Mixed system for culture process and purification process for preparing antibody pharmaceuticals

Abstract

The present invention relates to a mixed system for a culture process and a purification process for preparing an antibody pharmaceutical, in which at least one device selected from a bioreactor, a chromatography device, and a filtration device is made of at least one material selected from a single-use (SU) bag and stainless steel (SS), at least one device selected from a preparation tank and a storage tank for a culture medium and a buffer is made of an SS material, thereby simultaneously obtaining the advantages of an SS process system and an SU process system, cross contamination can be prevented by independent operation of a culture unit and a purification unit, and a process system is designed to be arranged so that outflow from the separate culture unit is caused to flow into at least one purification unit by using a control part to prevent a bottleneck phenomenon in the purification process, whereby, when the mixed system is used in the preparation of an antibody pharmaceutical, the economic efficiency and efficiency of the process can be improved, and a more efficient smart factory can be realized.

Description

Technical Field

[0001] This invention relates to a mixing system for the culture and purification processes used in the preparation of antibody pharmaceuticals. Background Technology

[0002] Biopharmaceuticals can be broadly categorized into new biological drugs, biobetters, and biosimilars. Compared to chemically synthesized drugs, they have fewer side effects, require less preclinical data for development, and their efficacy and safety are easier to predict, resulting in a higher clinical success rate. Therefore, active technological development is underway globally.

[0003] The biopharmaceutical process includes the development of initial candidate substances and cell lines, upstream processing (USP), downstream processing (DSP), and finished product processing steps. In particular, in the case of biosimilar product manufacturing, the process optimization in the USP and DSP processes is directly related to price competitiveness. Therefore, there is an increasing focus on optimizing the process for preparing biosimilars with low cost, high purity, and high yield.

[0004] The culture process is equivalent to the process of continuously increasing the number of cells through cell division over about 6 weeks after the cell line is thawed, from the initial stage of less than 1 liter flask to the final stage of production bioreactor of more than 15,000 liters. In this case, the culture methods used include batch culture, fed-batch culture, continuous culture, perfusion culture, etc.

[0005] Furthermore, the purification process involves using various chromatography and filtration operations to extract proteins for pharmaceutical use from culture media containing cells and cell debris with high purity and high efficiency. In this process, column purification, virus removal, ultrafiltration / percolation, and other procedures are carried out through chromatography and filtration.

[0006] On the other hand, the configurations and devices used in the cultivation and purification processes described above can be divided into stainless steel (SS) and single-use (SU) systems using disposable bags or tubes in terms of materials. Among them, the SS process system, which includes stainless steel equipment, has the advantages of being easy to implement on a large scale, having low operating costs, and being easy to automate. However, it has high initial installation costs, is susceptible to contamination, and is prone to downstream bottleneck phenomena in the purification process due to the large-scale development of bioreactors.

[0007] The recently introduced SU process system uses disposable bags or tubes with volumes ranging from 0.1 to 2000 liters as the equipment configuration. Compared with the SS process system, the initial installation cost is relatively low, and only the corresponding parts can be replaced in case of contamination, thus having the advantage of strong anti-contamination capability. However, it has limitations in terms of scale-up and has been pointed out to have disadvantages such as continuous operating costs caused by frequent bag replacement and a large amount of labor input during equipment replacement.

[0008] In the biopharmaceutical field today, more and more companies are providing contract manufacturing organizations (CMOs) for clinical trials and commercial drugs, and one-stop services from cell line development to process development, scale-up and commercial production are being perfected.

[0009] To meet the diverse needs of clients in the biopharmaceutical CMO business, significant flexibility is required due to multi-product manufacturing and frequent changes over processes. However, with the widely used SS (Self-Sustaining) process systems, bioreactors cannot be easily replaced, resulting in a situation where production capacity must match the installed equipment. Furthermore, the capacity in the purification process should increase with the scaling up of the culture process, but the columns used for purification are generally limited in size (2.0M), leading to frequent bottlenecks in the purification process and hindering the ability to flexibly respond to customer demands. Summary of the Invention

[0010] The problem the invention aims to solve

[0011] In view of the above-mentioned problems, the present invention aims to appropriately reflect the needs of various customers in the biopharmaceutical CMO business and ensure flexibility caused by multi-product production and frequent changeovers. Therefore, it aims to provide a hybrid system for the culture and purification processes of antibody pharmaceutical preparations. In the device configuration of the culture and purification units for antibody pharmaceutical preparations, at least one device selected from bioreactors, chromatography, and filtration devices is made of at least one material selected from disposable (SU) bags and stainless steel (SS), and at least one device selected from culture medium and buffer preparation tanks and storage tanks is made of SS material. This simultaneously obtains the advantages of both SS and SU process systems. Cross-contamination is prevented by the independent operation of the culture and purification units, and the process system is designed and arranged so that the effluent from a separate culture unit can flow into at least one purification unit using a control unit, thus preventing bottlenecks in the purification process.

[0012] Furthermore, the technical problems to be solved by the present invention are not limited to those described above. Those skilled in the art to which this invention pertains can clearly understand other unmentioned technical problems through the following description.

[0013] means for solving problems

[0014] This document provides a mixing system for the culture and purification processes of preparing antibody pharmaceuticals. The mixing system includes at least one cultivation unit and at least one purification unit. As an apparatus configuration for the culture process, the at least one cultivation unit includes: a media preparation tank (MP) for pre-preparing culture media; a media hold tank (MH) for receiving and storing culture media from the media preparation tank; a feed stream for flowing a feed liquid containing thawed cells and culture media into a bioreactor; at least one bioreactor, having a stirring device, for receiving thawed cells and culture media from the feed stream and increasing the number of cells through cell division; and an effluent stream for discharging the culture medium containing the cells cultured in the bioreactor. As an apparatus configuration for the purification process, the at least one purification unit includes: a buffer preparation tank (BP) for pre-preparing buffer solutions; a buffer hold tank (MH); and a buffer hold tank (MH). The buffer preparation tank (BH) receives and stores buffer solution; chromatography uses culture medium received from the culture unit and buffer solution received from the buffer storage tank to remove impurities mixed in the culture medium to improve the purity of the target protein; and at least one filtration device arranged before or after the chromatography for buffer exchange and concentration (filtration system), wherein, in the device configuration of the culture unit and purification unit, at least one device selected from the bioreactor, chromatography and filtration device is made of at least one material selected from the single-use bag (SUB) and stainless steel (SS), and at least one device selected from the preparation tank and storage tank of the culture medium and buffer solution is made of SS material.

[0015] Furthermore, in this paper, a culture unit and a purification unit arranged on the same line constitute a suite unit. The culture unit and the purification unit operate independently. The culture unit in the suite is connected to at least one purification unit selected from the purification units in the same suite and the purification units in another suite, so as to avoid bottlenecks in the purification process.

[0016] Furthermore, this document provides a mixing system for the culture and purification processes of antibody pharmaceutical preparations, wherein the mixing system has a multi-layer structure, wherein a floor of a unit kit is formed by multiple layers, and under the control of a control unit, the effluent stream discharged along the discharge line of each culture unit flows horizontally into the purification unit in the same kit located in the same layer, and vertically into the purification unit in another kit located in a different layer.

[0017] Furthermore, this document provides a mixed system for the culture and purification processes of antibody pharmaceutical preparations, wherein the chromatography of the purification unit is selected from one or a combination of affinity chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and mixed-mode chromatography.

[0018] Furthermore, this document provides a mixed system for the culture and purification processes of preparing antibody pharmaceuticals, wherein the chromatography in the purification unit consists of cation exchange chromatography for primary purification of the culture medium received from the culture unit; hydrophobic interaction chromatography for secondary purification of the culture medium recovered from the cation exchange chromatography; and anion exchange chromatography for tertiary purification of the culture medium recovered from the hydrophobic interaction chromatography, all sequentially linked together.

[0019] Furthermore, this document provides a mixing system for the culture and purification processes of preparing antibody pharmaceuticals, wherein the filtration device is at least one filter selected from ultrafiltration filters and percolation filters.

[0020] Furthermore, in this document, the mixing system is used to prepare a mixture of abavomab, abciximab, adalimumab, adecatumumab, alemtuzumab, attumomab, attumomab pentetate, anatumomab, and anatumomab. mafenatox, acitumomab, atlizumab, basiliximab, bectumomab, ectumomab, belimumab, benalizumab, bevacizumab, brentuximab, canakinumab, capromab, capromab pendiptidePendetide, catumaxomab, certolizumab, clivatuzumab tetraxetan, daclizumab, denosumab, eculizumab, edrecolomab, efalizumab, etaracizumab, ertumaxomab, fasomumab, fontolizumab, gemtuzumab, girentuximab, golimumab, ibritumomab, igovomab, infliximab iximab), ipilimumab, labetuzumab, mepolizumab, muromonab, muromonab-CD3, natalizumab, necitumumab, nimotuzumab, ofatumumab, omalizumab, oregovomab, palivizumab, panitumumab, ranibizumab, rituximab, satumomab, sulesomab, ibritumomab, tetanibrimomabTiuxetan, Tocilizumab, Tositumomab, Trastuzumab, Ustekinumab, Visilizumab, Votumumab, Zalutumumab, Brodalumab, Anrukinzumab, Bapineuzumab, Dalotuzumab, Demcizumab, Ganitumab, Iotuzumab, Mavrilimumab, Moxetumomab pasudotox, rilotumumab, sifalimumab, tanezumab, tralokinumab, tremelimumab, urelumab, adornase alfa, Rebif, becaplermin, alteplase, laronidase, alefacept, aflibercept, raxibacumab, darbepoetin alfa, becaplermin concentrate, interferon beta-1b, botulinum toxin type A, rasburicase, asparaginase, epioetin Alfa, etanercept, recombinant agarsidase beta, interferon alfacon-1, interferon alfa-2a, anakinra, botulinum toxin type B, pegfilgrastim, oprelvekin, filgrastim, denileukin diftitox, peginterferon alfa-2aA system comprising at least one antibody pharmaceutical product from the group consisting of alfa-2a, aldesleukin, recombinant human deoxyribonuclease alfa, interferon beta-1a, becaplermin, recombinant reteplase, interferon alfa-2, tenecteplase, drotrecogin alfa, rilonacept, romiplostim, methoxypolyethylene glycol-epoetin beta, C1 esterase inhibitor, idursulfase, recombinant alglucosidase alfa, abatacept, galsulfase, palifermin, and interferon γ-1b.

[0021] Invention Effects

[0022] According to the hybrid system of the present invention, in the apparatus configuration of the culture unit and purification unit for preparing antibody pharmaceuticals, at least one device selected from bioreactors, chromatography and filtration devices can be made of at least one material selected from disposable (SU) bags and stainless steel (SS), and at least one device selected from the preparation tank and storage tank of culture medium and buffer can be made of SS material, thereby simultaneously obtaining the advantages of SS process system and SU process system, and preventing cross-contamination by operating the culture unit and purification unit independently.

[0023] Furthermore, according to the mixing system of the present invention, by designing and arranging the process system so as to allow the effluent discharged from individual culture units to flow into at least one purification unit by using a control unit, thereby preventing bottleneck phenomena in the purification process.

[0024] Therefore, the use of the hybrid system in antibody pharmaceutical manufacturing can improve the economy and efficiency of the process, enabling a more efficient smart factory. Attached Figure Description

[0025] Figure 1 To briefly illustrate a hybrid system, according to an embodiment of the present invention, in the antibody pharmaceutical preparation process, a device configuration consisting of SU disposable bags and SS materials is appropriately designed and arranged.

[0026] Figure 2 To briefly illustrate the hybrid system, according to another embodiment of the invention, a suite consisting of a culture unit and a purification unit is arranged in a multilayer structure with multiple layers, and an apparatus configuration for allowing the effluent discharged from the culture unit to flow into at least one purification unit.

[0027] Figure 3 To illustrate the hybrid system briefly, according to another embodiment of the invention, the effluent discharged along the discharge line of each culture unit is directed by a control unit to flow horizontally into a purification unit located in the same suite on the same layer, and vertically into a purification unit located in another suite on a different layer. Detailed Implementation

[0028] The terminology used herein is for describing exemplary embodiments only and is not intended to limit the invention. Unless the context clearly specifies otherwise, singular expressions include plural expressions. It should be understood that, in this document, terms such as “comprising,” “possessing,” or “having” are intended to indicate the presence of an implemented feature, step, structural element, or combination thereof, rather than precluding the presence or additional possibility of one or more other features or steps, structural elements, or combinations thereof.

[0029] Furthermore, when the present invention refers to each layer or element being formed "on" or "above" each layer or element, it means that each layer or element is formed directly on each layer or element, or that other layers or elements may be additionally formed between each layer, on the object, or on the substrate.

[0030] The invention can be modified in various ways and can take many forms, with specific embodiments described in detail below by way of example. However, this is not intended to limit the invention to the specific form disclosed, and it should be understood to include all modifications, equivalents, and substitutions within the spirit and scope of the invention.

[0031] It should be understood that, in this invention, the term "suite" as used throughout the specification and the scope of the invention claims refers to a unit space in which a series of devices, such as bioreactors, supply lines, discharge lines, various sensors, ports, valves, etc., are designed and arranged for the cultivation or purification process.

[0032] Furthermore, in this invention, the term "part" as used throughout the specification and the scope of the invention claims can refer to a software or hardware structural element, and a "part" can perform certain functions. However, "part" is not intended to be limited to software or hardware. A "part" can be configured to reside on an addressable storage medium and can be configured to refresh one or more processors. Thus, as an example, a "part" includes structural elements such as software structural elements, object-oriented software structural elements, class structural elements, and task structural elements, processes, functions, attributes, procedures, subroutines, program code segments, drivers, firmware, microcode, circuits, data, databases, data structures, tables, arrays, and variables. The functions provided within structural elements and "parts" can be combined into a smaller number of structural elements and "parts," or further separated into additional structural elements and "parts."

[0033] According to one embodiment of the present invention, a "part" can be implemented as a processor and a memory. The term "processor" should be interpreted broadly to include general-purpose processors, central processing units (CPUs), microprocessors, digital signal processors (DSPs), controllers, microcontrollers, state machines, etc. In some cases, "processor" can refer to application-specific integrated circuits (ASICs), programmable logic devices (PLDs), field-programmable gate arrays (FPGAs), etc. The term "processor" refers to a combination of processing devices, such as a combination of a DSP and a microprocessor, a combination of multiple microprocessors, a combination of one or more microprocessors with a DSP core, or any other such configuration.

[0034] The term "memory" should be broadly interpreted to include any electronic component capable of storing electronic information. The term "memory" includes various types of processor-readable media such as Random Access Memory (RAM), Read-Only Memory (ROM), Non-Volatile Random Access Memory (NVRAM), Programmable Read-Only Memory (PROM), Erasable Programmable Read-Only Memory (EPROM), Electrically Erasable Programmable Read-Only Memory (EEPROM), Flash Memory, magnetic or optical data storage, registers, etc. If the processor can read information from the memory and / or write information to the memory, the memory is said to be in a state of electronic communication with the processor. Memory integrated into the processor is in a state of electronic communication with the processor.

[0035] The following describes in further detail the mixing system for the culture and purification processes of antibody pharmaceuticals according to specific embodiments of the present invention.

[0036] Ensure flexibility within the suite (Intra Suite Flexibility)

[0037] A mixing system for the culture and purification processes of preparing antibody pharmaceuticals according to an embodiment of the present invention includes at least one culture unit and at least one purification unit. The at least one culture unit, configured as an apparatus for the culture process, includes: a media preparation tank for pre-preparing media; a media hold tank for receiving and storing media from the media preparation tank; a feed stream for flowing a feed liquid containing thawed cells and culture media into a bioreactor; at least one bioreactor having a stirring device for receiving thawed cells and culture media from the feed stream and increasing the number of cells through cell division; and an effluent stream for discharging culture medium containing cells cultured from the bioreactor as an effluent stream.

[0038] At least one purification unit, configured as an apparatus for the purification process, includes: a buffer preparation tank for pre-preparing buffer solutions; a buffer hold tank for receiving and storing buffer solutions from the buffer preparation tank; chromatography for removing impurities mixed in the culture medium using culture medium received from the culture unit and buffer solutions received from the buffer hold tank to improve the purity of the target protein; and at least one filtration device arranged before or after the chromatography for buffer exchange and concentration. In the apparatus configuration of the culture unit and purification unit, at least one device selected from the bioreactor, chromatography, and filtration device may be made of at least one material selected from single-use (SU) bags and stainless steel (SS), and at least one device selected from the culture medium and buffer preparation tank and the buffer hold tank may be made of SS material.

[0039] More specifically, the antibody pharmaceutical preparation process includes the following steps: development of initial candidate materials and cell lines, culture process (USP), purification process (DSP), and finished product process.

[0040] First, the culture process (USP) is equivalent to the process of continuously increasing the number of cells through cell division over approximately 6 weeks after the cell line is thawed, from the initial stage in flasks smaller than 1 liter to the final stage in a production bioreactor of over 15,000 liters.

[0041] According to one embodiment of the present invention, as a collection of apparatus configurations for a culture process, a culture unit may include: a media preparation tank for pre-preparing media; a media hold tank for receiving and storing media from the media preparation tank; a feed stream for flowing a feed stream containing thawed cells and culture media into a bioreactor; at least one bioreactor having a stirring device for receiving thawed cells and culture media from the feed stream and increasing the number of cells by cell division; and an effluent stream for discharging culture medium containing cells cultured from the bioreactor as an effluent stream.

[0042] Next, the purification process (DSP) is equivalent to the process of extracting proteins for pharmaceutical use from culture media containing cells and cell debris with high purity and high efficiency through the operation of various chromatography and filtration.

[0043] According to one embodiment of the present invention, as a collection of apparatus configurations for a purification process, a purification unit may include: a buffer preparation tank for pre-preparing buffer solutions; a buffer hold tank for receiving and storing buffer solutions from the buffer preparation tank; chromatography for removing impurities mixed in the culture medium using culture medium received from the culture unit and buffer solutions received from the buffer hold tank to improve the purity of the target protein; and at least one filtration system arranged before or after chromatography for buffer exchange and concentration.

[0044] On the other hand, the configurations and devices used in the cultivation and purification processes can be divided into stainless steel (SS) and single-use (SU) systems using disposable bags or tubes in terms of materials. Among them, the SS process system, which includes stainless steel devices, has the advantages of being relatively easy to implement on a large scale, having low operating costs, and being easy to automate. However, it has high initial installation costs, is susceptible to contamination, and is prone to downstream bottleneck phenomena in the purification process due to the large-scale development of bioreactors.

[0045] The recently introduced SU process system uses disposable bags or tubes with volumes ranging from 0.1 to 2000 liters as the equipment configuration. Compared with the SS process system, the initial installation cost is relatively low, and only the corresponding parts can be replaced in case of contamination, thus having the advantage of strong anti-contamination capability. However, it has limitations in terms of scale-up and has been pointed out to have disadvantages such as continuous operating costs caused by frequent bag replacement and a large amount of labor input during equipment replacement.

[0046] The inventors have discovered that, in the configuration of the culture and purification units constituting the culture and purification steps for preparing antibody pharmaceuticals, when at least one device selected from bioreactors, chromatography and filtration devices is made of at least one material selected from SU disposable bags and stainless steel, and at least one device selected from culture medium and buffer preparation tanks and storage tanks is made of SS material, the advantages of both SS and SU process systems can be obtained simultaneously. Furthermore, when the culture and purification units are operated independently, cross-contamination can be prevented. Moreover, when the process system is designed and arranged to use a control unit to allow the effluent discharged from a separate culture unit to flow into at least one purification unit, bottleneck phenomena in the purification process can be prevented, thereby completing the present invention.

[0047] Specifically, according to one embodiment of the present invention, in the device configuration of the culture unit and purification unit, at least one device selected from bioreactors, chromatography and filtration devices may be made of at least one material selected from single-use (SU) bags and stainless steel (SS), and at least one device selected from the preparation tank and storage tank of the culture medium and buffer may be made of SS material (see reference). Figure 1 ).

[0048] As an example, the bioreactor, a key component in the device configuration for both the culture and purification units, can be made of SU material. Considering the characteristics of the target pharmaceutical product and the corresponding processes, the chromatography and filtration devices can be flexibly made of either SU or SS material. For secondary device configurations requiring larger capacities, the preparation and storage tanks for culture media and buffer solutions can be made of SS material. On the other hand, the term "SU (Sigle-Use) disposable bag" as used throughout this document and the claims can encompass both SU disposable bags and disposable tube structures.

[0049] In biopharmaceutical contract manufacturing (CMO), when key equipment such as bioreactors, chromatography, and filtration devices are configured with SU (sulfuric acid) material, its lightweight and easily replaceable properties allow for configuration changes and replacements based on the type and quantity of antibody pharmaceuticals required. Therefore, it can easily handle multi-product production and frequent changeovers according to various customer needs, and offers the advantage of flexibility within a complete suite (ensuring intra-suite flexibility).

[0050] Furthermore, based on factors such as volume capacity, turndown ratio, and mass transfer coefficient, SU material bioreactors can be easily replaced with equipment optimized for customer needs, target products, and the resulting processes. Similarly, based on factors such as dynamic binding capacity, linear velocity, concentration capacity, and flow rate, chromatography and filtration devices can be easily replaced with equipment optimized for customer needs, target products, and purification performance.

[0051] Therefore, in the CMO business, we can provide our clients with the best productivity at an engineering-reasonable cost.

[0052] Furthermore, when the cultivation and purification processes are configured as a hybrid system, the advantages of the SS process system (easy to implement on a large scale, low operation cost, and easy to automate) and the SU system (relatively low initial installation cost and strong resistance to contamination as only the corresponding parts need to be replaced in case of contamination) can be simultaneously obtained. Moreover, with a hybrid system, when the core and body components in the design suite are arranged in the closest possible configuration, liquids can be quickly transferred, and the manpower required for assembling the tubes connecting the components can be minimized.

[0053] Ensure inter-suite flexibility.

[0054] In a hybrid system for the culture and purification processes of antibody pharmaceutical preparation according to another embodiment of the present invention, a culture unit and a purification unit arranged on the same line constitute a suite unit. The culture unit and the purification unit operate independently. The culture unit in the suite unit can be connected to at least one purification unit selected from the purification units in the same suite unit and the purification units in another suite unit to avoid bottlenecks in the purification process.

[0055] More specifically, a unit suite is a unit space comprising a culture unit and a purification unit, the culture unit and the purification unit being arranged horizontally on the same line, and the culture unit and the purification unit being arranged sequentially.

[0056] However, even if the culture unit and the purification unit are not arranged in the same unit kit, they operate independently. Therefore, the culture unit in one unit kit does not necessarily have to be connected to the purification unit in the same unit kit. It can be connected to at least one purification unit selected from the purification units in the same unit kit and the purification units in another unit kit.

[0057] As an example, the hybrid system may have a multi-layered structure, wherein a floor arranging a unit suite is formed by multiple layers. Under the control of a control unit, the effluent stream discharged along the discharge line of each culture unit can flow horizontally into a purification unit located in the same suite on the same layer, or vertically into a purification unit located in another suite on a different layer (see reference). Figure 2 ).

[0058] On the other hand, in this document, the term "horizontal inflow" should not be understood as meaning that the discharge line of the culture unit itself must be formed horizontally so that the outflow moves horizontally. Even if the discharge line is constructed in a mixed horizontal and vertical manner, as long as it flows into the purification unit located in the same layer (within the same kit), it can be understood as "horizontal inflow". The term "vertical inflow" should be understood as the discharge line of the culture unit entering the purification unit located in a kit located in a different layer from the same kit.

[0059] On the other hand, when the outflow is transported to a higher position along the discharge pipeline, it can be transported using clean and oil-free air (COA), and when it is transported to a lower position, it can be transported by gravity.

[0060] In traditional biopharmaceutical processes, the processes are typically configured with culture and purification units in a 1:1 ratio. In this case, the capacity of the chromatography columns used in the purification step (DSP) is limited (maximum). Therefore, even though high productivity is ensured by scaling up the culture process (USP), deep-seated bottlenecks that are not effectively addressed emerge in the purification process. For example, insufficient capacity in the chromatography process requires more than two chromatography cycles, thus causing process time delays.

[0061] Conversely, in the hybrid system according to the invention, cells cultured in an expanded-scale culture unit flow into at least one non-operational purification unit, for example, two or three purification units, to achieve simultaneous purification, thus allowing for flexible purification processes and effectively preventing bottlenecks in the purification process.

[0062] As an example, when multiple purification units are matched into a culture step to produce trastuzumab as a humanized IgG1 monoclonal antibody, the process time can be innovatively reduced (e.g., by 1 day) compared to a conventional process system where culture and purification units are matched 1:1 (ensuring inter-suite flexibility).

[0063] On the other hand, the effluent flowing from the discharge line of each culture unit into at least one purification unit is controlled by a control unit, which may include at least one device selected from a processor and a memory. The processor can execute instructions stored in the memory. Alternatively, the processor may include, for example, a central processing unit (CPU), a graphics processing unit (GPU), or both. As an example, the process can be automated (adjusted and controlled) by using the processor and memory in the control unit. As an example, the control unit according to an embodiment of the present invention may be a Programmable Logic Controller (PLC).

[0064] On the other hand, the chromatography of the purification unit according to an embodiment of the present invention can be selected from one or a combination of affinity chromatography, ion exchange chromatography, hydrophobic interaction chromatography and mixed-mode chromatography.

[0065] Chromatography is used to remove host cell proteins and host cell DNA from antibody products (primarily active antibodies, isoform antibodies, host cell proteins (HCPs), host cell-derived DNA, and cell growth factors, etc.) prepared from host cells to prepare a high-quality antibody population. As an example, the chromatography in the purification unit can be a series of chromatography steps: cation exchange chromatography for primary purification of the culture medium received from the culture unit; hydrophobic interaction chromatography for secondary purification of the culture medium recovered from the cation exchange chromatography; and anion exchange chromatography for tertiary purification of the culture medium recovered from the hydrophobic interaction chromatography. However, this is not a limitation, and various design modifications can be made according to customer needs and the type and production volume of antibody pharmaceuticals.

[0066] On the other hand, the filtration device according to an embodiment of the present invention can be at least one filter selected from ultrafiltration filters and percolation filters.

[0067] An ultrafiltration filter (UF) is any technical configuration that uses a semi-permeable membrane to treat a solution or suspension. This semi-permeable membrane allows solvent or small solute molecules to pass through while retaining large molecules. Ultrafiltration filters can be used to increase the concentration of large molecules in a solution or suspension.

[0068] A diafiltration filter (DF) is a technical structure associated with a specific type of filtration that re-filters retentate by diluting it with a solvent to reduce the components in the soluble permeate. Diafiltration filters can be used to alter other properties of solutions or suspensions of macromolecules, such as pH, ionic strength, salt composition, buffer composition, or macromolecular properties.

[0069] On the other hand, each of the culture unit and purification unit may also be configured with a product hold tank for intermediate storage of intermediate products and process liquids, the product hold tank being made of SS material. Furthermore, the purification unit may also include a series of devices for virus inactivation and virus removal.

[0070] On the other hand, the mixing system according to one embodiment of the present invention can be used to prepare a mixture selected from abagovomab, abciximab, adalimumab, adecatumumab, alemetuzumab, attumomab, and pentiazem attumomab. Pentetate, Anatumomab, Anatumomab Mafenatox, Arcitumomab, Atlizumab, Basiliximab, Bectumomab, Ectumomab, Belimumab, Benralizumab, Bevacizumab, Brentuximab, Canakinumab, Capromab, Capromab Pendetide, Catumaxomab, Certolizumab, Clivatuzumabtetraxetan, daclizumab, denosumab, eculizumab, edrecolomab, efalizumab, etaracizumab, ertumaxomab, fanolesomab, fontolizumab, gemtuzumab, girentuximab, golimumab, ibritumomab, igovomab, infliximab, ipilimumab, labetizumab tuzumab), mepolizumab, muromonab, muromonab-CD3, natalizumab, necitumumab, nimotuzumab, ofatumumab, omalizumab, oregovomab, palivizumab, panitumumab, ranibizumab, rituximab, satumomab, sulesomab, ibritumomab, tetanibritumomab Tiuxetan, Tocilizumab, Tositumomab, Trastuzumab, Ustekinumab, Visilizumab, Votumumab, Zalutumumab, Brodalumab, Anrukinzumab, Bapineuzumab, Dalotuzumab, Demcizumab, Ganitumab, Iotuzumab, Mavrilimumab, Moxetumomabpasudotox, rilotumumab, sifalimumab, tanezumab, tralokinumab, tremelimumab, urelumab, adornase alfa, Rebif, becaplermin, alteplase, laronidase, alefacept, aflibercept, raxibacumab, darbepoetin alfa, becaplermin concentrate, interferon beta-1b, botulinum toxin type A, rasburicase, asparaginase, and epioetin. Alfa, etanercept, recombinant agalsidase beta, interferon alfacon-1, interferon alfa-2a, anakinra, botulinum toxin type B, pegfilgrastim, oprelvekin, filgrastim, denileukin diftitox, peginterferon alfa-2a, aldesleukin, recombinant human deoxyribonuclease (dornase) Alfa, interferon beta-1a, becaplermin, reteplase, interferon alfa-2, tenecteplase, drotrecogin alfa, rilonacept, romiplostim, methoxypolyethylene glycol-epoetinA system for preparing antibody pharmaceuticals consisting of at least one of the following groups: beta, C1 esterase inhibitor, idursulfase, recombinant alglucosidase alfa, abatacept, galsulfase, palifermin, and interferon gamma-1b, can be used in various ways throughout the manufacturing process of antibody drugs, such as novel biological drugs, improved biological pharmaceuticals (biologics), and biosimilars.

[0071] In the hybrid system of the present invention as described above, at least one device selected from bioreactors, chromatography and filtration devices for the preparation of antibody pharmaceuticals is made of at least one material selected from disposable (SU) bags and stainless steel (SS), and at least one device selected from culture medium and buffer preparation tanks and storage tanks is made of SS material. Thus, the advantages of both SS and SU process systems can be obtained simultaneously, and cross-contamination can be prevented by the independent operation of the culture and purification units.

[0072] Furthermore, the process system is designed and arranged in the mixing system of the present invention so that the effluent discharged from the individual culture unit is directed to flow into at least one purification unit using the control unit to prevent bottlenecks in the purification process.

[0073] Therefore, when the hybrid system is used in antibody pharmaceutical manufacturing, the economy and efficiency of the process can be improved, and a more efficient smart factory can be achieved.

[0074] The specific embodiments of the present invention have been described and illustrated above. However, it will be apparent to those skilled in the art that the present invention is not limited to the described embodiments, and various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, these modifications or variations should not be understood solely from the technical spirit or viewpoint of the present invention, and the modified embodiments should be considered to fall within the scope of protection of the present invention.

Claims

1. A hybrid system for a culture process and a purification process for preparing an antibody pharmaceutical product, comprising at least one culture unit and at least one purification unit, a culture medium preparation tank for pre-preparing a culture medium; a culture medium storage tank receiving the culture medium from the culture medium preparation tank and storing the culture medium; a feed line making a feed stream comprising thawed cells and the culture medium flow into a bioreactor; at least one bioreactor having a stirring device, receiving the thawed cells and the culture medium from the feed stream, and increasing the cell population by cell division; and a discharge line making a culture solution comprising the cells cultured in the bioreactor flow out as a flow-out stream, at least one purification unit configured as a device for a purification process, comprising: a buffer preparation tank for pre-preparing a buffer; a buffer storage tank receiving the buffer from the buffer preparation tank and storing the buffer; a chromatography removing impurities mixed in the culture solution to increase the purity of a target protein using the culture solution received from the culture unit and the buffer received from the buffer storage tank; and at least one filtration device disposed before or after the chromatography to perform buffer exchange and concentration, wherein, one culture unit and one purification unit disposed on the same line constitute one unit set, the culture unit and the purification unit independently operate, the hybrid system has a multi-layer structure, a layer in which one unit set is disposed is formed of a plurality of layers, by control of a control portion, the flow-out stream discharged along the discharge line of each culture unit horizontally flows into the purification unit in the same set located in the same layer, and vertically flows into the purification unit in another set located in a different layer, in the device configuration of the culture unit and the purification unit, the bioreactor is made of a disposable bag material, the chromatography and the filtration device are made of a disposable bag material or a stainless steel material, and at least one device selected from the preparation tank and the storage tank of the culture medium and the buffer is made of a stainless steel material. The at least one culture unit configured as a device for the cultivation process comprises:

2. The hybrid system for a culture process and a purification process for preparing an antibody pharmaceutical product according to claim 1, wherein, the chromatography of the purification unit is one selected from the group consisting of affinity chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and mixed mode chromatography, or a combination thereof.

3. The hybrid system for a culture process and a purification process for preparing an antibody pharmaceutical product according to claim 2, wherein, the chromatography of the purification unit is a chromatography in which cation exchange chromatography for primary purification of the culture solution received from the culture unit, hydrophobic interaction chromatography for secondary purification of the culture solution recovered from the cation exchange chromatography, and anion exchange chromatography for tertiary purification of the culture solution recovered from the hydrophobic interaction chromatography are sequentially connected.

4. The hybrid system for a culture process and a purification process for preparing an antibody pharmaceutical product according to claim 1, wherein, the filtration device is at least one filter selected from the group consisting of an ultrafiltration filter and a diafiltration filter.

5. The hybrid system for a culture process and a purification process for preparing an antibody pharmaceutical product according to claim 1, wherein, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The mixing system is used to prepare a mixture of abavoxib, abciximab, adalimumab, adelimumab, alenmab, atormumab, pentate atormumab, macarimumab, melamumab, asimomumab, tosicillinumab, baliximab, betumumab, etamerumab, belimumab, benalizumab, bevacizumab, bentoximab, canamaximab, calcimerab, calcimerab pentosine, caputoxumab, cetoximab, titan-krituzumab, dacrolimus, denosumab, eculizumab, ezolizumab, efalizumab, and ilexacillinumab. Irmazolizumab, Fasomumab, Avantuzumab, Giemuzumab, Gefitinib, Golimumab, Igvovomab, Infliximab, Iplimumab, Labetuzumab, Meporibumab, Moroumab, Moroumab-CD3, Nataluzumab, Neximumab, Nitozumab, Ofamumab, Omazumab, Ogvovomab, Palizumab, Parumumab, Ranibizumab, Rituximab, Satumumab, Thioxamumab, Ibemumab, Tetan Ibemumab, Tocilizumab, Tosimoumab, Trastuzumab, Utecumab, Veximumab, Vortoximab, Zalutuzumab Monoclonal antibodies, padarumab, antraluzumab, bavizumab, daratumumab, densizumab, ganitumumab, iizumab, malfralimumab, pakmonumab, rituximab, cifamumab, tanizumab, trolurumab, trimemumab, ureruzumab, alfastrase, ribavirin, becaprolem, alteplase, laronidase, afaciliprcept, aflibercept, raxicurumab, afadabepoetin, interferon β-1b, botulinum toxin A, raburicase, asparaginase, alfaeporin, etanercept, recombinant alglucosidase β, compound alpha interferon-1, interferon α-2a The system comprises at least one antibody pharmaceutical product from the group consisting of anaspirin, botulinum toxin B, pegylated filgrastim, olprene interleukin, filgrastim, denitroglycerin-diphtheria toxin conjugate, pegylated interferon α-2a, adefovir, recombinant human alfadeoxyribonuclease, interferon β-1a, recombinant reteplase, interferon α-2, teneteplase, tegaserod α, linalopropyl, romistim, methoxy-pegylated erythropoietin, C1 esterase inhibitor, idoxurase, recombinant aglucosidase α, abatacept, thiodicarboxamide, parivamine, and interferon γ-1b.

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