can significantly reduce undesirable contaminants, which is important for aseptic processes where such disposable vessels and components are used.

[0108] A primary application of the processes and systems according to the above aspects and embodiments is the purification of biopharmaceuticals. These include cells, cell fragments, protein-based compounds (e.g., antibodies, viruses, virus-like particles, RNA, DNA, etc.). Other applications include the chemical and food industries, water treatment, etc. [Brief explanation of the drawings]

[0109] These and other aspects are described in detail with reference to the following drawings. [Figure 1] FIG. 1 is a schematic diagram of an exemplary system for configuring and / or setting up a downstream process for processing biomass to obtain an end product. [Figure 2] FIG. 1 is a schematic diagram of another exemplary system for processing biomass to obtain an end product. [Figure 3] FIG. 1 is a representative method diagram for setting, configuring, and / or controlling a biological process based on sensor information. [Figure 4] FIG. 1 is a block diagram of an exemplary process for treating biomass in an exemplary system including a bioreactor. [Figure 5] FIG. 1 shows an example of the dependence of bioreactor filter volume and filter area on cell number. [Figure 6A] FIG. 1 is a block diagram of one major purification stage. [Figure 6B] FIG. 1 is a block diagram of an exemplary modular purification stage that includes multiple smaller connectable purification stages. [Figure 7] FIG. 1 shows an example of the dependency of virus reduction on differential pressure during virus filtration for three different monoclonal antibodies. [Figure 8] FIG. 1 is a block diagram of a representative pre-purification stage connected to a main purification stage. [Figure 9] FIG. 1 is a block diagram of an exemplary purification process with multiple membrane absorbers. [Figure 10]FIG. 1 is a block diagram of an exemplary purification process with intermediate storage tanks. DETAILED DESCRIPTION OF THE INVENTION

[0110] 1 is a schematic diagram of an exemplary system 10 for configuring and / or setting up a downstream process for processing biomass to obtain an end product. The system 10 includes a receiving device 102 for receiving a measurement 12 of at least one characteristic of an upstream process used to obtain biomass to be processed in the downstream process (upstream characteristic). The measurement 12 of the at least one upstream characteristic is transmitted to the receiving device 102 via a suitable communications network 14, such as a computer network, wirelessly, or by any other suitable communications means. The measurement 12 of the at least one upstream characteristic may be measured and / or transmitted online or offline. Additionally or alternatively, the receiving device 102 is configured to receive at least one measurement or at least one characteristic of the downstream process (downstream characteristic). The measurement of the at least one downstream characteristic may be measured and / or transmitted online or offline.

[0111] The at least one upstream and / or downstream characteristic can characterize biomass or products before, during, and / or after processing in an upstream and / or downstream processing stage or stages, process parameters of any upstream and / or downstream processing stage or stages, and / or other relevant process characteristics. As described above, the at least one upstream and / or downstream characteristic is measured by a respective sensor that is part of system 10 for configuring and / or setting and / or controlling a downstream process.

[0112] Representative online upstream features include any of the following features: · pH (e.g. used to set / control pH parameters of downstream processes); Conductivity (e.g. used to set / control conductivity parameters of downstream processes); · Temperature (e.g. used to set / control temperature parameters of downstream processes, typically in the range of 4°C to 30°C); · Culture volume (used to configure / set / control downstream processes, e.g., diatomaceous earth cell harvesting process); · Antifoam concentration (e.g. used to configure / set / control downstream processes, e.g. high antifoam concentration is negative for downstream processes); Cell density, cell culture turbidity, cell viability (used to configure / set / control downstream processes such as e.g. diatomaceous earth treatment, setting clarification (purification) settings such as centrifugal force settings, filter settings, chromatography settings); Flow sensor parameters, including sensor quality (used to configure / set / control continuous downstream processes, e.g., from perfusion cultures); · Spectroscopic data showing, for example, total protein concentration; · metabolite and / or medium concentrations; Pressure values ​​of conduits (tubes, etc.) and / or bioreactors, etc. (usually in the range of 0.1-4 bar); · Viscosity in the bioreactor or at the bioreactor outlet (usually in the range of 1-50 cP).

[0113] Typical offline upstream features include any of the following features: ·Cell viability; Total protein concentration obtained by offline measurement or offline sample; Lactate dehydrogenase or other enzyme activity; Upstream product quality, e.g., of monoclonal antibodies; ·Upstream product aggregation levels; ·Product concentration; ·DNA / HCP concentration.

[0114] Typical downstream features include: · Turbidity; Conductivity; ·Cell density: ·Cell viability; ·viscosity; · Pressure; ·Flow rate; · Temperature (usually between 4°C and 30°C); · metabolite and / or medium concentrations; · Pollutant concentrations; Protein concentration.

[0115] The system 10 further includes at least one processor 104 (e.g., constituting or forming part of a computer-aided control unit) configured to determine at least one downstream process parameter based on the received at least one measurement value of at least one upstream and / or downstream characteristic. The at least one processor 104 is further configured to automatically set up, configure, and / or control at least one processing stage or processing operation of the downstream process based on the determined at least one downstream process parameter. The configuring, configuring, and / or controlling is achieved by issuing one or more control signals to at least one actuator, which performs the determined control upon receiving the control signal from the at least one processor 104. The actuators may be, for example, valves controlled by respective control signals received from the processor 104. The processor 104 further includes a database 106 for storing measurements of one or more upstream and / or downstream characteristics and / or predetermined (functional) relationships or laws linking the one or more upstream and / or downstream characteristics to one or more downstream characteristics. The database 106 may be a stand-alone unit linked to the at least one processor 104 by a suitable communication link, for example via the Internet, WLAN, or the like.

[0116] Optionally, the processor 104 may be configured to set, configure and / or control the upstream process based on the received at least one measurement of the at least one downstream characteristic.

[0117] Setting, configuring and / or controlling the downstream and / or upstream processing stages may include influencing or adjusting at least one upstream and / or downstream process parameter, respectively, which may be a parameter associated with any downstream and / or upstream processing stage, respectively.

[0118] For example, the at least one processor 104 determines the type and / or number of processing stages (e.g., purification stages) to be connected or disconnected in the downstream process based on the measured value of the at least one characteristic and predetermined parameterization / laws, and generates respective control signals to open or close respective valves associated with each processing stage.

[0119] Additionally or alternatively, the at least one processor 104 determines at least one process parameter of the processing stages after and / or before the first processing stage or stages, and issues control signals to respective actuators to control the at least one process parameter in these stages, such as the pressure and / or dilution and / or other characteristics of the product supplied to the particular processing stage or stages, the pressure within the particular processing stage or stages, the temperature, etc.

[0120] In one example, at least one additional sensor is provided to measure at least one characteristic at the output of a particular processing stage, for example to monitor the efficiency of the purification process. The measured value is provided to the at least one processor 104 and used to control the particular processing stage based on the measurement signal from the sensor. Thus, the overall process can be further optimized.

[0121] 2 is a schematic diagram of an exemplary system 100 for processing biomass to produce products, including multiple processing stages. System 100 includes an upstream processing subsystem 100A and a downstream processing subsystem 100B.

[0122] The upstream processing subsystem 100A includes at least one bioreactor 110. The bioreactor 110 can be of any size, from a small, laboratory-sized bioreactor to a very large bioreactor with a volume of approximately 2000 L or more. Bioreactors of various sizes are available, for example, from Sartorius Stedim Biotech. Measurements of at least one upstream characteristic of the upstream process performed by the upstream processing subsystem 100A are transmitted to the downstream processing subsystem 100B via a communications network 14, such as a computer network, by wireless or other suitable communications means. The transmitted measurements of the at least one upstream characteristic are used to configure or set up the downstream process performed by the downstream processing subsystem 100B.

[0123] The downstream processing subsystem 100B includes multiple processing stages, the number, type, size, etc. of which may vary depending on the specific application. As shown in Figure 2, one or more processing stages of the downstream processing subsystem 100B are configured or set based on the measurement data received from the upstream processing subsystem 100A.

[0124] In the example shown in FIG. 2, downstream processing subsystem 100B includes a Protein A chromatography stage 120 followed by a viral inactivation stage 180. The viral inactivation stage 180 includes multiple substages 181-186, each performing a specific subprocess or group of subprocesses. Substage 181 is an agitation stage, such as a 1000 L Palletank® agitation stage from Sartorius Stedim Biotec. Substage 182 is a low-pH viral inactivation stage, such as a FlexAct® VI agitation stage from Sartorius Stedim Biotec. Substage 183 is an agitation stage, such as a 1000 L Palletank® agitation stage from Sartorius Stedim Biotec. Substages 184 and 185 are filtration stages, using, for example, Sartopure® GF 0.65 μm filtration units, and substage 186 is an agitation stage, for example, a 1000 L Palletank® agitation stage from Sartorius Stedim Biotec. The processing stages shown in FIG. 2 are only exemplary. As noted above, other stages, or combinations of stages, other types, sizes, etc., can be used.

[0125] Measurements of at least one characteristic of the process performed by one or more stages of the downstream processing subsystem 100B (downstream characteristic) are obtained and transmitted to other stages of the downstream processing subsystem 100B via a communications network 140, such as a computer network. The transmitted measurement of the at least one downstream characteristic is also used to configure or set up the at least one other stage to which these measurements are transmitted. The measurement of the at least one upstream characteristic and / or the measurement of the at least one downstream characteristic form part of process-related data 160 exchanged within the downstream processing subsystem 100B and are used to configure, set up and / or control one or more downstream processing stages. The exchange of process-related data is managed, for example, by appropriately configured processing equipment.

[0126] For example, the exchanged process-related data 160 may comprise one or more characteristics of the Protein A chromatography stage 120 that are measured and transmitted via a communication network (e.g., a computer network) 140 to the viral inactivation stage 180 and / or other downstream stages, including the number of chromatography cycles, progress, volume of one chromatography cycle, buffer strength or amount, buffer type, pH of the eluate, etc. Based on the received characteristics, one or more process parameters of the inactivation stage and / or other downstream stages are configured or set.

[0127] FIG. 3 is a schematic diagram of an exemplary method for setting up, configuring and / or controlling a biological process, for example, using the system shown in FIGS.

[0128] As noted above, a biological process includes an upstream process in which biomass (such as a cell culture) is produced, and a downstream process in which the biomass produced by the upstream process is processed into an end product that meets target quality and purity requirements. The downstream process includes at least one purification stage 18 that purifies the input biomass, for example, by removing (separating or filtering) at least a portion of undesirable materials.

[0129] At least one characteristic of an upstream process (upstream characteristic) and / or a downstream process (downstream characteristic) is measured, and that measurement, optionally along with other measurements, can be used to influence (e.g., set, configure, and / or control) at least one upstream process parameter and / or at least one downstream process parameter. The upstream and / or downstream measured characteristics 22 used to influence the downstream and / or upstream process are collectively referred to as influences / disturbance factors / characteristics. As noted above, such characteristics are measured online and offline by appropriate sensors.

[0130] Representative characteristics are described above and include, but are not limited to: pressure (typically in the range of 0.1-4 bar), volumetric flow rate, turbidity, viscosity (typically in the range of 1-50 cP), product concentration (typically in the range of 1-200 g / L), cell concentration, undesired substances (impurities, contaminants, etc.) and their composition (e.g., fractions of DNA, proteins, aggregates, etc.), temperature (typically in the range of 4°C-30°C), and filter performance (e.g., increase or decrease in pressure, retention time, etc.). Representative disturbance characteristics that may be monitored include errors in the concentration of target molecules or other target substances, errors in the amount and / or composition of undesired substances (impurities, contaminants, etc.) in intermediate and / or final products, temperature errors, and errors in filter performance (e.g., increase or decrease in pressure, error in filter capacity, retention time, deposition rate, binding capacity, flow rate, etc.).

[0131] In one example, at least one measurement value of at least one upstream characteristic can be used to affect at least one downstream parameter, e.g., to set, configure, or control at least one parameter of at least one downstream purification stage. Similarly, at least one measurement value of at least one downstream process characteristic can be used to affect at least one upstream parameter 16 and / or at least one downstream parameter 20. For example, as described above, at least one measurement value of at least one characteristic of a first downstream processing stage can be used to affect (e.g., set, configure, or control) at least one process parameter of a second downstream processing stage and / or the first downstream processing stage itself (e.g., using a feedback control loop and / or predictive control techniques). The second downstream processing stage can be a stage following the first processing stage or a stage preceding the first processing stage. The same principles apply when the first and / or second processing stages are upstream processing stages.

[0132] Typical process parameters that may be configured, set, and / or controlled include the number and / or type of purification stages (e.g., filtration stages), filter area, duration of purification operations (e.g., filtration, chromatography, and / or centrifugation operations), centrifugal force, pressure, amount of diluent or other additives, pump discharge, temperature, etc.

[0133] The configurations, settings and / or controls are intended to reach and / or maintain (optimal) target characteristics, for example, by reducing or compensating for errors in the concentration of target molecules or other target substances, errors in the amount and / or composition of impurities in intermediate and / or final products, temperature errors, errors in filter performance (e.g., pressure increases / decreases, filter capacity errors, retention times, deposition rates, binding capacities, flow rates, etc.).

[0134] Below are some examples of process parameters to set, configure, and / or control based on measurements of upstream and / or downstream characteristics, for example, using the systems shown in FIGS. 1 and 2 and the method shown in FIG. 3:

[0135] Table 1 shows typical upstream process (USP) features and their respective downstream process (DSP) parameters that are set / configured or adjusted / controlled. In Table 1, Category 1 represents cells or cell cultures, Category 2 represents products, Category 3 represents impurities, and Category 4 represents process control parameters. Each measured USP feature is assigned different levels of priority depending on its importance, e.g., 1: high priority, 2: medium priority, and 3: low priority.

[0136] [Table 1] TIFF0007746377000002.tif204170TIFF0007746377000003.tif220170TIFF0007746377000004.tif175170TIFF0007746377000005.tif166170

[0137] It is not necessary to consider all of the USP features listed in Table 1 when configuring a DSP process. For example, only high priority USP features or high and medium priority USP features may be considered. Generally, configuration of at least one DSP process stage or operation is performed automatically based on at least one of the upstream features listed in Table 1.

[0138] Further examples of configuration of downstream processes based on upstream features are given below.

[0139] Biomass Refining In one example, the at least one measured characteristic includes live cell concentration, viability, and / or total wet cell weight in or at the outlet of a bioreactor used in an upstream process, or in or at the outlet of an intermediate storage tank. Instead of total wet cell weight, the turbidity of the bioreactor contents may be measured (e.g., online or offline). Turbidity is a summary indicator / parameter for live cells, dead cells, and cell fraction.

[0140] The viable cell concentration is measured online, for example, by a capacitance sensor. Alternatively, the viable cell concentration can be measured offline. The total wet cell weight is measured by a respective gravimeter. The turbidity is measured by a respective turbidity sensor. Furthermore, at least one measured characteristic includes the average cell diameter / size and / or particle size distribution in or at the outlet of a bioreactor used in an upstream process or in or at the outlet of an intermediate storage tank.

[0141] Based on the measurements, the type and / or number of purification methods and / or purification stages are determined and each configured or controlled as described above. For example, based on the measurements, a cell separation method and certain process parameters (such as the type and / or number of filters) are determined.

[0142] Non-limiting examples of process parameter settings based on representative measured characteristics are given below: First, typical process parameter settings: Characteristics measured at the output of the bioreactor: Bioreactor volume: 120L Viable cell concentration (vcd) (Chinese hamster ovary): 13*10^6 cells / mL Survival rate 89% Wet cell weight (wcd) 60g / L Turbidity: 1700NTU Average cell diameter 19μm Selected separation stage Filtration by two stages of depth filtration followed by sterile filtration to first separate large cells and then small particles: 1st stage: Depth filters: 3x Sartoclear DL90 cassettes (0.8m each) 2 Filter area, retention rate 15μm | 2μm) Second stage: Depth filter: 2x Sartoclear DL20 cassettes (0.8m each) 2 Filter area, retention rate 0.8μm | 0.4μm) Sterile filters: 2x Sartopore2 XLG, size 0 (0.52 m each) 2 Filter area, pore size 0.8μm|0.2μm)

[0143] In one example, all of the determined number of filtration stages can be connected or activated simultaneously. Alternatively, additional filtration stages can be connected in sequence, with new filtration stages being connected / activated when certain conditions are reached. For example, a new filtration stage can be connected or activated if a certain pressure limit is reached at or after a particular filtration stage or group of filtration stages, if the turbidity after a particular filtration stage or group of filtration stages is higher than a certain threshold, and / or if the increase in turbidity after a particular filtration stage or group of filtration stages is greater than a certain limit (a sudden or abrupt increase in turbidity indicating particle breakthrough).

[0144] For example, for a given measured viability, the number of filtration stages can be increased with increasing wet cell weight and / or viable cell concentration. For example, for a given measured viability, the number of filtration stages can be increased when the wet cell weight is greater than a certain threshold (e.g., 90 g / L) and / or when the viable cell concentration is greater than a certain threshold.

[0145] Additionally, for a given measured wet cell weight, the number of filters in the first depth filtration stage can be increased with increasing viable cell concentration, e.g., if the measured viable cell concentration for a given wet cell weight is above a certain threshold, the number of filters in the first depth filtration stage can be increased.

[0146] Additionally, for a given cell concentration, the number of filters in the second depth filtration stage and / or sterile filtration stage can be increased as the wet cell weight and / or turbidity increases, e.g., if the wet cell weight and / or turbidity for a given cell concentration is higher than a predetermined limit, the number of filters in the second depth filtration stage and / or sterile filtration stage can be increased.

[0147] Furthermore, for a known particle size distribution, the filter area can be determined according to the proportion of large and small particles.

[0148] Second, typical process parameter settings Characteristics measured at the bioreactor output: turbidity of the cell culture, typically in the range of 1500–2500 NTU; Wet cell weight (wtc) of the cell culture, typically in the range of 6% to 8%; Viable cell density (vcd) of cell culture, typically in the range of 15–20 mln cells / mL.

[0149] Cell isolation configuration and settings For cell separation, three different filtration stages are used, with the filter areas or filter volumes of the three stages in a predetermined ratio, for example about 2:1:0.75 or any other suitable ratio.

[0150] The filter area of ​​each individual filtration stage is determined according to the amount of cell suspension to be processed. For example, the first filtration stage has a filter capacity expressed by a filter area-to-volume ratio of about 50 L / m2. The filter capacities of the second and third filtration stages are determined according to a predetermined ratio.

[0151] The first filtration stage may be a depth filtration stage using, for example, a depth filter with two different retentive layers (e.g., with retention rates of 15 mm and 2 mm). The second filtration stage may be a finer depth filtration stage using, for example, a depth filter with two different retentive layers (e.g., with retention rates of 0.8 mm and 0.4 mm). The third filtration stage may be a sterile filtration stage using a sterile filter with two membranes with different pore sizes (e.g., 0.8 mm and 0.2 mm).

[0152] For example, if a filter having the above characteristics does not exist, other numbers of filters and / or other filter areas may be used.

[0153] If the measured turbidity is greater than 2500 NTU (e.g., if the measured turbidity is approximately 3000 NTU) and the wet cell weight and / or viable cell density are within the ranges described above (see "Characteristics Measured at the Output of the Bioreactor"), the filter area of, for example, the second and / or third filtration stages may be increased. If the wet cell weight and / or viable cell density are within the ranges described above, a turbidity greater than 2500 NTU typically indicates that many small particles cannot be retained / filtered out in the first filtration stage and should therefore be processed in one or more subsequent filtration stages. As a general rule, the higher the measured turbidity, the larger the overall filter area.

[0154] Relationships between measured characteristics, such as the wet cell weight / viable cell density relationship and / or the turbidity / wet cell weight relationship and / or the volume / wet cell density relationship, may also be used to initially determine or select the type of purification stage (e.g., centrifugation stage, filtration stage, chromatography stage, etc.) and then determine the configuration / settings of each selected purification stage.

[0155] The three filtration stages and filters described above are exemplary, and different numbers and / or types of filtration stages and filters may be used. For example, if the cell suspension to be purified contains mostly intact (living) cells and few damaged cells, it is possible to use fewer filtration stages and filters. For example, two filtration stages can be used, one of which is a depth filtration stage, instead of the three filtration stages described above.

[0156] The above principles also apply to other purification stages, such as other types of filtration stages, chromatography stages, etc.

[0157] In another example, the measured upstream characteristic may be, for example, titer. High titer multiplied by throughput yields a large amount of product. Generally, the higher the titer, the less volume is loaded into / across the chromatography column during the loading step. Thus, with increasing titer in the USP process, larger size and / or greater number of chromatography columns and / or a greater number of cycles are configured / configured in the DSP process. Additionally, the column exchange sequence, loading scenario, and / or sequence can be configured appropriately.

[0158] Table 2 shows a typical setup / configuration of the downstream process (DSP) based on the titer measured during the upstream process (USP).

[0159] [Table 2]

[0160] Additionally or alternatively, the measured upstream characteristic may be cell viability. Table 3 shows representative settings / configurations for downstream processes based on measured upstream cell viability. Typically, the settings for the clarification (purification) operation (e.g., g-force of the centrifugation stage) are determined based on the measured / target cell viability. As a general rule, the higher the target viability at the end of centrifugation, the lower the g-force of the centrifugation stage.

[0161] Additionally or alternatively, clarification (purification) settings (e.g., g-force of centrifugation stage, duration of centrifugation, etc.) are selected based on the targeted degree of sedimentation. For example, the higher the targeted degree of sedimentation (regardless of cell viability), the higher the centrifugation g-force and / or the longer the duration of centrifugation.

[0162] [Table 3]

[0163] Additionally or alternatively, the measured upstream characteristic may be (viable) cell density or concentration. Generally, the higher the measured (viable cell) density or concentration, the larger the filter area and / or number of filters and / or number of filtration cycles, etc. This also applies to the measured biomass. That is, the larger the amount of measured biomass, the larger the filter area and / or number of filters and / or number of filter cycles, etc.

[0164] Tables 4A and 4B show representative setups / configurations for downstream processes based on measured upstream cell densities or concentrations. Specifically, Table 4A shows a representative selection of downstream cell separation methods for CHO cells based on measured upstream cell densities or cell concentrations. Table 4B shows representative configurations / configurations for filters used for CHO cell separation based on measured upstream cell densities or cell concentrations.

[0165] [Table 4A]

[0166] [Table 4B]

[0167] Additionally or alternatively, the measured upstream characteristic may be pH. Table 5 shows a typical configuration / setting for a downstream process based on the measured upstream pH. The pH configuration / setting will vary depending on the pH requirement (target pH) of the particular processing stage. If the pH is within the target range, no further adjustment is necessary. If the pH is outside the target range, the addition of a pH corrector (acid or base type) may be required. The greater the deviation from the target pH, the greater the amount of pH corrector.

[0168] [Table 5]

[0169] Additionally or alternatively, the measured upstream characteristic may be temperature. Table 6 shows a typical configuration / settings for a downstream process based on the measured upstream temperature.

[0170] [Table 6]

[0171] The settings, including the (functional) relationships or laws linking the upstream characteristics and downstream parameters in Tables 1-6 above, are stored in database 106 and used to set up, configure, and / or control the downstream process.

[0172] At least one of the upstream characteristics listed in Tables 1-6 above is also measured at a particular stage of the downstream process and used to set up or configure one or more subsequent stages of the downstream process. A representative example of a characteristic measured at a downstream processing stage and used to configure subsequent downstream processing steps is conductivity. Other representative characteristics include pH, pressure, temperature, cell density, turbidity, cell viability, flow rate, metabolite and / or media concentrations, contaminant concentrations, protein concentrations, etc.

[0173] As noted above, various other upstream and downstream characteristics may be measured and used alone or in combination to set / configure and / or control the downstream process. Further examples of downstream process control are described in more detail below. [Example]

[0174] Example 1: Post-bioreactor cell separation Figure 4 shows a block diagram of an exemplary process for processing biomass in an exemplary system including a bioreactor, the process including a cell separation stage after a biomass growth stage in the bioreactor.

[0175] The system includes a bioreactor 30, a control unit 32 (as part of or part of a downstream setup, configuration, and / or control system) including at least one processor. The system further includes a set of purification stages 34A-34D disposed downstream of the bioreactor 30 for cell separation. The purification stages 34A-34D may be, for example, filtration stages, chromatography stages, centrifugation stages, etc. In the example shown in Figure 4, the purification stages 34A-34D are connected in parallel. Other connection patterns (such as series connections or combinations of parallel and series connections) are also possible.

[0176] Each of the purification stages 34A-34D can be connected or disconnected within the process flow path via a respective actuator 36A-36D (e.g., a valve). Each of the actuators 36A-36D is connected to and controlled by the control unit 32. For example, each of the actuators 36A-36D can be opened or closed based on a control signal from the control unit 32, thus connecting or disconnecting the respective purification stages 34A-34D.

[0177] The control unit 32 is further connected to a plurality of sensors and receives measurement signals therefrom. The plurality of sensors includes, for example, a sensor for determining the concentration of a particular substance or ingredient and / or biomass. The sensor for determining the ingredient concentration may be, for example, a spectroscopic sensor (e.g., a near-infrared sensor, a Raman sensor, an absorption sensor, etc.). The sensor for determining the biomass concentration may be, for example, a turbidity sensor, an impedance sensor, a capacitance sensor, etc.

[0178] Exemplary features and disturbance features that may be measured and monitored by one or more sensors are, for example, the features described in relation to Figures 1 to 3. In particular, exemplary features that may be measured by a sensor include, but are not limited to, the following features: Upstream: Pressure (typically in the range 0.1-4 bar), volumetric flow rate, turbidity, viscosity (typically in the range 1-50 cP).

[0179] Exemplary disturbance characteristics monitored by each sensor include, but are not limited to, errors in the concentration of a target molecule or other target substance, errors in the amount and / or composition of impurities in the input product, intermediate product, and / or final product, temperature errors, errors in filter performance (e.g., errors in pressure, filter capacity, filters, etc.).

[0180] Based on the measurement results, the control unit 32 determines whether additional purification stages need to be connected, if so, how many additional stages, and / or the settings of each purification stage, and issues respective control signals to the actuators 36A-36D to ensure optimal purification stage capacity, thereby reducing or avoiding product losses or complex product regeneration processes.

[0181] In the embodiment shown in FIG. 4, the sensor includes: W a weight sensor (e.g., a weigh scale) configured to measure the weight of the biomass contained in the bioreactor 30, i.e., the weight of the biomass to be processed in a downstream process; B. a sensor, such as a turbidity sensor, that measures at least one property of the biomass in or at the outlet of the bioreactor 30; P1 is a pressure sensor placed upstream of the group of purification stages 34A-34D to measure the pressure at the input to said group of purification stages or at the outlet of the bioreactor 30, the pressure at the outlet of the bioreactor typically being in the range of 0.1 to 4 bar; P2 is a pressure sensor located downstream of separation stages 34A-34D to measure the pressure at the outlet of the purification stages or at the inlet of a processing stage (not shown) following purification stages 34A-34D.

[0182] Measurement signals from these sensors are transmitted to a control unit and used to configure, set and / or control at least one process parameter, in particular at least one parameter of a downstream process.

[0183] In particular, turbidity sensor B (or other suitable sensor) measures cell count within bioreactor 30 or at its outlet. Gravimeter W measures the mass or volume of the bioreactor to be processed (e.g., purified) in a downstream process. In the downstream process, multiple purification stages 34A-34D (e.g., filtration stages) are provided that can be connected in parallel for cell separation. Based on measurement signals from the turbidity sensor and gravimeter and predetermined parameterization or laws (e.g., stored in a database), control unit 32 determines the number of purification stages 34A-34D to be connected and their respective control signals. Based on the control signals, respective valves 36A-36D associated with each purification stage are controlled, e.g., opened or closed to connect or disconnect the respective purification stages 34A-34D. Control unit 32 (together with respective actuators) further controls other characteristics of the product stream to each purification stage 34A-34D, e.g., flow rate, pressure, temperature, etc., based on measurement signals from sensors W, B, P, and, optionally, other sensors, e.g., volumetric flow rate sensors, viscosity sensors, temperature sensors, etc.

[0184] For example, the control unit 32 may optionally further monitor the blocking level of a particular purification stage or group of purification stages with the aid of additional pressure, flow, velocity, viscosity, or other suitable sensors located before and / or after each purification stage 34A-34D and / or before and / or after a group of purification stages 34A-34D. Based on the measurement results, the control unit 32 determines whether additional purification stages are required, how many additional stages are required, and / or what settings each purification stage should have, to ensure optimal purification stage capacity, and issues respective control signals to the actuators 36A-36D. Thus, product losses or complex product regeneration processes can be reduced or avoided.

[0185] Figure 5 shows an example of the dependency of filter volume and filter area on the measured cell number in the bioreactor, where the X coordinate represents the measured cell number in the bioreactor and the Y coordinate represents the required filter volume [L / m 2 ] and the required filter area [m 2 The dependencies may be stored in a suitable format in a database or other data storage unit connected to or part of the control unit 32 and used to set up, configure and / or control downstream processes, in particular the purification stages 34A-34D.

[0186] By selectively connecting and / or disconnecting individual purification stages, only the filter area necessary to achieve a smooth and efficient purification process is connected / active at any given time. As discussed above, this prevents overdimensioning and its resulting drawbacks. For example, it reduces or eliminates purification process dead volumes and the resulting significant product losses. In a continuous process, a constant volumetric flow rate can be quickly achieved in subsequent purification stages, significantly reducing the time that the product being processed in a particular purification stage is held / processed.

[0187] The control of the purification process / stage carried out with the aid of the control unit 32 may further include determination and control steps for controlling further process parameters or devices such as pump power (pump discharge flow rate), agitation speed, retention time of intermediate tanks, etc. The control may be based on measurement signals received from one or more of the above sensors or from any suitable additional or alternative sensors.

[0188] As described in relation to FIG. 3 , the multiple purification stages (such as their number, type and / or other settings), as well as the optional additional processing stages, are set up, configured and / or controlled to reach and / or maintain (optimal) target properties, for example, by reducing or compensating for errors in the concentration of the target molecule or other target substance, errors in the amount and / or composition of impurities in the input, intermediate and / or final product, temperature errors, errors in filter performance (e.g., errors in pressure, filter capacity, filters, etc.). In the above embodiment, four connectable purification stages 34A-34D are shown, however, the number of connectable purification stages is not limited to four and may be more or less than four.

[0189] Example 2: Reducing residence time in sterile filtration stages As mentioned above, using a single purification stage or module with a large filter area can lead to blocking of part of the filter area, while other parts remain unused, especially when the product volumetric flow rate is low. After blocking of part of the filter area, the purified product may begin to flow to other previously unused parts. However, because the blocked parts remain in the respective purification stage for a relatively long time until the entire purification process is completed, breakthrough of undesired substances that should be removed, i.e., filtered out, may occur. This is a particularly serious problem for sterile filtration processes, where breakthrough of bacteria or other similar substances that should be filtered out may occur.

[0190] By dividing the total filter area provided by one purification stage into multiple connectable modules or purification stages with smaller filter areas, individual purification stages can be added or connected only when needed, for example, when blocking of a particular purification stage is detected. This improves the efficiency of the overall process. Furthermore, blocked purification stages can be removed or disconnected, thus avoiding or preventing breakthrough of undesired substances.

[0191] FIG. 6A schematically illustrates a single large purification stage 34 with a predetermined (large) filter area, while FIG. 6B illustrates an example in which the purification stage 34 shown in FIG. 6A is divided into multiple purification stages 34A, 34B, and 34C with smaller filter areas. Each of the multiple purification stages 34A-34C can be individually connected or disconnected by a respective actuator 36A-36C and 37A-37C, where the actuators 36A-36C are located on the input side of each purification stage 34A-34C and the actuators 37A-37C are located on the output side of each purification stage 34A-34C. The actuators 36A-36C and 37A-37C are connected to a control unit (not shown), such as the control unit 32 described above. The actuators 36A-36C and 37A-37C are controlled by control signals from the control unit, as described above. This allows the individual purification stages 34A-34C to be actively and flexibly connected and disconnected, enabling a variety of connection patterns.

[0192] As described in connection with Figures 3-5, the number of purification stages activated at a given time in the downstream process and / or the filter area provided by the purification stages are determined and controlled by a control unit based on a number of measured characteristics to reach and / or maintain (optimal) target properties. Typical measured characteristics by which the number of purification stages activated at a given time is determined include upstream and / or downstream pressure, volumetric flow rate, volumetric flow rate, turbidity, viscosity, temperature, etc. Typical monitored disturbance characteristics include errors in the concentration of target molecules or other target substances, errors in the amount and / or composition of impurities in intermediate and / or final products, temperature errors, and errors in filter performance (e.g., pressure increases / decreases, filter capacity errors, retention times, etc.).

[0193] Example 3: Determining the optimal operating point for viral filtration The effect of operating pressure on virus filtration is generally known: depending on the operating pressure, virus filtration / retention capacity may vary (see, for example, Biotechnol Prog. 2017 Sep;33(5):1294-1302). In one example, the operating pressure before (i.e., upstream of) a virus filtration stage or a group of virus filtration stages is measured by a suitable pressure sensor, and based on the measured pressure value, a control unit (such as control unit 32 described above) issues a control signal to add or remove (i.e., connect or disconnect) at least one additional virus filtration stage. In particular, the control unit is configured to perform control of the filtration stages when a virus filtration stage is connected or disconnected (e.g., as shown in FIG. 6B ) so that the operating pressure is maintained within a predetermined optimal range. This is particularly important in quasi-continuous processes, because the total filter surface to be provided in such processes is relatively large, and therefore a relatively low flow rate initially does not allow for a sufficient pressure difference.

[0194] Instead of, or in addition to, pressure, the number and / or characteristics or settings of (additional) virus filtration stages may be determined based on other measured characteristics described in connection with Figure 3. Exemplary measured characteristics include, but are not limited to: Upstream: pressure (usually in the range of 0.1-4 bar), volumetric flow rate, volumetric flow rate, viscosity (usually in the range of 1-50 cP), temperature (usually in the range of 4°C-30°C); Downstream: pressure, temperature, turbidity, impurities, flow rate, etc.

[0195] Typical monitored disturbance features include errors in the concentration of target molecules or other target substances, errors in the amount and / or composition of impurities in intermediate and / or final products, temperature errors, errors in filter performance (e.g., increases or decreases in pressure, errors in filter capacity, retention times, etc.).

[0196] Figure 7 shows an example of the dependency of virus reduction on differential pressure as a function of differential pressure during virus filtration for three different monoclonal antibodies (mAb A, mAb B, and mAb C). In Figure 7, the x-axis shows differential pressure in units of [bar], and the y-axis shows the log reduction of minute virus of mice (Log [virus concentration in the filtrate divided by virus concentration in the feedstream]). The dependency can be stored in a suitable format in a database or other storage unit and used to set up, configure, and / or control downstream processes, particularly the virus filtration stage.

[0197] Example 4: Connection of a pre-filter, e.g., for sterile filtration In one example, a prestage (e.g., a pre-filtration stage) is used to increase the capacity of the actual main purification stage or purification stages (e.g., filtration stage(s)) being used. The main purification stage may be, for example, a sterile filtration stage, and a pre-filter is connected upstream of the main sterile filtration stage. The output or capacity of a prestage, such as a pre-filtration stage, may vary due to variations in the filter material and / or variations in the supplied product solution. This may result in case-by-case variations in the results of the pre-filtration stage, especially in continuous processes.

[0198] FIG. 8 shows a block diagram of an example of pre-purification stages 38A-38C (e.g., pre-filtration stages) connected to a primary purification stage 40 (e.g., a main filter). Each of the pre-purification stages 38A-38C is connected to a respective actuator 36A-36C, which is controlled by a control unit (not shown), such as the control unit 32 described above. The actuators 36A-36C may be, for example, valves that open or close upon receiving a control signal from the control unit, thus disconnecting or connecting the respective pre-purification stages 38A-38C as needed. Sensor B at the outlet of the pre-purification stages monitors the biomass / product at the outlet of the pre-purification stages. Sensor B may be a turbidity sensor or any other suitable sensor.

[0199] In one example, the quality of purification (e.g., filtration) of the pre-purification stage(s) is monitored by sensor B, for example by measuring the turbidity of the filtrate or other suitable parameter. If the measured turbidity or other parameter exceeds a predetermined value, the control unit issues a control signal to connect (i.e., add) an additional pre-purification stage (e.g., an additional pre-filtration stage). The additional pre-purification stage is connected in series or parallel to the other pre-purification stages or purification stages. Thus, it is possible to maintain the turbidity within a predetermined range and ensure or improve the performance of the main purification stage or purification stages.

[0200] Exemplary measured characteristics by which the control unit configures, sets, and / or controls the pre-filtration stage include upstream measured pressure and / or volumetric flow rate, and downstream measured turbidity. Exemplary monitored disturbance characteristics include errors in the concentration of target molecules or other target substances, errors in the amount and / or composition of impurities in the intermediate and / or final products, temperature errors, errors in filter performance of the main and pre-filtration stage(s) (e.g., pressure increases / decreases, filter capacity errors, retention times, etc.).

[0201] Example 5: Control of flow-through polishing in the purification stage by membrane adsorber Flow-Through-Polishing is a chromatographic filtration step in which the target material passes through the filtering medium and unwanted material is retained on the filter by chromatographic interactions.

[0202] In one example, the chromatographic filtration step is achieved by multiple adsorber modules (each corresponding to a separate purification stage), which can be connected and disconnected as needed.

[0203] 9 shows a block diagram of a typical purification process using multiple membrane absorbers 42A-42C, each connected to a respective actuator 36A-36C. Each actuator 36A-36C is controlled by a control unit (not shown), such as the control unit 32 described above. For example, the actuators 36A-36C may be valves that open or close in response to control signals from the control unit, thus disconnecting or connecting the respective membrane absorbers 42A-42C. The following sensors are connected to the input side of the membrane absorber group: P: pressure sensor; F: flow sensor; UV: UV sensor with wavelength of e.g. 280nm to detect the concentration of molecules.

[0204] A sensor UV for measuring the concentration of molecules is connected to the output side of the group of film absorbers 42A-42C.

[0205] The measurements from the individual sensors are transmitted to a control unit that uses them to control at least one downstream process parameter, for example, by generating a control signal to connect or disconnect at least one additional membrane absorber.

[0206] The following examples relate to sequential switching on / connection of absorber modules, for example increasing the number of absorber modules from n to n+1, or decreasing the number of absorber modules from n to n-1.

[0207] As mentioned above, in the case of continuous processes with long processing times (e.g. perfusion processes), immediately switching on or connecting a purification stage providing the entire adsorption capacity is problematic, since it results in large dead volumes, insufficient feed pressure to achieve a uniform distribution of the processed product, and large output fluctuations due to changes in product flow and / or filter material.

[0208] To mitigate and / or avoid the above problems, a sensor control system is used as follows: If the pressure measured at the inlet of a group of membrane absorbers 42A-42C is lower than a first pressure required to ensure uniform flow through the processing stage, the control unit issues a control signal to reduce the number of membrane absorbers from n to n-1 by disconnecting one of the membrane absorbers. Each membrane absorber is disconnected by its respective actuator (e.g., a valve) upon receiving a control signal from the control unit. If the measured pressure exceeds a second pressure required to ensure uniform flow, an additional membrane absorber is connected, thereby increasing the number of membrane absorbers from n to n+1. Of course, it is also possible to connect or disconnect more than one membrane absorber at a time. It is also possible to connect and disconnect membrane absorbers depending on measured characteristics of the product's volumetric flow rate and / or viscosity, for example to compensate for variations in the product's volumetric flow rate and / or viscosity due to changes in the product and / or filter.

[0209] The following are non-limiting examples of configurations and / or control of continuous processing methods: The 500 L product solution output from a 500 L perfusion bioreactor needs to be continuously processed in a downstream process; The volumetric flow rate of the fluid requiring continuous filtration is approximately 0.35 L / min. The product concentration is 10g / L, i.e., approximately 5kg of product needs to be processed per day. In the "polishing" purification stage, 5 kg of product can be processed per liter of membrane adsorber (e.g., the capacity of Sartorius-Stedim's Sartobind Q). This requires a minimum membrane capacity of 1 liter per day (3.6 m 2 This means that a .NET Framework equivalent to Zaltobind is required. To ensure uniform flow, a flow rate of 5 MV per minute (MV: membrane volume) is recommended. For Zaltobind Q, the recommended flow rate is approximately 5 L / min. The recommended flow rate is several times greater than the volumetric flow rate of the fluid to be treated (approximately 0.35 L / min). To meet the recommended flow rate, a membrane adsorber with a total membrane volume of approximately 70 mL is required. The proposed connection of individual connectable membrane absorbers with smaller membrane volumes allows the targeted process parameters (e.g. volumetric flow rate or total volume) to be achieved reliably and efficiently. Furthermore, due to the small dead volume, it is possible to achieve early process monitoring at the outlet of a separation stage or group of separation stages. For example: A 1 L membrane has a dead volume of approximately 1.3 L, i.e., the processing time for the filtrate to reach the outlet of each separation stage and the respective sensors located at the outlet is at least 4.6 minutes; A 0.07 L membrane has a dead volume of about 0.11 L, i.e. the filtrate reaches the outlet of the separation stage and the sensor already placed at said outlet after a processing time of about 0.5 minutes.

[0210] In the above embodiments, other purification stages or modules, such as other filter stages, chromatography stages, etc., may be used in place of membrane absorbers 42A-42C.

[0211] Furthermore, in addition to or as an alternative to the upstream and / or downstream characteristics described above, one or more of the following characteristics may be measured and the measurements used by the control unit to configure, set, and / or control the membrane absorber. Exemplary measured characteristics include: Upstream: pressure (usually in the range of 0.1-4 bar), volumetric flow rate, viscosity (usually in the range of 1-5 cP), temperature (usually in the range of 4°C-30°C), amount and / or composition of impurities (e.g. fractions of DNA, proteins, aggregates, etc.); Downstream: Amount and / or composition of impurities (e.g., DNA, protein, aggregate, etc. fractions).

[0212] Typical disturbance features to be monitored include errors in the concentration of target molecules or other target substances, errors in the amount and / or composition of impurities in intermediate and / or final products, temperature errors, and errors in filter performance (e.g., binding capacity, flow performance, etc.).

[0213] Example 6: Adaptation of a separation stage in a combined process using intermediate storage tanks According to one embodiment, a sensor control system is provided that includes connected processing stages and an intermediate storage tank (i.e., an intermediate storage stage). The use of an intermediate storage tank in a system including connected processes is known, for example, from U.S. Patent Application Publication No. 2013 / 0260419. As mentioned above, in a sensor control system according to one embodiment of the invention, one or more separation stages or modules can be actively connected or disconnected (i.e., added or removed) based on signals received from at least one sensor that measures at least one process and / or product characteristic.

[0214] FIG. 10 shows a block diagram of an example of a purification process that uses a system that includes an intermediate storage tank 44 for temporarily storing the product output from the "m"th process step (e.g., the mth downstream process step) before supplying it to the "m+1"th process step.

[0215] Sensor L measures the liquid level as an indicator of volume, and sensor B measures the biomass in the intermediate storage tank 44. Sensor F, located at the outlet of the intermediate storage tank 44, measures the flow rate as an indicator of the volumetric flow rate. A group of downstream processing stages 46A-46C comprising the "m+1"th processing step are connected to the outlet of the intermediate storage tank 44 via respective actuators (e.g., valves) 36A-36C. The actuators 36A-36C are connected to and controlled by a control unit (not shown), such as the control unit 32 described above.

[0216] For example, the system can be used as follows: The product output from the mth processing stage is stored in an intermediate storage tank (intermediate storage stage). At least one product and / or process characteristic is sensed or measured by at least one appropriate sensor (e.g., sensors L, B, and F). The at least one sensor measures at least one characteristic in the intermediate storage tank 44 at the outlet or inlet of the intermediate storage tank 44. The at least one measured characteristic may be, for example, the amount and / or concentration of the product in the intermediate storage tank 44, and / or the concentration of at least one contaminant in the product in the intermediate storage tank 44, the amount of particles in the product in the intermediate storage tank 44, etc. Based on the at least one measured characteristic, the next processing stage (processing stage m+1) is configured and / or controlled by the control unit.

[0217] In particular, the m+1th processing step may be a group of “n” connected processing stages or modules 46A-44C, e.g., “n” purification stages or modules. The control unit can determine the number of processing stages or modules required (e.g., the number of purification stages or modules) based on at least one measured characteristic and send control signals to the respective actuators 36A-36C to connect (add) or disconnect (disconnect) the determined number of individual processing stages or modules (e.g., purification stages or modules). The at least one measured characteristic may be, for example, product and / or contaminant concentration, and / or particle properties and / or amount in the intermediate storage tank 44 or at its outlet.

[0218] In one embodiment, the m+1 processing step performed in the m+1 processing stage is initiated only if at least one measured value of at least one characteristic reaches a predetermined value or is within a predetermined range. For example, the m+1 processing stage is initiated only if the amount of product of processing step "m" in the intermediate storage tank 44 reaches a predetermined value or is within a predetermined range. The available amount of product in the intermediate storage tank 44 is determined based on the at least one measured (product) characteristic.

[0219] In the above embodiments, in addition to or as an alternative to the above upstream and / or downstream features, one or more of the following features may be measured and used by the control unit to configure, set and / or control process steps m and m+1 and their respective processing stages. Exemplary features to be measured include: Upstream: volume, viscosity (usually in the range of 1-5 cP), amount and / or composition of impurities (e.g. fractions of DNA, proteins, aggregates, etc.), product concentration (e.g. in the range of 1-200 g / L), turbidity.

[0220] Typical disturbance characteristics to be monitored include errors in the concentration of target molecules or other target substances, errors in the amount and / or composition of impurities in intermediate and / or final products, temperature errors, errors in filter performance (e.g., binding capacity, flow performance, etc.), errors in product concentration, etc.

[0221] The above examples relate to the automated setup, configuration, and / or control of individual processing stages, such as the automated connection and disconnection of individual purification stages in a downstream process. Of course, the above principles can be applied at any level of process granularity, such as the automated setup, configuration, and / or control of individual processing sub-stages of a particular processing stage. Similarly, the above principles can be applied to the automated setup, configuration, and / or control of individual groups of processing stages. Furthermore, the number of processing stages and steps is not limited to the number shown in the figures, but can be more or less. Similarly, the above principles can be applied not only to the types of processing stages described above, but also to other types of processing stages or operations, such as upstream processing stages or operations and / or their sub-stages.

[0222] The computational techniques described herein can be implemented in digital electronic circuitry, or in computer hardware, firmware, software, or in combinations of them. Where appropriate, aspects of these systems and techniques can be implemented in a computer program product embodied in, for example, a computer-readable storage device for execution by a programmable processor; method steps are carried out by the programmable processor to execute a program of instructions and perform functions by operating on input data and generating output.

[0223] To provide for user interaction, a computer system is used that includes a display device, such as a monitor or LCD screen and keyboard, for displaying information to the user, a pointing device, such as a mouse or trackball, a touch screen, or other device by which the user can provide input to the computer system. The computer system is programmed to provide a graphical user interface through which computer programs interact with the user.

[0224] Although numerous embodiments and examples have been described, it should be understood that various modifications may be made. For example, the steps described may be performed in a different order and still achieve desirable results. Furthermore, individual features of different embodiments and examples may be combined. Accordingly, other embodiments are within the scope of the following claims.

[0225] Furthermore, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. [Explanation of symbols]

[0226] 10. System for configuring and / or setting up and / or controlling downstream processes for processing biomass 102 receiving device 104 processors 106 databases 12 Upstream measurements 14 Communication networks (e.g. computer networks) 16 Upstream process parameters 18 downstream refining stages 20 Downstream Process Parameters 22 Measured upstream and / or downstream characteristics 30 Bioreactor 32 Control Unit 34A-34D Purification stages (e.g., filtration stages) 36A-36D Actuators (e.g. valves) 38A-38C Pre-purification stages (e.g., pre-filtration stages) 40 Primary purification stage (e.g., primary filtration stage) 42A-42C Membrane absorber 44 Intermediate storage tank W Weight Sensor B. Biomass sensor P, P1, P2 pressure sensors F Flow sensor UV (e.g., UV sensor with wavelength of 230-300 nm) L level sensor 100 Biomass Processing Systems 100A Upstream Processing Subsystem 100B Downstream Processing Subsystem 110 Bioreactor 120 Protein A Chromatography Stage 140 Communication networks (e.g. computer networks) 160 Processing-related data 180 Virus Inactivation Stage 181 Mixing stage 182 Low pH virus inactivation stage 183 Mixing Stage 184, 185 Filtration stage 186 Mixing Stage

Claims

1. A computer-implemented method for configuring and / or setting up and / or controlling a downstream process for processing a cell culture produced by an upstream process to obtain a product, comprising: receiving at least one measurement of at least one upstream characteristic that is a characteristic of the cell culture or a processing stage or operation used to produce the cell culture, and / or at least one measurement of at least one downstream characteristic that is a characteristic of the product or a processing stage or operation of a downstream process; determining at least one downstream process parameter based on the received at least one measurement; configuring and / or setting and / or controlling at least one downstream processing stage or processing operation based on the determined at least one downstream process parameter; Including, The downstream process includes multiple downstream processing stages or operations that can be connected in parallel or sequentially; the at least one process parameter includes the number and / or type of downstream processing stages or operations to be connected or disconnected; said configuring and / or setting and / or controlling including connecting or disconnecting a predetermined number of downstream processing stages; The method wherein the downstream processing stage or operation that is connected or disconnected is a purification stage or operation.

2. wherein the at least one upstream characteristic comprises a viable cell density, a capacitance, a cell viability, and / or a cell turbidity of the cell culture, and determining the at least one downstream process parameter comprises: selecting a refining stage or operation; determining at least one process parameter of the selected purification stage or operation based on the received measurements of at least one of viable cell density, capacitance, and / or cell viability; The method of claim 1 , comprising:

3. Selecting a purification stage or operation includes selecting either a filtration stage or operation and a centrifugation stage or operation; If a filtration stage or operation is selected, the at least one process parameter comprises at least one of the following parameters: type of filtration stage or operation, number of filters, filter area, pressure, flow rate, amount of diatomaceous earth, and treatment time; The method of claim 2 , wherein if a centrifugation stage or operation is selected, the at least one process parameter includes processing time, processing volume, and centrifugal force.

4. 4. The method of claim 1, wherein the at least one upstream characteristic comprises a titer of the cell culture, and wherein determining the at least one downstream process parameter comprises determining at least one process parameter of a chromatography stage or operation based on the received titer measurement, the at least one process parameter comprising one or more of dimensioning, load, cycle time, flow rate, and number of chromatography columns.

5. 5. The method of claim 1, wherein the at least one upstream characteristic comprises a host cell-derived protein and / or DNA concentration of the cell culture, and determining the at least one process parameter comprises determining at least one process parameter of an anion or cation exchange chromatography stage or operation based on the received measured value of the host cell-derived protein and / or DNA concentration, and the at least one process parameter comprises one or more of a chromatography column and / or membrane adsorber volume, a buffer volume, a number of cycles, and a processing time.

6. 6. The method of claim 1, wherein the at least one upstream characteristic comprises a type and / or amount of at least one contaminant, and wherein determining the at least one downstream process parameter comprises determining a cell culture dilution parameter, a cycle time, and / or a column size to process based on the received measurements of the type and / or amount of the at least one contaminant.

7. The method of claim 6 , wherein the at least one upstream characteristic comprises an amount of antifoam agent and / or an amount of block polymer used in the processing stage or operation.

8. 8. The method of claim 1, wherein the at least one upstream characteristic comprises a pH value and / or an amount of at least one pH corrective agent, and determining the at least one downstream process parameter comprises determining an amount and / or type of at least one pH corrective agent to use in the downstream process based on the received measured pH value and / or amount of at least one pH corrective agent.

9. the at least one upstream characteristic comprises an amount of lipids and / or epidermal growth factor and / or peptides in the cell culture, and determining the at least one downstream process parameter comprises determining at least one purification operation parameter based on the received measurements of the amount of lipids and / or epidermal growth factor and / or peptides; and / or the at least one upstream characteristic comprises at least one quality characteristic of the cell culture, and determining the at least one downstream process parameter comprises determining whether to initiate a downstream process based on the received measurement value of the at least one quality characteristic; and / or the at least one upstream characteristic includes a processing temperature of the processing stage or operation, and determining the at least one downstream process parameter includes determining cooling or heating of a processing fluid for a downstream process based on the received processing temperature; and / or the at least one upstream characteristic comprises cell turbidity of the cell culture, and determining at least one downstream process parameter comprises determining at least one purification operation parameter based on the received cell turbidity measurement; and / or the at least one upstream characteristic includes a buffer system and / or buffer capacity of a medium used in the processing stage or operation, and determining the at least one downstream process parameter includes determining a pH adjustment parameter based on a measurement of the buffer system and / or buffer capacity of the received medium; and / or 9. The method of claim 1, wherein the at least one upstream characteristic comprises a throughput of the processing stage or operation, and determining the at least one downstream process parameter comprises determining a dimensioning of the downstream process based on received throughput measurements.

10. 10. The method of any one of claims 1 to 9, wherein said receiving comprises receiving a plurality of measurements of each of a plurality of upstream process characteristics used to obtain the cell culture to be processed in a downstream process and / or a plurality of measurements of a downstream processing stage or operation.

11. 11. The method of claim 10, wherein the purification stage or operation is one of a filtration stage, a pre-filtration stage, a chromatography stage, or a centrifugation stage.

12. 12. The method according to claim 10 or 11, wherein said at least one process parameter further comprises at least one parameter characterizing the dimensioning of a predetermined number and / or type of downstream processing stages or operations.

13. 13. The method of any one of claims 10 to 12, wherein the at least one downstream characteristic comprises at least one of the pressure, volumetric flow rate, volumetric flow rate, turbidity, viscosity, product amount and / or concentration, contaminant amount and / or concentration, and temperature of the processing stage or operation.

14. A computer program comprising instructions which, when executed by a computer, cause the computer to carry out the method according to any one of claims 1 to 13.

15. 14. A system for configuring and / or setting up and / or controlling a downstream process for treating a cell culture to obtain a product, the system comprising at least one processor and at least one actuator controlled by said processor configured to perform the method according to any one of claims 1 to 13.

16. Configuring and / or setting up and / or controlling downstream processes for treating a cell culture according to the method of any one of claims 1 to 13; processing said cell culture using a downstream process so configured and / or configured and / or controlled; 10. A method of treating a cell culture comprising:

17. performing an upstream process to obtain a cell culture that is processed in a downstream process; The method of claim 16 , further comprising: measuring at least one characteristic of the upstream process and / or the downstream process.

18. A system configured to process a cell culture, comprising: a system for configuring and / or setting up and / or controlling a downstream process according to claim 15, comprising at least one processor configured to perform the method for configuring and / or setting up a downstream process for treating a cell culture according to any one of claims 1 to 13; at least one processing stage configured to process said cell culture by using a downstream process configured and / or set up and / or controlled as described above; Including, the system.

19. at least one processing stage configured to perform an upstream process, thereby obtaining a cell culture that is processed in a downstream process; at least one measurement device that measures at least one characteristic of the upstream process online or offline; 20. The system of claim 18, further comprising:

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