KR102130434B1 - System for managing utility of bio industrial - Google Patents

Abstract

The present invention relates to a system for managing bio industrial utilities capable of effectively reducing production time and yield. According to the present invention, the system for managing bio industrial utilities comprises: a cultivation process control step of controlling power and operation air of cultivation equipment for artificially cultivating cells; a cell separation process control step of controlling power and operation of cell separation equipment to discharge discarded cells from the cells cultivated through the cultivation equipment by using a washing material; a protein purification process control step of controlling power and operation of protein purification equipment based on a preset purification condition to purify proteins from which the discarded cells are separated through the cell separation equipment; and a complete product process control step of controlling power and operation of complete product equipment based on a preset complete product waste processing condition to process complete product waste of a medical product in which the proteins are purified through the protein purification equipment.

Description

Bio-industry utility management system {SYSTEM FOR MANAGING UTILITY OF BIO INDUSTRIAL}

The present invention relates to a system for managing utilities in the bio-industry, and more particularly, to a bio-industry utility management system capable of controlling the entire process of drug preparation from cell culture through one integrated platform.

In general, in order to manufacture pharmaceuticals, a process of culturing cells through the composition of culture conditions, separating waste cells from cultured cells, and purifying proteins is required to process the finished waste.

At this time, each process, for example, a cell culture process, a cell separation process, a protein purification process, and a completion process, etc., are individually progressed through respective equipment and respective control equipment that controls power energy and operation of each equipment.

However, in the conventional manufacturing method in which each process for manufacturing pharmaceuticals is individually performed, there is a problem in that a process failure or the like is often caused by equipment and equipment control characteristics for each process. It has the fundamental problem of being degraded.

Korean Patent Publication No. 2019-0010490 (Publication date: Jan. 30, 2019)

The present invention is to provide a bio-industry utility management system that can process from cell culture to drug completion through a single integrated platform.

The present invention is to provide a computer-readable recording medium storing a computer program that allows the processor to perform the bio-industry utility management method.

The present invention is to provide a computer program stored in a computer-readable recording medium so that the processor can perform the bio-industry utility management method.

The problem to be solved by the present invention is not limited to those mentioned above, and another problem to be solved that is not mentioned can be clearly understood by a person having ordinary knowledge to which the present invention belongs from the following descriptions. will be.

The present invention, according to one aspect, the control step of the culture process for controlling the power energy and operating air of the culture equipment for the stable culture of the cell, and waste cells using the washing material from the cells cultured through the culture equipment A cell separation process control step of controlling the power energy and operation of the cell separation equipment to be discharged, and the power energy and operation of the protein purification equipment under predetermined purification conditions for purifying proteins separated from the waste cells through the cell separation equipment. A protein purification process control step to control, and a finalization process control step to control the power energy and operation of the finalization equipment under the preset finalization waste treatment conditions for processing the final wastes of the protein-purified pharmaceutical product through the protein purification equipment. Can provide a method for managing bio-industry utilities.

The power energy of the present invention may include thermal energy (high/low temperature) for temperature control of the culture equipment and electrical energy for stirring and control of the culture equipment.

The working air of the present invention can operate pneumatic valves (Pneumatic Valve) and actuators (Actuator).

The cell separation equipment of the present invention may include a high-speed centrifugal separator (Centrifuge) and a gear pump for transporting the recovered culture product.

The cleaning material of the present invention may include potassium hydroxide (CIP-100) and phosphoric acid (CIP-200).

The present invention, according to another aspect, a computer-readable recording medium storing a computer program for the processor to perform the bio-industry utility management method, the bio-industry utility management method, the power energy of the culture equipment for stable culture of cells And a culture process control step of controlling the operating air, and a cell separation process control step of controlling the power energy and operation of the cell separation equipment so that the waste cells are discharged using the washing material from the cells cultured through the culture equipment. A protein purification process control step of controlling the power energy and operation of the protein purification equipment under predetermined purification conditions to purify the proteins from which the waste cells are separated through the cell separation equipment, and pharmaceutical products having protein purified through the protein purification equipment It can provide a computer-readable recording medium including a finalization process control step that controls the power energy and operation of the finalization equipment under preset waste disposal conditions for processing the final wastes.

According to another aspect of the present invention, a computer program stored in a computer-readable recording medium so that a processor can perform a bioindustry utility management method, wherein the bioindustry utility management method comprises: a culture equipment for stable culture of cells. A culture process control step of controlling power energy and operating air, and a cell separation process control step of controlling power energy and operation of the cell separation equipment so that waste cells are discharged using washing materials from cells cultured through the culture equipment. And, a protein purification process control step of controlling the power energy and operation of the protein purification equipment under predetermined purification conditions to purify the proteins separated from the waste cells through the cell separation equipment, and the protein purified through the protein purification equipment It is possible to provide a computer program comprising a final process control step that controls the power energy and operation of the final equipment with preset final waste treatment conditions for processing the final waste of the pharmaceutical product.

The present invention, according to another aspect, a cell culture control panel for controlling the power energy and operating air of the culture equipment for stable culture of cells, and waste cells using washing materials from cells cultured through the culture equipment Cell separation control panel for controlling the power energy and operation of the cell separation equipment so that the discharge, and the cell separation equipment through the cell separation equipment to purify the protein and the power energy and operation of the protein purification equipment under predetermined purification conditions to purify the separated protein It includes a protein purification control panel to control, and a preparation and final control panel to control the power energy and operation of the finalization equipment under predetermined finalization waste treatment conditions for processing the final wastes of the pharmaceutical products purified by the protein purification equipment. Can provide a bio-industry utility management system.

According to an embodiment of the present invention, it is possible to process from the cultivation of cells to the completion of pharmaceutical products through a single integrated platform, thereby reducing production time of products and effectively improving production yield.

1 is a block diagram of a bio-industry utility management system according to an embodiment of the present invention.
Figure 2 is a flow chart showing the main process for performing process control for the manufacture of pharmaceuticals in accordance with an embodiment of the present invention.
3 is a schematic diagram schematically showing a series of processes in which the manufacture of a pharmaceutical product proceeds according to an embodiment of the present invention.
Figure 4 is a schematic diagram showing the first cell culture process in sequence.
5 is an exemplary view showing an example of the principle and operating conditions of a high-speed centrifuge used in cell separation equipment.

First, advantages and features of the present invention and methods for achieving them will be clarified with reference to embodiments described below in detail together with the accompanying drawings. Here, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms, and only these embodiments allow the disclosure of the present invention to be complete, and are generally in the technical field to which the present invention pertains. Since it is provided by way of example to enable a person with knowledge of to clearly understand the scope of the invention, the technical scope of the present invention should be defined by the claims.

In addition, in the following description of the present invention, when it is determined that a detailed description of known functions or configurations may unnecessarily obscure the subject matter of the present invention, the detailed description will be omitted. And, the terms to be described later are terms defined in consideration of functions in the present invention, which can be changed according to intentions or customs of users, operators, and the like. Therefore, the definition should be made based on the technical idea described throughout the description of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings.

1 is a block diagram of a bioindustry utility management system according to an embodiment of the present invention, the management system according to this embodiment is a device control system 110, cell culture control panel 112, cell separation control panel ( 114), a protein purification control panel 116, and a preparation and completion control panel 118, and the like.

Referring to Figure 1, the device control system 110 is a panel for performing control of each process, such as cell culture control panel 112, cell separation control panel 114, protein purification control panel 116, preparation and completion The control panel 118 may be provided with a function of integrally sequential control, and the device control system 110 may perform, for example, process equipment control and utility equipment control. .

Here, for controlling process equipment, for example, MCS/DCS (Manufacturing Conrol System/Distribeted Control System) may be used, and for utility equipment control, for example, an EBI system (Enterprise Building Integration system) may be used.

First, the cell culture control panel 112 supplies power energy of a culture equipment (not shown) such as a bioreactor for stable culture of cells that can be used in the manufacture of pharmaceuticals, and also controls operating air, etc. Can provide the function of Here, the working air is for operating the pneumatic valve (Pneumatic Valve) and actuators (Actuator).

In a large division, the cell culture control panel 112 may supply thermal energy (high/low temperature) for temperature control of the culture equipment (or culture tank) and electrical energy for stirring and control of the culture tank, wherein Culture agitation is important for the following reasons, so stable power and control are required.

(1) Improve O2 Transfer

1-1) Transfer Energy To Broth

1-2) Enhance Dispersion of Gas

1-3) Reduce Bubble Size

(2) Improve Heat Transfer

2-1) Uniform Broth Temperature

2-2) Good Transfer Efficiency at Vessel Wall

(3) Provide a Homogenous Environment

3-1) Mixing of Components

3-2) Good Control, Temp, pO2, pH

Here, the first cell culture process, as shown in FIG. 4 as an example, may be performed in the following order.

1) Establish cell line that can stably maintain cell specificity despite repeated proliferation

2) Divided into vials and stored frozen in cell banks (eg, minus 180℃)

3) thawing working cell bank (WCB)

4) Preparation of media and initial culture of Shake Falsk

5) Inject the culture solution transferred to the inoculation bottle into the bioreactor (Seed Bioreactor)

6) Start production process

And, for the cell culture, for example, the following three process gases may be supplied to the culture equipment as a gas raw material.

1) Carbon dioxide: for adjusting hydrogen ion concentration (pH) by carbonic acid buffer solution in the medium

2) Oxygen: prevents bubbles and improves dispersion, energy transfer

3) Nitrogen: the source of culture deterioration, pollution prevention, and product transfer

And, the size of the reactor is different for each cell culture step, and accordingly, the process gas may be controlled by a mass flow controller (MFC) to meet the cell culture conditions.

pH: 6.7~7.1, Dissoved Oxygen: 40%, Pressure: 0.2barg, Top Air Flow Rate: 2~10 LPM, Bottom Air Flow Rate: 0.1~0.4 LPM

Vessel Volumes per Minute (VVM) may be used as an aeration reference unit.

Typical Cell Culture Bioreactor Gas Flows

[Sparge]

1) Air: 0.001 to 0.05 VVM

2) O2: 0.001 to 0.05 VVM

3) CO2: 0.001 to 0.01 VVM

4) N2: 0.001 to 0.01 VVM

[Headspace]

1) Air: 0.01 to 0.1 VVM

2) N2: 0.01 to 0.1 VVM

Next, the cell separation control panel 114 may provide functions such as controlling the cell separation equipment (not shown) so that the waste cells are discharged using the washing material from the cells cultured through the culture equipment.

Here, the cell separation equipment may include, for example, a high-speed centrifugal separator (Centrifuge) and a gear pump (gear pump) for the transport of the recovered culture product (product), and, for example, as a washing material input to the cell separation equipment, for example Potassium hydroxide (CIP-100) and phosphoric acid (CIP-200) may be used, and other sterilizing agents may be citric acid, glacial acetic acid, isopropyl alcohol, and the like.

As an example, the celltrion-producing drug may be a by-product of animal cells, and cell debris, impurities, and cells of animal cells are mixed with WFI in a cell separation and purification process. It can be discharged in the form of wastewater, and these wastewater can be largely composed of the following two types.

(1) Organic waste (Biowaste)-wastewater containing cells or fragments of cells

(2) Process Waste-Wastewater generated during the process, including buffer wastewater and CIP wastewater.

Here, in the case of organic waste, inert sterilization in a bio-inactivation system (eg Bio-inactivation System) for bacterial, viral and cell disruption before being transferred to a wastewater treatment plant (WWT) , 60 seconds, etc.) at a temperature of 80° C. and then transferred to a wastewater treatment plant.

In addition, process wastewater can be collected in a collection tank together with organic waste, and then treated with chemicals and neutralization in a wastewater treatment plant. In addition, wastewater that is difficult to treat in a wastewater treatment plant such as other elements (Urea) may be collected in a special storage tank and then treated separately.

In addition, the principle and operating conditions of the high-speed centrifugal separator used in the cell separation equipment may be in the form as shown in FIG. 5 as an example.
As shown in FIG. 5, the high-speed centrifugal separator has a plurality of disks stacked therein, and the centrifugal force due to rotation is applied in the horizontal direction, so that the higher the RPM of the bowl and the larger the radius of the disk, the better the separation. It is a structure. In addition, the more the disks are stacked, the more the contact area of the culture medium increases, which is advantageous for separation. If the distance between the plurality of disks is close, a set distance is formed, which is advantageous for cell precipitation.

Next, the protein purification control panel 116 of the protein purification equipment (not shown) to the pre-set purification conditions to purify proteins (eg, removal of impurities, protein concentration control, etc.) from the waste cells through the cell separation equipment. It can provide functions such as controlling power energy and operation. Here, the purification waste is mainly process wastewater, and can be purified in a similar manner as in the cell separation process.

At this time, the equipment that requires electric power in the protein purification equipment is a chromatography skid, a chromatography column, a tangential flow filtration, and a column packing skid, respectively. It may include a circulation pump and a pneumatic valve actuator (Pneumatic Valve Actuator).

Finally, the preparation and finalization control panel 118 controls power energy and operation of the finalization equipment (not shown) with preset finalization waste treatment conditions for processing the final waste of the protein-purified pharmaceutical product through the protein purification equipment. And the like. Here, the finished waste may consist of organic waste and process wastewater, which can be treated in a similar manner as in the cell separation process.

Figure 2 is a flow chart showing the main process for performing process control for the manufacture of pharmaceuticals according to an embodiment of the present invention, Figure 3 is a schematic diagram showing a series of processes in which the manufacture of pharmaceuticals according to an embodiment of the present invention It is a schematic diagram showing.

Referring to FIG. 2, the cell culture control panel 112 supplies power energy of a culture equipment such as a bioreactor for stable culture of cells that can be used for the manufacture of pharmaceuticals, and also controls operating air (cells). Culture process control) (step 202). In Fig. 3, reference numeral [1] shows a schematic diagram of a cell culture process.

That is, the cell culture control panel 112 may supply thermal energy (high/low temperature) for temperature control of the culture equipment and electrical energy for stirring and control of the culture tank, and a pneumatic valve and Actuators can be operated.

Then, the cell separation control panel 114 controls the cell separation equipment (cell separation process control) so that the waste cells are discharged using the washing material from the cells cultured through the culture equipment (step 204). In Fig. 3, reference numeral [2] shows a model for the cell separation process. Here, the cell separation equipment, for example, may include a high-speed centrifuge (Centrifuge) and a gear pump (gear pump) for the transport of the recovered culture product (product).

Next, in the protein purification control panel 116, power energy and operation of the protein purification equipment under predetermined purification conditions for purifying proteins (eg, removing impurities, adjusting protein concentration, etc.) through the cell separation equipment are discarded cells. Control (protein purification process control) (step 206). In Fig. 3, reference numeral [3] shows a model for the protein stagnation process.

Subsequently, the preparation and finished control panel 118 controls the power energy and operation of the finished equipment with preset finished waste treatment conditions to control the finished waste of the drug whose protein is purified through the protein purification equipment (completed process control). (Step 208). In Fig. 3, reference numeral [4] shows a model for the drug preparation process.

Meanwhile, combinations of each block of the block diagram and each step of the flowchart may be performed by computer program instructions. These computer program instructions may be mounted on a processor of a general purpose computer, special purpose computer, or other programmable data processing equipment, so that instructions executed through a processor of a computer or other programmable data processing equipment may be used in each block or flowchart of the block diagram. In each step, means are created to perform the functions described.

These computer program instructions can also be stored in a computer readable or computer readable memory or the like that can be directed to a computer or other programmable data processing equipment to implement a function in a particular way, so the computer readable or computer readable memory The instructions stored in it are also possible to produce an article of manufacture containing instructions means for performing the functions described in each step of each block or flowchart of the block diagram.

In addition, since computer program instructions may be mounted on a computer or other programmable data processing equipment, a series of operation steps are performed on the computer or other programmable data processing equipment to generate a process executed by the computer to generate a computer or other program. It is also possible for instructions to perform possible data processing equipment to provide steps for performing the functions described in each block of the block diagram and in each step of the flowchart.

Further, each block or each step may represent a module, segment, or portion of code that includes at least one executable instruction for executing the specified logical function(s). It should also be noted that in some alternative embodiments it is possible that the functions mentioned in blocks or steps occur out of order. For example, it is possible that two blocks or steps shown in succession are actually executed substantially simultaneously, or those blocks.

The above description is merely illustrative of the technical idea of the present invention, and those of ordinary skill in the art to which the present invention pertains may have various substitutions, modifications, changes, etc. without departing from the essential characteristics of the present invention. You will easily see this possible. That is, the embodiments disclosed in the present invention are not intended to limit the technical spirit of the present invention, but to explain the scope of the technical spirit of the present invention.

Therefore, the protection scope of the present invention should be interpreted by the claims that will be described later, and all technical ideas within an equivalent range should be interpreted as being included in the scope of the present invention.

110: device control system
112: cell culture control panel
114: cell separation control panel
116: protein purification control panel
118: dispensing and finished control panel

Claims (6)

A culture process control step of controlling power energy and operating air of the culture equipment for stable culture of cells;
A cell separation process control step of controlling the power energy and operation of the cell separation equipment so that the waste cells are discharged using the washing material from the cells cultured through the culture equipment;
A protein purification process control step of controlling power energy and operation of the protein purification equipment under predetermined purification conditions for purifying proteins separated from the waste cells through the cell separation equipment;
Comprising a control step of controlling the finished energy to control the power energy and operation of the finished equipment to a predetermined finished waste processing conditions for processing the finished waste of the protein purified drug through the protein purification equipment,
Carbon dioxide, oxygen and nitrogen are supplied as gas raw materials to the culture equipment,
The cell separation equipment includes a high-speed centrifuge (Centrifuge) and a gear pump (gear pump) for the transfer of the recovered culture product (gear),
The high-speed centrifugal separator is a type in which a plurality of disks are stacked inside, and the centrifugal force due to rotation is applied in a horizontal direction, so that the higher the RPM of the bowl and the larger the radius of the disk, the better the separation.
Equipment that requires electric power in the protein purification equipment is a chromatographic skid, a chromatography column, a tangential flow filtration, and a column packing skid for each. Includes Circulation Pump and Pneumatic Valve Actuator
Bioindustry utility management method. According to claim 1,
The power energy of the culture equipment,
Thermal energy (high/low temperature) for temperature control of the culture equipment and electrical energy for stirring and control of the culture equipment
Bioindustry utility management method. According to claim 1,
The working air,
Pneumatic Valves and Actuators
Bioindustry utility management method. delete According to claim 1,
The cleaning material,
Containing potassium hydroxide and phosphoric acid
Bioindustry utility management method. delete

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