Buffer preparation and transfer system for antibody pharmaceutical production process

Abstract

This invention relates to a buffer preparation and transfer system for antibody pharmaceutical manufacturing processes. The system is designed with a control unit to automate the preparation and transfer of various buffer solutions while simultaneously using on / off valves and flow control valves to transfer concentrated component solutions to buffer storage tanks to control the buffer concentration and composition. This significantly reduces labor input, shortens process time, and reduces the number of buffer preparation tanks corresponding to individual buffer storage tanks. It also helps ensure safe distances between processes and saves facility space. Furthermore, the automation system ensures operator safety. Additionally, it minimizes the risk of corrosion from using highly concentrated buffer solutions and further reduces process time. It also offers the advantages of uniform buffer quality and the ability to prepare buffer solutions according to the desired recipe.

Description

Technical Field

[0001] This invention relates to a buffer preparation and transfer system for antibody pharmaceutical preparation processes. 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] On the other hand, the purification process must include a chromatography step using the molecular properties of proteins (surface charge or hydrophobicity, etc.) to remove impurities and obtain high-purity antibodies. In this case, various buffer solutions are used. Conventional buffer preparation processes involve manually preparing buffer solutions one by one using a 1:1 matching system of buffer preparation tanks and buffer storage tanks, supplemented by devices for diluting and concentrating buffers. According to this existing technology, the tank installation requires a large facility area, and the manual preparation of buffer solutions results in a significant investment of labor and time. Furthermore, the powder used for buffer preparation can release chemicals during operation, posing a potential health hazard to workers. Summary of the Invention

[0010] The problem the invention aims to solve

[0011] In view of the above problems, the present invention aims to provide a buffer preparation and transfer system for antibody pharmaceutical preparation processes. This system addresses the preparation and transfer of various buffer solutions used in the chromatography step of antibody pharmaceutical purification. Unlike conventional buffer preparation systems where buffer solutions are manually prepared one by one with a 1:1 matching ratio between the buffer preparation tank and the buffer storage tank, the present invention automates the preparation and transfer of various buffer solutions using a control unit. Simultaneously, it controls the transfer of concentrated component solutions to the buffer storage tank via on / off valves and flow control valves to regulate the buffer concentration and composition. This significantly reduces the large amount of labor required for individual buffer preparation processes such as weighing, adding powder, stirring, and transferring, and also significantly shortens the process time.

[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 buffer preparation and transfer system for an antibody pharmaceutical preparation process, comprising: at least one concentrated component tank for receiving a concentrated component solution from a buffer preparation tank; a first conduit connected to a first discharge line through which the concentrated component solution is discharged from the concentrated component tank; at least one buffer hold tank (BH) arranged in parallel, having concentrated component inflow lines branching from the first conduit; a second conduit connected to a second discharge line through which buffer solution is discharged from each of the buffer hold tanks; a chromatography system connected to the second conduit; and a control unit that controls the opening and closing of a switch valve located on the first discharge line of each concentrated component tank based on a preset value, or controls the flow rate by a flow control valve located on the concentrated component inflow line that allows the concentrated component to flow into each buffer hold tank, to transfer the concentrated component solution to each buffer hold tank.

[0015] Furthermore, this document provides a buffer preparation and transfer system for antibody pharmaceutical preparation processes, wherein a water-for-injection line for injecting water for injection is connected to each buffer storage tank, the buffer storage tank performing batch conditioning of the injected concentrated component solution and water for injection.

[0016] Furthermore, this document provides a buffer preparation and transfer system for an antibody pharmaceutical preparation process, wherein the control unit compares a measured value obtained by at least one sensor selected from a weight sensor, a conductivity sensor, and a pH sensor located in each buffer storage tank with a preset reference value to control the opening and closing of a switch valve located on a first discharge line of each concentrated component tank, and regulates the flow rate by a flow control valve located on a concentrated component inflow line that allows the concentrated component solution to flow into each buffer storage tank, thereby controlling the buffer concentration and composition in each buffer storage tank.

[0017] Furthermore, this document provides a buffer preparation and transfer system for antibody pharmaceutical preparation processes, wherein the switching valve is a pinch valve and the flow control valve is a diaphragm valve.

[0018] Furthermore, this document provides a buffer preparation and transfer system for antibody pharmaceutical preparation processes, wherein the concentrated component container is made of single-use (SU) bag material and the buffer storage container is made of stainless steel (SS) material.

[0019] Furthermore, this document provides a buffer preparation and transfer system for antibody pharmaceutical preparation processes, 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.

[0020] Furthermore, this document provides a buffer preparation and transfer system for antibody pharmaceutical preparation processes, wherein the buffer preparation and transfer system is applied to 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-2aAlfa-2a, Aldesleukin, Recombinant human alfadeoxyribonuclease alfa, Interferon beta-1a, Becaplermin, Recombinant reteplase, Interferon alfa-2, Tenecteplase, Drotecogin alfa, Rilonacept, Romiplostim, Methoxypolyethylene glycol-epoetin beta, C1 esterase inhibitor, Idursulfase, Recombinant alglucosidase alfa The preparation and transfer of buffer solutions for the purification process of at least one antibody pharmaceutical product from the group consisting of alfa, abatacept, galsulfase, palifermin, and interferon-γ-1b.

[0021] Invention Effects

[0022] In the buffer preparation and transfer system according to the present invention, unlike the conventional buffer preparation process which uses manual preparation of buffer solutions one by one with buffer preparation tanks and buffer storage tanks matched 1:1, the device is designed to use a control unit to automate the preparation and transfer of various buffer solutions, while using on / off valves and flow control valves to transfer concentrated component solutions to the buffer storage tank to control the concentration and composition of the buffer solution. This reduces the large amount of labor required for individual buffer preparation processes such as weighing of buffer reagents, adding powder, stirring, and transferring, and significantly shortens the process time.

[0023] Furthermore, unlike existing technologies, the buffer preparation and transfer system according to the present invention can reduce the number of buffer preparation tanks corresponding to independent buffer storage tanks, thus helping to ensure safe distances between processes and ensure facility area, and can also ensure the safety of operators through an automated system.

[0024] Furthermore, the buffer preparation tank and concentrated component tank are made of single-use (SU) bags, which minimizes the risk of corrosion (such as acid corrosion of metals) caused by the use of highly concentrated buffer solutions and eliminates the need for separate washing and sterilization processes, thus further shortening the process time.

[0025] In addition, compared with existing technologies, it has the advantages of uniform buffer quality and the ability to prepare buffer according to the required recipe. Attached Figure Description

[0026] Figure 1 This is a schematic diagram illustrating a buffer preparation and transfer system for an antibody pharmaceutical preparation process implemented according to an embodiment of the present invention.

[0027] Figure 2 This is a diagram that briefly illustrates a buffer preparation and transfer system for antibody pharmaceutical preparation processes according to the prior art.

[0028] Figure 3 This is a diagram that briefly illustrates a buffer preparation and transfer system for an antibody pharmaceutical preparation process according to another prior art.

[0029] Figure 4 This is a diagram that briefly illustrates a buffer preparation and transfer system for an antibody pharmaceutical preparation process according to another prior art. Detailed Implementation

[0030] 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.

[0031] 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.

[0032] 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.

[0033] On the other hand, it should be understood that the term "component" used throughout the specification and the scope of the invention claims refers to a single component of the buffer solution.

[0034] 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."

[0035] 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.

[0036] 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.

[0037] The following describes in further detail a buffer preparation and transfer system for antibody pharmaceutical preparation processes according to specific embodiments of the present invention.

[0038] Buffer preparation and transfer system for antibody pharmaceutical manufacturing processes

[0039] A buffer preparation and transfer system for an antibody pharmaceutical preparation process according to an embodiment of the present invention may include: at least one concentrated component tank for receiving concentrated component solution from a buffer preparation tank; a first conduit connected to a first discharge line through which the concentrated component solution is discharged from the concentrated component tank; at least one buffer hold tank arranged in parallel, having concentrated component inflow lines branching from the first conduit; a second conduit connected to a second discharge line through which buffer solution is discharged from each buffer hold tank; a chromatography system connected to the second conduit; and a control unit that can control the opening and closing of a switch valve located on the first discharge line of each concentrated component tank based on a preset value, or can control the flow rate by means of a flow control valve located on the concentrated component inflow line that allows the concentrated component to flow into each buffer hold tank, so as to transfer the concentrated component solution to each buffer hold tank.

[0040] 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.

[0041] The purification process involves using various chromatography and filtration techniques to extract proteins for pharmaceutical use from culture media containing cells and cell debris with high purity and efficiency.

[0042] According to one embodiment of the present invention, a set of apparatus configurations for a purification step includes a purification unit comprising: a buffer preparation tank (BP) 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 step 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 the chromatography for buffer exchange and concentration.

[0043] At least one concentrated component tank for storing concentrated component solutions may be provided between the buffer preparation tank and the buffer storage tank.

[0044] On the other hand, the purification process must include a chromatography step using the molecular properties of proteins (surface charge or hydrophobicity, etc.) to remove impurities and obtain high-purity antibodies. In this case, various buffer solutions are used. Conventional buffer preparation processes involve manually preparing buffer solutions one by one using a 1:1 matching system of buffer preparation tanks and buffer storage tanks, supplemented by devices for diluting and concentrating buffers. According to this existing technology, the tank installation requires a large facility area, and the manual preparation of buffer solutions results in a significant investment of labor and time. Furthermore, the powder used for buffer preparation can release chemicals during operation, posing a potential health hazard to workers.

[0045] The inventors have discovered that, unlike conventional buffer preparation processes that involve manually preparing buffer solutions one by one with buffer preparation tanks and storage tanks matched in a 1:1 ratio, by designing the device configuration to automate the preparation and transfer of various buffer solutions using a control unit, while simultaneously using on / off valves and flow control valves to transfer concentrated component solutions to the buffer storage tank to control the form of buffer concentration and composition, and by using single-use (SU) bags for both the buffer preparation tank and the concentrated component tank, the significant labor input associated with individual buffer preparation processes such as weighing, adding powder, stirring, and transferring buffer solutions can be reduced. This significantly shortens the process time, thereby minimizing the risk of corrosion (such as acid corrosion of metals) caused by using highly concentrated buffer solutions, and eliminating the need for separate washing and sterilization processes, thus further shortening the process time. This invention thus completes the present invention.

[0046] Specifically, according to one embodiment of the present invention, at least one concentrated component tank may be provided, which receives concentrated component solutions from buffer preparation tanks for preparing various components of buffer solutions, wherein the buffer solution serves as a liquid buffer and acidity regulator for stabilizing protein extraction, and a buffer storage tank may be provided for delivering the concentrated component solution components and water for injection from the concentrated component tank to chromatography. Furthermore, the concentrated component tank is connected to at least one buffer storage tank via a first conduit connected to a first discharge line discharging the concentrated component solution and a concentrated component inflow line branching from the first conduit. Additionally, a switch valve is located on the first discharge line, and a flow control valve is located on the concentrated component inflow line. Furthermore, a second discharge line discharging from each buffer storage tank is connected to a second conduit, which is connected to chromatography (see reference). Figure 1On the other hand, in order to prepare the required buffer solution, the at least one concentrated component tank may each contain a single component constituting the buffer solution; for example, the at least one concentrated component tank may contain different buffer solution components.

[0047] On the other hand, as an apparatus configuration of a buffer preparation and transfer system according to an embodiment of the present invention, the buffer preparation tank, the concentrated component tank, the buffer storage tank, the first discharge line, the first pipe, the second discharge line, the second pipe, and the chromatography can be made of at least one material selected from stainless steel (SS) and disposable (SU) bags. For example, the system can be a mixed system containing SS material and disposable (SU) bags.

[0048] On the other hand, in this invention, the buffer preparation tank and the at least one concentrated component tank can be disposable bags. When the buffer preparation tank and the concentrated component tank are made of the aforementioned material, compared with conventional SS material configurations, the risk of corrosion (such as acid corrosion of metals) caused by the use of highly concentrated components is minimized, and difficulties in washing and sterilization are reduced. Moreover, new processes can be performed simply by replacement, thus shortening process time. Furthermore, the term "single-use (SU) bag" used throughout the specification and claims can refer to both single-use (SU) bags and configurations including washable plastic bottles.

[0049] Furthermore, the buffer preparation and transfer system according to the present invention uses a highly concentrated concentrated component solution, so the size can be reduced to 1 / 25 of that of conventional buffer preparation tanks. The buffer storage tank also uses water for injection to control the concentration immediately after receiving the concentrated component and before chromatography injection, thus reducing the burden caused by buffer storage. As a result, the size can be reduced to 1 / 10 of that of conventional buffer storage tanks.

[0050] On the other hand, according to an embodiment of the present invention, a water-for-injection line for injecting water for injection can be connected to each of the buffer storage tanks, which can condition the injected concentrated component solution and water for injection in batches. Furthermore, the water for injection can be mixed with at least one concentrated component solution injected into the buffer storage tank to control the concentration of the buffer solution. Additionally, at least one component solution can be allowed to flow into the buffer storage tank under flow control via a control unit to prepare the required buffer solution.

[0051] On the other hand, a buffer preparation and transfer system according to an embodiment of the present invention includes a control unit.

[0052] The control unit can be configured to control the opening and closing of the switch valve on the first buffer solution discharge line of each concentrated component tank by comparing the measured value measured by at least one sensor selected from the weight sensor, conductivity sensor and pH sensor installed in each buffer solution storage tank with a preset reference value, or by adjusting the flow rate by a flow control valve on the concentrated component inflow line that allows the concentrated component solution to flow into each buffer solution preparation tank, so as to control the buffer solution concentration and composition in each buffer solution storage tank.

[0053] Specifically, the control unit may include at least one device configuration selected from a processor and a memory, wherein the processor can execute instructions stored in the memory. On the other hand, 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 means of the processor and memory in the control unit.

[0054] As an example, the control unit according to an embodiment of the present invention can be a Programmable Logic Controller (PLC). In particular, when the control unit is a PLC, the opening and closing of the on / off valve, such as a pinch valve, located on the first discharge line of each concentrated component tank can be controlled by comparing the measured value measured by at least one sensor selected from the weight sensor, conductivity sensor, and pH sensor installed in each buffer storage tank with a preset threshold, or by controlling the flow rate through the flow control valve, such as a diaphragm valve, located on the concentrated component inflow line that allows the concentrated component solution to flow into each buffer storage tank, thereby controlling the buffer concentration and composition in the buffer storage tank.

[0055] In existing buffer preparation and transfer methods, water for injection (WFI) is filled into the preparation vessel, followed by the addition of a quantitatively weighed buffer component. After stirring, conductivity and pH are adjusted, and the volume is confirmed. The buffer solution is then filled in. After filtration, the entire buffer solution is transferred to a buffer storage tank. In each step of the purification process, as various buffer solutions are used, the buffer preparation and transfer process needs to be repeated (see reference). Figure 2 ).

[0056] While each product and process varies, in a single batch of production, the amount of buffer solution used in the purification process is several times that used in the culture process. Furthermore, as described above, the buffer solution preparation tanks and storage tanks are matched 1:1, resulting in a need for a large facility area to install individual tanks, a significant labor input, and delays in process time.

[0057] Furthermore, recognizing this problem, an inline conditioning system has been commercialized. This system uses a skid to control the flow rate of each concentrated component solution, mixing it within the skid's internal tubing and injecting it directly into the column. However, this system is very expensive and, compared to traditional methods, suffers from significant variability in buffer quality and requires substantial validation time (see [reference]). Figure 3 ).

[0058] In addition, another approach emerging as an alternative to traditional buffer preparation and transfer methods is to place the buffer in a buffer storage tank instead of a column. This method uses multiple pumps to control the flow rate and a line mixer installed on the transfer line for mixing. However, this also results in significant waste and issues with quality control, such as batch preparation (see [reference]). Figure 4 ).

[0059] Conversely, in the case of the present invention, by simply automating the preparation and transfer of various buffer solutions using a control unit, and controlling the concentration and composition of the buffer solution by transferring the concentrated component solution to the buffer storage tank through switching valves and flow control valves, the large amount of labor required for individual buffer preparation such as weighing buffer reagents, adding powder, stirring, and transferring can be reduced, and the process time can be significantly shortened.

[0060] Furthermore, reducing the number of buffer preparation tanks corresponding to independent buffer storage tanks helps ensure safe distances between processes and save facility space, and can also ensure the safety of operators through automation systems.

[0061] Furthermore, the buffer preparation tank and the concentrated component tank are made of single-use (SU) bags, which minimizes the risk of corrosion (such as acid corrosion of metals) caused by the use of highly concentrated buffer solutions and eliminates the need for separate washing and sterilization processes, thus further shortening the process time. Compared with existing technologies, it also has the advantages of uniform buffer quality and the ability to prepare buffer solutions according to the required recipe.

[0062] On the other hand, the buffer preparation and transfer system according to an embodiment of the present invention can be applied to abavomarb, 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-epoetinThe preparation and transfer of buffer solutions for the purification process of at least one antibody pharmaceutical product from the group consisting of beta, C1 esterase inhibitors, 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.

[0063] Furthermore, the system according to the present invention can be effectively applied to cases where the composition of the washing and elution buffers used in chromatography (cation exchange, hydrophobic interaction exchange, anion exchange, etc.) processes in antibody pharmaceutical purification is simplified (e.g., cases where multiple buffers are prepared by adding only one component, even if they contain two or more components). In this case, the buffer preparation tank does not need to be matched 1:1 with the buffer storage tank, thus providing the advantage of ensuring safe distances between processes and maximizing facility space compared to existing technologies.

[0064] Furthermore, when using the buffer preparation and transfer system described above for antibody pharmaceutical preparation processes, various buffer solutions can be easily prepared through an automated system, without the need to prepare individual buffer solutions one by one.

[0065] Table 1

[0066]

[0067] Table 2

[0068]

[0069] As an example, the buffer solutions required for the cation exchange chromatography process are shown in Tables 1 and 2 above. When the buffer solutions are manually prepared according to the existing technology, a total of 7 buffer solutions and buffer preparation tanks are required. In addition, it requires a large amount of labor for the separate preparation of buffer solutions, such as weighing of buffer reagents, adding powder, stirring and transferring, and the process time is significantly increased.

[0070] Conversely, when the concentrated component solution and the control unit are used in accordance with the present invention to quantitatively inject the concentrated component solution and water for injection into the buffer storage tank through an automated process, there are a total of 4 component tanks (NaAc, Hac, NaCl and NaOH) in Table 1 and a total of 3 component tanks (HCl, Hac and NaOH) in Table 2. Automated buffer preparation can be achieved with just these, thus improving the economy and efficiency of the process.

[0071] As described above, the buffer preparation and transfer system of the present invention differs from conventional buffer preparation systems that use manual preparation of buffer solutions one by one with a 1:1 matching of buffer preparation tanks and buffer storage tanks. The device is designed to automate the preparation and transfer of various buffer solutions using a control unit, while controlling the concentration and composition of the buffer solution by transferring concentrated component solutions to the buffer storage tank through switching valves and flow control valves. This reduces the large amount of labor required for individual buffer preparation processes such as weighing of buffer reagents, adding powder, stirring, and transferring, and significantly shortens the process time.

[0072] Furthermore, unlike existing technologies, the buffer preparation and transfer system of the present invention can reduce the number of buffer preparation tanks corresponding to independent buffer storage tanks, thus helping to ensure safe distances between processes and ensure facility area, and can also ensure the safety of operators through an automated system.

[0073] Furthermore, the buffer preparation tank and concentrated component tank of the buffer preparation and transfer system of the present invention are made of single-use (SU) bags, which can minimize the risk of corrosion (such as acid corrosion of metals) caused by the use of highly concentrated buffer solutions, and can eliminate the need for separate washing and sterilization processes, thus further shortening the process time.

[0074] In addition, compared with existing technologies, it has the advantages of uniform buffer quality and the ability to prepare buffer according to the required recipe.

[0075] 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 buffer preparation and transfer system for an antibody pharmaceutical production process, wherein, include: At least one concentrated component tank receives concentrated component solutions from a buffer preparation tank; A first pipeline is connected to a first discharge pipeline, through which the concentrated component solution is discharged from the concentrated component tank; At least one buffer storage tank arranged in parallel has concentrated component inflow lines branching from the first pipe; A second pipeline is connected to a second discharge pipeline through which the buffer solution is discharged from each of the buffer solution storage tanks; Chromatography, connected to the second conduit; and Control Department The control unit controls the opening and closing of the on / off valve on the first discharge line of each concentrated component tank based on preset values, or controls the flow rate through a flow control valve on the concentrated component inflow line that allows the concentrated component to flow into each buffer storage tank, so as to transfer the concentrated component solution to each buffer storage tank. The water-for-injection line for injecting water for injection is connected to each of the buffer storage tanks. The water for injection and the concentrated component solution are injected into the buffer storage tank. The mixture is then mixed within the buffer storage tank and its condition is adjusted in batches. The state-conditioned buffer solution is then transferred to the chromatography column via the second conduit. The control unit compares measured values ​​from at least one sensor selected from weight sensors, conductivity sensors, and pH sensors located in each buffer storage tank with preset reference values ​​to control the opening and closing of the on / off valves on the first discharge line of each concentrated component tank, or to regulate the flow rate via flow control valves on the concentrated component inflow lines that allow the concentrated component solution to flow into each buffer storage tank, thereby controlling the buffer concentration and composition in the buffer storage tanks. The buffer solution preparation tank and the concentrated component tank are made of disposable bags, and the buffer solution storage tank is made of stainless steel.

2. The buffer solution preparation and transfer system for antibody pharmaceutical preparation according to claim 1, wherein, The switching valve is a pinch valve, and the flow control valve is a diaphragm valve.

3. The buffer solution preparation and transfer system for antibody pharmaceutical preparation according to claim 1, wherein, The chromatography is selected from one or a combination of affinity chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and mixed-mode chromatography.

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